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Question 11 - 2000, Paper 1

What is the hepatorenal syndrome?  List causes, mechanism, diagnosis and treatment

College Answer

The hepatorenal syndrome  is defmed as profound oliguria and avid sodium  retention in the setting of severe liver dysfunction.

{a) Causes: 
Can occur in the setting of both acute and acute-on-chronic liver disease of almost any cause 
eg. hepatitis, gestational liver failure, cirrl:tosis. 

(b) Mechanism: 
The  pathogenesis  appears  to be purely  functional  in  that  recovery:of :liver  function  or-· 
transplantation  of  the  failing  kidney  leads  to  recovery  of ·renal ·function.  Mechanisms··· implicated  include: hyperdynamic· circulation  with  lowering  of  renal  perfusion  pressure, activation   of   the  sympathetic   nervous   system   and   a  combination   of   precapillary vasoconstriction and past capillary dilatation  by vasoactive mediators leading to decreased glomerular  ultrafiltration  coefficient.  Hypovolaemia  and  raised  intra abdominal  pressure from ascites may also be factors. 

(c) Diagnosis: 
Is based on history (deteriorating renal function in the presence of severe liver disease) and the  combination   of  avid  sodiwn   retention  (UNa   <30mmolll),  oliguria,   unremarkable urinalysis and  sediment,  absence  of  obstruction and  exclusion  of  intravascular  volume depletion. 

(d) Treatment: 
Classic teaching is that. in the absence of liver function recovery or liver transplantation, 
there  is  no  treatment  other  than renal  replacement  therapy  for  established  hepatorenal 
syndrome. Other measures to be considered or experimental are: 
•  Volume expansion and albumin infusion 
•  Paracentesis 
•  Relief of portal hypertension (TIPS, shunt) 
•  Vasopressin analogs (omipressin), experimental 
•  Prostaglandin analogs -experimental

Discussion

Briefly, what is hepatorenal syndrome

Hepatorenal syndrome is kidney injury as the consequence of gradually reducing renal blood flow, in the context of gradually worsening liver failure.

Mechanism of hepatorenal syndrome

  • Worsening hepatic function leads to worsening peripheral arterial vasodilation
  • Vasodilation leads to increased cardiac output, renin-angiotensin-aldosterone overactivity, and sympathetic overactivity
  • As a result, renal arterial vascular resistance increases in proportion to splanchnic and systemic arterial vasodilation
  • This, there is progressive renal vasoconstriction and thus decreased glomerular filtration.
  • In addition to this, worsening hepatic failure results in increasing ascites pressure (and thus decreasing renal perfusion pressure)

Causes of hepatorenal syndrome

  • Sepsis of any origin
  • Nephrotixic drugs in a patient with cirrhosis, particularly NSAIDs
  • Rapid diuresis
  • GI bleeding

Diagnosis

  • This is a diagnosis of exclusion. The following criteria apply:
    • presence of liver disease and portal hypertension
    • increase in creatinine to over 133micromol/L
    • no other obvious cause of renal failure
    • no microscopic hematuria
    • no reponse to fluid challenge (i.e. no pre-renal failure)

Treatment of hepatorenal syndrome

  • Albumin and fluid resuscitation
  • Terlipressin
  • Noradrenaline
  • Octreotide

if all else fails, TIPS procedure may be appropriate.

References

UpToDate has an excellent synopsis of hepatorenal syndrome.

 

However, if you are cheap, you need free articles.

 

Salerno, Francesco, et al. "Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis." Postgraduate medical journal 84.998 (2008): 662-670.

 

Solà, Elsa, Mónica Guevara, and Pere Ginès. "Current treatment strategies for hepatorenal syndrome." Clinical Liver Disease 2.3 (2013): 136-139.

Question 1a - 2001, Paper 2

A forty-two (42) year old man has been well, apart  from a history of alcohol induced liver dysfunction and portal hypertension.  He has abstained from alcohol for the past 8 months after being told that  it would kill him.   After  a  large  haematemesis he presents  drowsy, clinically shocked, with a blood pressure of 80 systolic, heart rate of 124 beats/minute, cold and clammy peripheries.  He is also clinically jaundiced.

(a)       Outline the principles of, and rationale for, the initial management of this patient.

College Answer

Principles of management include resuscitation (of someone who may well have lost >25% of blood volume), establishing a diagnosis, and definitive treatment while avoiding therapies that might worsen his underlying condition.

Resuscitation includes assessment of airway protection and breathing adequacy, which combined with neurological impairment indicates need for emergency intubation.

Circulatory support requires adequate intravenous access, but may not need to be too aggressive (as excessive resuscitation may worsen portal hypertension), and could be guided by factors including usual blood pressure (? accept MAP of 60 mmHg), urine output, and other signs of circulatory compromise.

Temporary use of a Sengstaken Blakemore tube (or equivalent eg Minnesota) may be considered if blood loss is uncontrollable. Invasive monitoring may be useful, but is not necessary in the early phase of resuscitation.

Establishing  a  diagnosis  for  the  cause  of  bleeding  includes  immediate  examination  (signs suggesting non-GI haemorrhage, chronic liver disease), history (from family/observers) of immediate event and possible precipitants (drugs, retching etc). Differential diagnosis of causes for jaundice should be considered (including hepatitic and toxins). More detailed history and examination will need to be completed later.

Immediate commencement of therapy (eg. intravenous vasoconstrictor such as somatostatin or vasopressin) should be considered while organising urgent endoscopy (which will usually result in banding or sclerotherapy for varices, and injection for some other pathologies). Initial investigations should include cross match, coagulation tests, full blood count, urea & electrolytes, liver function tests, blood glucose and paracetamol level. An ascitic tap should be undertaken early for microscopy and culture (as infection may well be present). Some rationale should have been given for the investigations listed.

Candidates should be aware of therapies that may be specifically required (correction of coagulopathy [FFP &/or platelets], prophylactic antibiotics, laxatives eg. lactulose; beta-blockers once stable, proton pump inhibitors) or contraindicated (sedatives worsening hepatic encephalopathy).

Discussion

I have attempted to force the coherent college answer into a familiar system.

(a)       Outline the principles of, and rationale for, the initial management of this patient.

  • Attention to the ABCS, with management of life-threatening problems simultanous with a rapid focused examination and a brief history. History will focus on determining whether the source of the bleeding was indeed the gut (rather than a tracheal or bronchial source) and whether the vomiting preceded the hematemesis (which would be suspicious for a Mallory-Weiss tear or Boerhaave's syndrome)
  • Airway:
    • This patient is likely to have hematemesis again; the airway needs to be protected
  • Breathing/ventilation
    • Once he is intubated, ventilation settings will depend on the specifics of gas exchange and lung compliance
  • Circulatory support
    • The inital stages of resuscitation will consist of replacement of blood and blood products
  • Supportive management
    • Sedation should consist of anaesthetic agens with a short half-life and no long-lasting metabolites, such as propofol and remifentanyl
  • Specific investigations
    • CXR to confirm ETT position and rule out GI perforation
    • FBC, G&H, coags, fibrinogen, EUC and CMP
    • Ultrasound of the abdomen to investigate the severity of portal hypertension
  • Specific management
    • This patient requires urgent gastroscopy and banding or sclerotherapy of the varices
    • If a gastroscopy cannot be performed urgently, he will need to have a CT angiogram, with a view to proceed to angioembolisation of the bleeding vessels.
    • If blood loss is uncontrollable and gastroscopy/angioembolisation is delayed, a Sengstaken-Blakemore tube can be advanced and an attempt to tamponade the bleeding can be made.
    • Lactulose should be used to decrease the likelihood of hepatic encephalopathy

References

Oh's Intensive Care manual: Chapter 42  (pp. 487)  Acute  gastrointestinal  bleeding  by Joseph  JY  Sung

arcia-Tsao, Guadalupe, and Jaime Bosch. "Management of varices and variceal hemorrhage in cirrhosis." New England Journal of Medicine 362.9 (2010): 823-832.

García-Pagán, Juan Carlos, et al. "Early use of TIPS in patients with cirrhosis and variceal bleeding." New England Journal of Medicine 362.25 (2010): 2370-2379.

Vlavianos, P., et al. "Balloon tamponade in variceal bleeding: use and misuse."BMJ: British Medical Journal 298.6681 (1989): 1158.

Reverter, Enric, and Juan Carlos García‐Pagán. "Management of an acute variceal bleeding episode." Clinical Liver Disease 1.5 (2012): 151-154.

Ioannou, G. N., J. Doust, and D. C. Rockey. "Terlipressin in acute oesophageal variceal haemorrhage." Alimentary pharmacology & therapeutics 17.1 (2003): 53-64.

Corley, Douglas A., et al. "Octreotide for acute esophageal variceal bleeding: a meta-analysis." Gastroenterology 120.4 (2001): 946-954.

Reiberger, Thomas, et al. "Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol." Gut62.11 (2013): 1634-1641.

Hou, Ming‐Chih, et al. "Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial." Hepatology 39.3 (2004): 746-753.

Question 1b - 2001, Paper 2

A forty-two (42) year old man has been well, apart  from a history of alcohol induced liver dysfunction and portal hypertension.  He has abstained from alcohol for the past 8 months after being told that  it would kill him.   After  a  large  haematemesis he presents  drowsy, clinically shocked, with a blood pressure of 80 systolic, heart rate of 124 beats/minute, cold and clammy peripheries.  He is also clinically jaundiced.

(b)  Variceal bleeding is diagnosed and it initially responds to therapy.

 48 hours post admission he remains on invasive respiratory support, with weak withdrawal response to pain despite minimal sedation, a persistent coagulopathy, and is inotrope dependent.  Serum bilirubin concentration is elevated (100 micromol/L [N 3-20]).

 He develops a further acute variceal bleed associated with hypotension.

Outline your management of this episode.

College Answer

Standard resuscitation goals and technique should be reiterated. Re-bleeding from varices requires repeat endoscopy for diagnosis and treatment. Additional treatments should be considered including vasoconstrictor infusions (eg. somatostatin or vasopressin with GTN), Trans-jugular Intra-hepatic Porto-systemic Shunt (TIPS), and surgical shunts (eg. spleno-renal). Balloon tamponade is being used less frequently because of a high incidence of complications (aspiration, oesophageal rupture, death).

Ongoing investigation and treatment of coagulopathy, and investigation of causes of jaundice should be undertaken. Treatment should include strategies to minimise hepatic encephalopathy.

Discussion

A systematic approach should be taken. I will not repeat the ABCs. Of course, one would ensure satisfactory maintenance of oxygenation and normotension. Certainly, one would replace the missing factors by transfusing blood products, as well as actual packed cells, and vitamin K.

Straight to the specific management:

  • Hemostasis:
    • Re-bleeding from varices requires re-endoscopy. Sclerotherapy and/or banding would be the ideal way of managing this bleed, as it would have the fewest complications.
    • A Sengstaken-Blakemore tube is an option, but even when it was popular the experienced users noted that optimal pharmacological therapy is better than inexperienced use of balloon tamponade
  • Reducing portal hypertension pharmacologically
  • Reducing portal hypertension invasively
    • TIPS decreases the chances of treatment failure in refractory variceal bleeding (in one study, the probability of remaining bleed-free was 97% in the TIPS group and 50% in the pharmacotherapy group)

References

Garcia-Tsao, Guadalupe, and Jaime Bosch. "Management of varices and variceal hemorrhage in cirrhosis." New England Journal of Medicine 362.9 (2010): 823-832.

 

García-Pagán, Juan Carlos, et al. "Early use of TIPS in patients with cirrhosis and variceal bleeding." New England Journal of Medicine 362.25 (2010): 2370-2379.

 

Vlavianos, P., et al. "Balloon tamponade in variceal bleeding: use and misuse."BMJ: British Medical Journal 298.6681 (1989): 1158.

 

Reverter, Enric, and Juan Carlos García‐Pagán. "Management of an acute variceal bleeding episode." Clinical Liver Disease 1.5 (2012): 151-154.

 

Ioannou, G. N., J. Doust, and D. C. Rockey. "Terlipressin in acute oesophageal variceal haemorrhage." Alimentary pharmacology & therapeutics 17.1 (2003): 53-64.

 

Corley, Douglas A., et al. "Octreotide for acute esophageal variceal bleeding: a meta-analysis." Gastroenterology 120.4 (2001): 946-954.

 

Reiberger, Thomas, et al. "Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol." Gut62.11 (2013): 1634-1641.

 

Question 1c - 2001, Paper 2

A forty-two (42) year old man has been well, apart  from a history of alcohol induced liver dysfunction and portal hypertension.  He has abstained from alcohol for the past 8 months after being told that  it would kill him.   After  a  large  haematemesis he presents  drowsy, clinically shocked, with a blood pressure of 80 systolic, heart rate of 124 beats/minute, cold and clammy peripheries.  He is also clinically jaundiced.

Variceal bleeding is diagnosed and it initially responds to therapy.  48 hours post admission he remains on invasive respiratory support, with weak withdrawal response to pain despite minimal sedation, a persistent coagulopathy, and is inotrope dependent.  Serum bilirubin concentration is elevated (100 micromol/L [N 3-20]).  He develops a further acute variceal bleed associated with hypotension.

(c) At 6 days there has been no further haematemeses. However he has a Glasgow Coma Score (GCS) of 5, despite no sedation.  His serum bilirubin concentration is now 350 micromol/L. Prothrombin time and serum creatinine concentration are twice normal.  A CT of the head shows no focal abnormality.  What supportive therapies and strategies would you have in place at this stage and why?

College Answer

Specific strategies to minimise hepatic encephalopathy should have been described if not already done so (including the use of lactulose). Precipitants must be minimised (treatment of infections, avoidance  of  sedatives,  correction  of  electrolyte  abnormalities/hypoxia, avoid  alkalosis,  limit dietary protein, consider unproven dietary supplements including BCAA etc.). Cautious volume expansion should be considered. Other reversible causes for renal dysfunction and coma should be sought and excluded. Management of ICP  may be necessary (and the CT does not exclude cerebral oedema). General supportive care should be considered (eg. physiotherapy, avoidance of line- related problems, family support etc.). Specific treatment may be required for ascites and its effects (drainage, colloid replacement etc).

Discussion

The college has given us a patient with a combination of several reasons to be encephalopathic; of these, the major one is liver failure -but we are also reminded that the creatinine has doubled.

Management of hepatic encephalopathy:

Specific management of hepatic encephalopathy

  • Lactulose
  • Rifaximin
  • Avoidance of hyponatremia
  • Nutritional management:
    • Branched-chain amino acids (BCAAs) and a reduced amount of aromatic amino acids
    • High fiber diet
    • Pro-biotics (though their benefit is unclear)

Management of the precipitating cause

  • Stop GI bleeding (endoscopy, banding, etc)
  • Antibiotics for SBP
  • Correct dehydration
  • Withdraw hepatotoxins

Supportive management of the encephalopathic patient

  1. Support the airway.  If the patient is comatose or uncooperative, they may require intubation in order to correct disorders of gas exchange (as they may not be compliant with NIV and chest physiotherapy)
  2. Wean ventilation to spontaneous mode as tolerated.​ Hypoxia and hpercapnea can be readily corrected if the patient is mechanically ventilated; otherwise, posture with chest physiotherapy and deep breathing exercises are crucial
    Avoid NIV; abdominal distension and a fluctuating level of consciousness will likely result in aspiration. HFNP is ok. 
  3. Support haemodynamically;
    noradrenaline +/- terlipressin may be appropriate if hepatorenal syndrome is suspected
    Albumin (20%) is a reasonable resuscitation fluid
    Hepatic flow should be optimised by monitoring for abdominal compartment syndrome
  4. Avoid sedation. As needed, use drugs which do not depend on hepatic metabolism (eg. remifentanyl).
    Cerebral oedema and the potential for intracranial catastrophe should be investigated with a CT brain
  5. Correct electrolyte derangement
  6. Monitor renal function (hepatorenal syndrome)
  7. Ensure BSL is monitored and supplemental glucose is made available
    Ensure thiamine is co-administerd with glucose!
  8. Correct clinically significant anaemia. 
    Address haematinic factor deficiencies.
  9. Antibiotics as appropriate: ceftriaxone may be required if SBP is a real possibility.
    Blood cultures and inflammatory markers should be collected.

Pursuit of other explanations for decreased level of consciousness:

  • Minimise sedation
  • Optimise oxygenation and ventilation
  • Screen for sepsis
  • Observe for physical signs suggestive of raised intracranial pressure
  • Manage uremia, and consider dialysis

References

Wendon, Julia, et al. "Critical care and cirrhosis: outcome and benefit." Current opinion in critical care 17.5 (2011): 533-537.

Riggio, Oliviero, et al. "Management of hepatic encephalopathy as an inpatient." Clinical Liver Disease 5.3 (2015): 79-82.

Bajaj, J. S. "Review article: the modern management of hepatic encephalopathy." Alimentary pharmacology & therapeutics 31.5 (2010): 537-547.

 

Amodio, Piero, et al. "The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus." Hepatology 58.1 (2013): 325-336.

 

Als-Nielsen, Bodil, Lise Lotte Gluud, and Christian Gluud. "Nonabsorbable disaccharides for hepatic encephalopathy." Cochrane Database Syst Rev 2 (2004).

 

Bass, Nathan M., et al. "Rifaximin treatment in hepatic encephalopathy." New England Journal of Medicine 362.12 (2010): 1071-1081.

 

Question 1d - 2001, Paper 2

A forty-two (42) year old man has been well, apart  from a history of alcohol induced liver dysfunction and portal hypertension.  He has abstained from alcohol for the past 8 months after being told that  it would kill him.   After  a  large  haematemesis he presents  drowsy, clinically shocked, with a blood pressure of 80 systolic, heart rate of 124 beats/minute, cold and clammy peripheries.  He is also clinically jaundiced.

 Variceal bleeding is diagnosed and it initially responds to therapy.  48 hours post admission he remains on invasive respiratory support, with weak withdrawal response to pain despite minimal sedation, a persistent coagulopathy, and is inotrope dependent.  Serum bilirubin concentration is elevated (100 micromol/L [N 3-20]).  He develops a further acute variceal bleed associated with hypotension.

At 6 days there has been no further haematemeses. However he has a Glasgow Coma Score (GCS) of 5, despite no sedation.  His serum bilirubin concentration is now 350 micromol/L. Prothrombin time and serum creatinine concentration are twice normal.  A CT of the head shows no focal abnormality.  

(d) His wife tells you that he had been recently unjustly fired from work and for the week prior to his admission had started to drink heavily again.   He had complained of headache for which he would frequently take paracetamol and had been eating poorly. She asks you what are his chances of survival. How do you respond?

College Answer

Prognosis of hepatic encephalopathy and associated organ dysfunction depends on whether the process is acute or chronic, and whether there are any reversible factors. The very high bilirubin level (350 mcgmol/L), and the fact that this man has rebled from his varices make his prognosis worse, but not unsalvageable. Shunting procedures may decrease his likelihood of further bleeding but are likely to worsen the encephalopathy.

Discussion

Severe hepatic encephalopathy in ICU seems to actually have a slightly better outcome than other sorts of organ system failures.

  • The mortality at 1 year is about 54% according to one small study.
  • Those patients who require nothing other than mechanical ventilation (i.e. ones who got intubated for low GCS and airway protection) tend to have better outcomes.
  • The ones which have ascites, varices (which bleed) as well as sepsis - their 1-year mortalty tends to be as high as 60%.
  • In spite of these grim numbers, the admission of cirrhosis patients to ICU is no longer viewed as a completely futile exercise, because there has been a gradual expansion of the treatment options available to them, and because their outcomes have improved with time.

Several things can be added, with regard to prognostication in chronic liver disease patients admitted to ICU:

  • Childs-Pugh at admission is associated with survival at 12 months (Warren et al, 2015). Specifically:
    • Class A = 100% survival at 12 months
    • Class B = 50% survival at 12 months
    • Class C = 25% survival at 12 months
  • The MELD score gives a 3- month  mortality prediction in patients awaiting a liver transplant:
    • 40 or more — 71.3% mortality
    • 30–39 — 52.6% mortality
    • 20–29 — 19.6% mortality
    • 10–19 — 6.0% mortality
    • <9 — 1.9% mortality
  • In ICU, the liver scores have little influence because many other organ systems play are role in death or survival. Well-rounded models (SOFA, APACHE) are better at predicting ICU outcomes than liver-specific scoring systems (Levesque et al, 2012)

References

Fichet, Jérôme, et al. "Prognosis and 1-year mortality of intensive care unit patients with severe hepatic encephalopathy." Journal of critical care 24.3 (2009): 364-370.

 

García-Martínez, Rita, Macarena Simón-Talero, and Juan Córdoba. "Prognostic assessment in patients with hepatic encephalopathy." Disease markers 31.3 (2011): 171-179.

 

Wendon, Julia, et al. "Critical care and cirrhosis: outcome and benefit." Current opinion in critical care 17.5 (2011): 533-537.

Fichet, Jérôme, et al. "Prognosis and 1-year mortality of intensive care unit patients with severe hepatic encephalopathy." Journal of critical care 24.3 (2009): 364-370.

García-Martínez, Rita, Macarena Simón-Talero, and Juan Córdoba. "Prognostic assessment in patients with hepatic encephalopathy." Disease markers 31.3 (2011): 171-179.

Wendon, Julia, et al. "Critical care and cirrhosis: outcome and benefit." Current opinion in critical care 17.5 (2011): 533-537.

Pugh, R. N. H., et al. "Transection of the oesophagus for bleeding oesophageal varices." British Journal of Surgery 60.8 (1973): 646-649.

Forman, Lisa M., and Michael R. Lucey. "Predicting the prognosis of chronic liver disease: an evolution from Child to MELD." Hepatology 33.2 (2001): 473-475.

Child, CG_, and J. G. Turcotte. "Surgery and portal hypertension." Major problems in clinical surgery 1 (1964): 1.

Malinchoc, Michael, et al. "A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts." Hepatology 31.4 (2000): 864-871.

Zimmerman, Jack E., et al. "Intensive care unit admissions with cirrhosis: Risk‐stratifying patient groups and predicting individual survival." Hepatology 23.6 (1996): 1393-1401.

Cholongitas, E., et al. "Systematic review: the model for end‐stage liver disease–should it replace Child‐Pugh's classification for assessing prognosis in cirrhosis?." Alimentary pharmacology & therapeutics 22.11‐12 (2005): 1079-1089.

Ho, Yu-Pin, et al. "Outcome prediction for critically ill cirrhotic patients: a comparison of APACHE II and Child-Pugh scoring systems." Journal of intensive care medicine 19.2 (2004): 105-110.

Cholongitas, E., et al. "Risk factors, Sequential Organ Failure Assessment and Model for End‐stage Liver Disease scores for predicting short term mortality in cirrhotic patients admitted to intensive care unit." Alimentary pharmacology & therapeutics 23.7 (2006): 883-893.

Levesque, Eric, et al. "Prospective evaluation of the prognostic scores for cirrhotic patients admitted to an intensive care unit." Journal of hepatology 56.1 (2012): 95-102.

Yeoh, Sern Wei, et al. "Cirrhotics Treated In Intensive Care Unit Have High Short Term Survival in the Absence of Extrahepatic Organ Dysfunction." Journal of Gastroenterology and Hepatology Research 5.2 (2016): 1984-1988.

Wiesner, Russell, et al. "Model for end-stage liver disease (MELD) and allocation of donor livers." Gastroenterology 124.1 (2003): 91-96.

Saliba, Faouzi, et al. "Cirrhotic patients in the ICU: prognostic markers and outcome." Current opinion in critical care 19.2 (2013): 154-160.

Peng, Ying, Xingshun Qi, and Xiaozhong Guo. "Child–Pugh Versus MELD Score for the Assessment of Prognosis in Liver Cirrhosis: A Systematic Review and Meta-Analysis of Observational Studies." Medicine 95.8 (2016).

Question 14 - 2001, Paper 2

List the information  that  can  be obtained  from  ascitic  fluid  analysis.    What are  your indications for an ascitic fluid tap?

College Answer

Ascitic fluid analysis provides – Fluid for General appearance

Albumin / protein content

Red cell count White cell count Culture and sensitivity Cytology

Biochemistry - amylase

Indications for performing a tap include: any patient with ascites and PUO, critical illness or suspected malignancy.

Discussion

I would expand the college list:

Information which can be derived from an ascitic fluid analysis:

  • Appearance - turbidity would be very suspicious for SBP
  • Albumin - to calculate serum/ascites albumin gradient
  • Amylase/lipase - to consider pancreatitis as the cause of ascites
  • LDH (low indicates hepatic cause, whereas >500 suggests malignancy)
  • Gram stain - for bacteria
  • India ink stain - for hyphae
  • ZN stain for acid-fast bacilli (tuberculosis)
  • Culture/sensitivities
  • Flow cytometry and cell count - RBC/WCC ratio would raise suspicion of SBP
  • Cytology - presence of malignant cells
  • alpha-foetoprotein - to investigate for HCC

Indications for ascitic fluid drainage:

  • Diagnostic
    • see above
  • Therapeutic
    • patient discomfort
    • respiratory compromise due to adominal pressure
    • abdominal compartment syndrome
    • infected ascitic fluid (i.e. as source control)
    • for peritoneal dialysis (this can be viewed as a therapeutic paracentesis

References

Bar-Meir, Simon, Emanuel Lerner, and Harold O. Conn. "Analysis of ascitic fluid in cirrhosis." Digestive diseases and sciences 24.2 (1979): 136-144.

Boyer, Thomas D., Arthur M. Kahn, and Telfer B. Reynolds. "Diagnostic value of ascitic fluid lactic dehydrogenase, protein, and WBC levels." Archives of internal medicine 138.7 (1978): 1103-1105.

Runyon, Bruce A., John C. Hoefs, and Timothy R. Morgan. "Ascitic fluid analysis in malignancy‐related ascites." Hepatology 8.5 (1988): 1104-1109.

 

Question 9 - 2002, Paper 1

Critically evaluate the use of cisapride, metoclopramide and erythromycin for gastric emptying in Intensive Care patients.

College Answer

Cisapride: selectively enhances physiologic release of acetylcholine at level of myenteric plexus. Part  of  effect  via  activation  of  serotonin  (5-HT4)  receptors.  Enhances  oesophageal  peristaltic activity, gastric emptying, intestinal propulsive activity and colonic transit. Extensively metabolised via cytochrome P450 3A4 enzymes. Highly protein bound. Only administered orally. Significant adverse effects and interactions, especially prolonged QT interval (and arrhythmias) in particular when administered in patients at risk of arrhythmias or when administered concurrently with drugs that  prolong  QT  or  drugs  that  inhibit  P450  3A4  enzymes  (e.g.  azole  antifungals,  macrolide antibiotics, and protease inhibitors). Problems with limited availability, restrictions on prescribing, large number of documented interactions.

Metoclopramide: mode of action unclear (? via selective dopamine-2 receptor antagonist effects); sensitises tissues to the action of acetylcholine (motility effects abolished by anticholinergic drugs and  narcotic  analgesics).  Increases  tone  and  amplitude  of  gastric  contractions,  relaxes  pyloric sphincter and increases peristalsis of duodenum and jejunum. Administered orally, IV or IM. Conjugated by liver and renally excreted (reduced clearance with renal failure). Minimal protein binding. Dopamine agonist activity responsible for adverse effects (e.g. sedation, dystonic/extrapyramidal reactions).

Erythromycin: macrolide antibiotic that seems to stimulate motilin receptors, and enhances motilin release from enterochromaffin  cells of duodenum. Enhanced contractile effects on gastric antrum and duodenum. Administered orally or intravenously  ( probably IV more effective). Highly protein bound. Substantial hepatic metabolism. Prolonged QT and arrhythmias reported, as have hepatic dysfunction, overgrowth of non-susceptible organisms and colitis (Cl. difficile). Elevated levels of many other drugs (as a result of inhibition of metabolism) can lead to toxicity (e.g. theophylline, HMG-CoA reductase inhibitors, anti-epileptics, digoxin, warfarin etc).

Discussion

One study ran all of these drugs against each other to evaluate their comparative efficacy. The only useful finding was that metoclopramide worked faster than cisapride. And then cisapride was withdrawn from the market, following concerns of toxicity. The current Canadian Critical Care Nutrition Guidelines only mention metoclopramide and erythromycin (as well as enteral naloxone).

Features

Metoclopramide

Erythomycin

Cisapride

Class and mechanism

Antiemetic;

Dopamine receptor antagonist

Enhances gastric emptying rate and increases the tone of the oeseophageal sphincter

Macrolide antibiotic;

Motilin receptor agonist, motilin release enhancer

Increases the automaticity of enteric nervous system motor function

Prokinetic

5-HT4 receptor agonist

Enhances oesophageal peristaltic activity, gastric emptying, intestinal propulsive activity and colonic transit (although in the wake of its discontinuation, many believe these effects were overstated).

Advantages

Low toxicity
Synergistic effect with erythromycin

Low toxicity
Synergistic effect with metoclopramide

None?

Adverse effects

Increased prolactin release
Dystonic reactions

Allergic reactions
QT prolongation

QT prolongation
Significant risk of arrhythmia
Numerous drug interactions

 

References

MacLaren, Robert, et al. "Sequential single doses of cisapride, erythromycin, and metoclopramide in critically ill patients intolerant to enteral nutrition: a randomized, placebo-controlled, crossover study." Critical care medicine 28.2 (2000): 438-444.

 

The best resource for all EBM in this topic is the Canadian Critical Care Nutrition Guidelineswebsite.

 

Society Of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition.Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient. Crit Care Med 2009 Vol. 37, No. 5 , 2009

Question 1 - 2003, Paper 1

Critically evaluate the strategies for prevention of gastrointestinal bleeding in the critically ill.

College Answer

Answers should address more than just prevention of gastric erosions/stress ulceration.

Consideration should be given to other causes including patients with known gastro-oesophageal varices (where sclerotherapy/banding, beta-blockers and techniques to lower venous pressure, and avoidance of local trauma should be considered).

With regard to stress ulceration many strategies have been employed, and should be considered in a broad answer.  General resuscitation of patients, correction of coagulopathy, early enteral feeding and avoidance of precipitants (eg. NSAIDs) in patients at risk are assumed to be beneficial (but not well studied).  Prospective randomised trials have generally compared drug regimens (antacids vs sucralfate vs H2-blockers vs proton pump inhibitors).  Other agents include prostaglandin analogs. Controversy surrounds the issues of widespread use of prophylactic agents, value of drugs vs placebo, nosocomial infection rates, and cost-benefit analyses.

Discussion

"Critically evaluate" demands a certain degree of structure. Contrary to the college answer, banding and sclerotherapy are not usually preventative techniques. If one were to dedicate any time during this ten minute answer to varices and leaking AVMs, one may wish to be very brief about it, as the meat is clearly in gastric ulceration.

Introduction

Gastrointestinal bleeding in the critically ill patient may be due to a variety of causes; these include bleeding from stress ulceration, oesophageal varices, and colonic polyps. Exacerbating causes include antiplatelet and anticoagulant medications, as well as poor perfusion of gastrointestinal mucosa in the context of shock. Given that in the ICU GI bleeding is combined with a series of other major organ dysfunction syndromes, it tends to have a castarophic mortality rate and it is important to be able to protect at-risk patients from this complication.

Rationale

Options:

  • Proton pump inhibitors
  • Histamine receptor antagonists
  • non-pharmacological management - protective role of enteral feeding

Advantages

  • Decreased risk of gastrointestinal bleeding
  • Decreased exposure to blood products, and the attendent risks thereof

Disadvantages

  • Decreased gastric acidity, thus increased risk of non-sterile aspiration
  • Increased risk of gastrointestinal bacterial overgrowth and translocation
  • Increased risk of Clostridium difficile infections
  • Economic disadvantage (cost)

Evidence for the routine use of ulcer prophylaxis

  • A recent meta-analysis suggests that the quality and quantity of the evidence is still poor, but on the weight of the available evidence there is neither a mortality improvement nor any increase in the risk of nosocomial pneumonia.
  • There appears to be no benefit for stress ulcer prophylaxis in patients who are tolerating enteral feeding, and in these patients stress ulcer prophylaxis is not needed.
  • There is insufficent evidence to recommend the mandatory use of stress ulcer prophylaxis in any specific patient group (again, 
  • Obviously, correcting coagulopathy (and not triggering any new coagulopathy, nor disabling the platelets with NSAIDs) is a good way to prevent catsatropic bleeding in the ICU.

Evidence to support one drug class over another

  • At the time of this paper having been written, there was insufficient evidence to recommend any specific medication (e.e H2As vs PPIs); however the Danes recommended PPIs, because they are more effective at keeping the gastric pH at over 4.0.
  • There is now lots of evidence, and it is still unclear whether PPIs or H2As are more effective. Pro-PPI studies include a big 2016 meta-analysis by Alshamsi et al, which revealed them to be more effective at preventing clinically significant episodes of bleeding. However, it must be pointed out that many of the studies which met inclusion criteria didn't even specify what they meant by "bleeding". When other meta-analysis authors selected studies  limited to ones with a low risk of bias, the results they arrived at were not significant (Barletta et al, 2016).

Summary

PPIs are indicated in at-risk patient in ICU who are intolerant of eneteral feeding, and who are otherwise at risk of gastrointestinal bleeding. Further research is required to discriminated between different classes of drugs in terms of efficacy, and to identify the at-risk population.

References

Steinberg, Kenneth P. "Stress-related mucosal disease in the critically ill patient: risk factors and strategies to prevent stress-related bleeding in the intensive care unit." Critical care medicine 30.6 (2002): S362-S364.

Marik, Paul E., et al. "Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis." Crit Care Med 38.11 (2010): 2222-2228.

Krag, Mette, et al. "Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients." Intensive care medicine 40.1 (2014): 11-22.

Madsen, Kristian Rørbæk, et al. "Guideline for Stress Ulcer Prophylaxis in the Intensive Care Unit." Danish medical journal 61.3 (2014): 1-4.

Alshamsi, Fayez, et al. "Efficacy and safety of proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis of randomized trials." Critical Care 20.1 (2016): 120.

Barletta, Jeffrey F., et al. "Stress ulcer prophylaxis." Critical care medicine44.7 (2016): 1395-1405.

Question 14 - 2003, Paper 1

List the potential  aetiology of a severely altered mental  status  in a 65-year-old man,  48 hours after major hepatic  resection for hepatocellular carcinoma.  Outline your management of this patient.

College Answer

Mental state could be severely depressed or patient may be agitated or confused.  

In general the potential aetiologies are the same, though some more likely in each type of state.   Consider: decreased oxygen delivery to braiin (hypoxaemia, low cardiac output, low blood pressure), effects of drugs (those administered or those withdrawing from), intracerebral pathology (thromboembolism, rarely bleed eg. into undetected secondaries), electrolyte disorders (especially glucose, Na and Calcium), infections (unlikely; eg. systemic/meningitis/encephalitis), postoperative confusional state (uncertain but probably multifactorial aetiology), post-ictal or psychiatric disorder.

Management involves exclusion of  reversible and  specific treatable causes considered likely/possible (eg. SpO2, vital signs, glucose, electrolytes, review drugs and history).  Appropriate treatment of any specific abnormalities detected. Protection of patient and staff with cautious use of restraint (chemical or physical) if absolutely necessary or specifically indicated.

Discussion

Potential aetiology for a severely altered mental status post hepatic resection:

  • Hypoxia due to intrapulmonary portosystemic shunting, atelectasis or aspiration
  • Hypercapnea due to right pleural effusion
  • Hepatic encephalopathy due to high ammonia
  • Cerebral oedema
  • Diminished capacity to metabolise anaesthetic drugs and sedatives
  • Intracranial haemorrhage in the context of coagulopathy
  • Septic encephalopathy post-operatively

Management:

Specific management of hepatic encephalopathy

  • Lactulose
  • Rifaximin
  • Avoidance of hyponatremia
  • Nutritional management:
    • Branched-chain amino acids (BCAAs) and a reduced amount of aromatic amino acids
    • High fiber diet
    • Pro-biotics (though their benefit is unclear)

Management of the precipitating cause

  • Stop GI bleeding (endoscopy, banding, etc)
  • Antibiotics for SBP
  • Correct dehydration
  • Withdraw hepatotoxins

Supportive management of the encephalopathic patient

  1. Support the airway.  If the patient is comatose or uncooperative, they may require intubation in order to correct disorders of gas exchange (as they may not be compliant with NIV and chest physiotherapy)
  2. Wean ventilation to spontaneous mode as tolerated.​ Hypoxia and hpercapnea can be readily corrected if the patient is mechanically ventilated; otherwise, posture with chest physiotherapy and deep breathing exercises are crucial
    Avoid NIV; abdominal distension and a fluctuating level of consciousness will likely result in aspiration. HFNP is ok. 
  3. Support haemodynamically;
    noradrenaline +/- terlipressin may be appropriate if hepatorenal syndrome is suspected
    Albumin (20%) is a reasonable resuscitation fluid
    Hepatic flow should be optimised by monitoring for abdominal compartment syndrome
  4. Avoid sedation. As needed, use drugs which do not depend on hepatic metabolism (eg. remifentanyl).
    Cerebral oedema and the potential for intracranial catastrophe should be investigated with a CT brain
  5. Correct electrolyte derangement
  6. Monitor renal function (hepatorenal syndrome)
  7. Ensure BSL is monitored and supplemental glucose is made available
    Ensure thiamine is co-administerd with glucose!
  8. Correct clinically significant anaemia. 
    Address haematinic factor deficiencies.
  9. Antibiotics as appropriate: ceftriaxone may be required if SBP is a real possibility.
    Blood cultures and inflammatory markers should be collected.

References

Wendon, Julia, et al. "Critical care and cirrhosis: outcome and benefit." Current opinion in critical care 17.5 (2011): 533-537.

Riggio, Oliviero, et al. "Management of hepatic encephalopathy as an inpatient." Clinical Liver Disease 5.3 (2015): 79-82.

Bajaj, J. S. "Review article: the modern management of hepatic encephalopathy." Alimentary pharmacology & therapeutics 31.5 (2010): 537-547.

Amodio, Piero, et al. "The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus." Hepatology 58.1 (2013): 325-336.

Als-Nielsen, Bodil, Lise Lotte Gluud, and Christian Gluud. "Nonabsorbable disaccharides for hepatic encephalopathy." Cochrane Database Syst Rev 2 (2004).

Bass, Nathan M., et al. "Rifaximin treatment in hepatic encephalopathy." New England Journal of Medicine 362.12 (2010): 1071-1081.

Question 10 - 2004, Paper 1

Outline the diagnostic features, complications and treatment of critically ill patients with pancreatitis.

College Answer

This is a complex field with a large amount of literature to collate. Pancreatitis is usually presents with persistent upper abdominal pain, associated with nausea and vomiting, which can be associated with signs of local tenderness through to peritonism, and/or signs of a systemic inflammatory response  (e.g.  fever,  tachycardia) or  signs  of  associated  disorders  (e.g.  jaundice  with  biliary obstruction) or rarely signs of complications (e.g. ecchymotic discoloration in flank [Grey-Turner’s sign] or peri-umbilical [Cullen’s sign] regions). These signs may be difficult to elicit or masked in critically ill patients. Investigations that assist in the diagnosis include: serum amylase (usually > 3 times normal) (serum lipase does not improve diagnostic accuracy); liver function tests (looking for evidence of obstructive pattern with gall stone induced pancreatitis); plain abdominal radiograph (excludes other aetiologies, and may show localised ileus [“sentinel loop”]; abdominal ultrasound (enlarged hypo-echoic pancreas, and looking for gall stones); and abdominal CT scan with contrast (confirm diagnois and looking for areas of necrosis or pseudocysts). Ranson’s criteria (or more recently Glasgow criteria or Imrie score) are used to assess severity and predict outcome, and they include white cell count (>16,000/mm3), glucose (>11 mmol/L), AST > 250 IU/L, Ca < 2mmol/L, hypoxaemia (<8kPa), and a decrease in haematocrit (>10%) and an increase in urea (>1.8 mmol/L).

Complications include: those associated with a systemic inflammatory response (e.g. myocardial depression/shock,  ARDS,  renal  failure,  death);  respiratory  (including  pleural  effucsion  and atelectasis);  metabolic  (including  hypocalcaemia,  glucose  disturbances);  and   intrabdominal problems (including ileus, necrosis, pseudo-cysts, abscess formation, etc).

Treatment should include: aggressive fluid resuscitation to stabilise the haemodynamic state, treatment of underlying cause (e.g. ERCP if gall stones present, withdrawal of offending drug), treatment of pain (morphine controversial), surgical treatment of complications (e.g. aspiration/drainage of infected collections) and general support of the critically ill patient. More contentious issues that should be considered include: early prophylactic broad spectrum antibiotics (evidence that decrease complications), prophylactic anti-fungal therapy, jejunal feeding (safe, feasible, cheaper than TPN, possibly of benefit), the use of somatostatin, octreotide or protease inhibitors (none have sufficient evidence base to use routinely), and the timing and nature of surgical interventions.

Discussion

This question dates back to a time when there was a whole massive period during which one had plenty of thinking room, planning, and then the process of written communication could take place at a civilised pace, without rush. Now, of course, a question like this has the candidate trying to fit the last 30 years of pancreatitis literature into a ten minute answer.

One patently cannot do this.

The suggested answer below is one which could easily be produced over the course of ten minutes.

Diagnostic features

  • Presentation with severe abdominal pain, nausea and vomiting on presentation
  • Metabolic acidosis and shock; hypocalcemia
  • Elevated pancreatic enzyme levels, of which lipase is the more pancreas-specific
  • An abdominal CT may reveal that a widened common bile duct is present, potentially with an impacted stone in the bile duct.

Complications

  • SIRS and hemodynamic compromise
  • renal failure
  • infection of pancreatic necrosis
  • hepatic failure
  • abdominal comaprtment syndrome
  • ARDS
  • hypocalcemia
  • metabolic acidosis
  • myocardial contractility depression
  • ileus

Treatment

  • Airway:
    • intubation may be required; aspiration may be a major risk
  • Breathing:
    • mechanical ventilation with PEEP titrated to permit recruitment of collapsed lung bases
    • As ARDS develops, tidal volumes may nee to be reduced and lung-protective ventilation may need to be adopted, with permissive hypercapnea
  • Circulation:
    • Initial stages of resuscitation will likely consist of fluids only
    • The SIRS response may lead to cardiovascular collapse; given that metabolic acidosis and SIRS-associated cardiomyopathy may also be present, inotropes as well as vasopressors will likely be required
  • Pain control:
    • this will be vitally important in the non-intubated patient, in order to maintain VQ matching by continuing deep breathing
  • Electrolytes- particularly calcium - must be carefully monitored
  • Fluid balance management neesd to be careful, and dialysis may be required
  • Feeds via the NG tube may be commenced; there does not appear to be any evidence that "pancreatic rest" is in any way beneficial. The necrotic pancreas is not going to be responsive to the normal secretory stimuli, and the
  • Coagulation factors need to be corrected, and careful surveillance of the abdominal vessels must occur, as the splenic artery has a tendency to form aneurysms and bleed everywhere
  • Antibiotics are probably not indicated
  • ERCP to manage the cause of CBD obstruction should take place at the earliest opportunity, as indicated. if there is no ERCP-amenable cause, surgical drainage of the necrotic pseudocyst may take place as soonas the pseudocyst has formed a sufficiently distinct "wall".
  • An alternative to surgical cyst drainage is endoscopic ultrasound-guided drainage, which may be a better option for the frail patient.

References

Wilmer, Alexander. "ICU management of severe acute pancreatitis." European journal of internal medicine 15.5 (2004): 274-280.

Question 1a - 2004, Paper 1

A 60-year-old woman has a right hemi-hepatectomy for invasive cholangio-carcinoma. She has been admitted to your unit for postoperative care

a)          Describe in detail what problems she may develop in the first 48 hours and how you would treat them?

College Answer

The perioperative complications could be classified into (1) that of any major upper abdominal surgery and (2) specifically that of a hemi-hepatectomy for cholangiocarcinoma; or divided into various systems, ie.

(1) Respiratory:                     Inadequate  or  excessive  analgesia,  pulmonary oedema  from  fluid overload, R. haemothorax, R. pneumothorax, R diaphragmatic dysfunction, V/Q mismatch from hepatic failure, aspiration and possibly early pulmonary infection or thromboembolism. Very rarely, intraoperative air embolism ®ARDS.
(2) Cardiovascular:                Hypotension from bleeding, epidural block, perioperative myocardial ischaemia / infarction, Arrhythmias associated with electrolyte abnormalities.
(3) Gastro-intestinal failure:   Prolonged ileus, pseudo-obstruction, ascites, G I haemorrhage. (4) Renal:                                                Hepatorenal syndrome, acute tubular necrosis, oliguria.
(5) Hepatic:                             Cholangitis, hepatic failure, encephalopathy, coagulopathy, (6) CNS:                                                Encephalopathy.
(7) Metabolic:                        hyperlactataemia, iNa+, lK+, hypoglycaemia.
(8) Premorbid condition:        Possible ulcerative colitis/primary sclerosing cholangitis: Therefore, medication issues ie steroids, immune state, nutritional status etc.

Treatment is basically meticulous perioperative care with special regard to fluid and electrolyte balance, analgesia, coagulation control, and specific and supportive therapy for any individual complications that develop ie encephalopathy, hepatorenal syndrome etc.

Discussion

This question closely resembles Question 1 from the second paper of 2006. In the interest of simplified revision, the answer to that question is reproduced below:

Post-operative Complications of Liver Surgery:

A Table of Problems and their Solutions

Problems Solutions
Airway issues Extubate them in ICU (no difference in duration of ICU stay, regardless of where they are extubated)
(Neelakanta et al, 1997).
Atelectasis Use NIV (reintubation rates will be improved- Narita et al, 2010)
Bleeding Use a low CVP strategy (2-5mmHg)
Intraoperatively, insist on occlusive manoeuvres (eg. Pringle manoeuvre)
Analgesia Remember the impaired clearance. Avoid benzodiazepines and long-acting opiates.
Epidural seems to increase fluid requirements: use PCA instead.
Delirium Hepatic encephalopathy may develop if the patient had abnormal liver function preoperatively. One is referred to the chapter on hepatic encephalopathy for details of its management (spoiler: a lot of lactulose is involved)
High lactate Expect it. Unlikely to be related to real shock (more a reflection of poor residual liver function)
Observe it.
Low phosphate Expect it. Replace it. The phosphate is being absorbed by the regenerating liver.
Renal failure In advanced cirrhosis, may represent hepatorenal syndrome.
In other situations, it may be pre-renal (i.e. due to inadequate fluid resuscitation) or due to intraoperative renal vascular or ureteric injury.
Fluid overload Use concentrated colloids to maintain intravascular volume (eg. 20% albumin).
Hypercatabolic state Early enteral nutrition (not much benefit from TPN - Hotta et al, 2002)
Optimal pre-operative nutrition is important.
Branched-chain amino acids (BCAAs) should be mentioned, in spite of the fact that tey are probably pointless in this setting.
Hypoglycaemia Attentive BSL monitoring
Coagulopathy Attentive coag monitoring; likely no need for correction unless there is active bleeding
Infection Mainly in the setting of bile leaks, abdominal collections, VAP or line-related sepsis. In any case, broad-spectrum cover will be deployed, some combination of an extended-spectrum β-lactam and lactamase inhibitor, eg. Tazocin.

References

Jarnagin, William R., et al. "Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade." Annals of surgery 236.4 (2002): 397-407.

Page, Andrew J., and David A. Kooby. "Perioperative management of hepatic resection." Journal of gastrointestinal oncology 3.1 (2012): 19-27.

Wrighton, Lindsay J., et al. "Postoperative management after hepatic resection." Journal of gastrointestinal oncology 3.1 (2012): 41-47.

Thorat, Ashok, and Wei-Chen Lee. Critical Care Issues After Major Hepatic Surgery. INTECH Open Access Publisher, 2013.

Pagano, Duilio, et al. "The unreliability of continuous postoperative lactate monitoring after extended hepatectomies: single center experience." Updates in surgery 67.1 (2015): 33-37.

Ciuni, Roberto, et al. "Nutritional aspects in patient undergoing liver resection." Updates in surgery 63.4 (2011): 249-252.

Hotta, Tsukasa, et al. "Evaluation of postoperative nutritional state after hepatectomy for hepatocellular carcinoma." Hepato-gastroenterology 50.53 (2002): 1511-1516.

Richter, B., et al. "Nutritional support after open liver resection: a systematic review." Digestive surgery 23.3 (2006): 139-145.

Marchesini, Giulio, et al. "Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial." Gastroenterology 124.7 (2003): 1792-1801.

Kim, Say-June, Dong-Goo Kim, and Myung Duk Lee. "Effects of branched-chain amino acid infusions on liver regeneration and plasma amino acid patterns in partially hepatectomized rats." Hepato-gastroenterology 58.109 (2010): 1280-1285.

Neelakanta, Gundappa, et al. "Early tracheal extubation after liver transplantation." Journal of cardiothoracic and vascular anesthesia 11.2 (1997): 165-167.

Narita, Masato, et al. "Noninvasive ventilation improves the outcome of pulmonary complications after liver resection." Internal Medicine 49.15 (2010): 1501-1507.

Question 2c - 2004, Paper 2

A 45-year-old intellectually handicapped man is admitted to your Intensive Care Unit for airway management.  He was nasally intubated for evacuation of a large dental abscess, which had caused airway compromise.

(c)       Over the next 48 hours he develops increasing jaundice, with severe derangement of his Liver Function  Tests. What are the likely causes, and how are you going to manage this problem?

College Answer

(c)       Over the next 48 hours he develops increasing jaundice, with severe derangement of his Liver Function  Tests. What are the likely causes, and how are you going to manage this problem?

The potential causes of jaundice and abnormal LFTs within the first 72 hours are many. The pattern of elevation may help the diagnosis (eg. hepatocellular pattern [elevated transaminases, but minor elevation of Alkaline Phosphatase], cholestatic [minor elevation of transaminases]), and a systematic approach is helpful. Most likely causes include infection (systemic sepsis, mild hepatitic/intravascular cholestasis, liver abscess, acalculous cholecystitis), drug induced (cholestatic/hepatitic), haemodynamic/shock (ischaemic hepatitis) or haemolysis (sepsis, early destruction of transfused blood). Pre-existing intercurrent diseases (hepatitis, gall stones) could also be present.

Management depends on the specific/likely aetiology. A careful history (including drug history [eg. high dose of paracetamol before presentation]) and clinical examination (eg. signs of right heart failure, chronic liver disease, abdominal pain) followed by specific liver function tests to delineate the pattern of abnormality (including alkaline phosphatase [AP], gamma glutamyl transpeptidase [GGT] and/or conjugated/unconjugated bilirubin). More specific blood tests may be indicated (eg. haemolysis screen or viral serology). Imaging of right upper quadrant with ultrasound (to assess obstruction &/or stones) would usually be indicated (± other imaging eg. nuclear medicine or CT scan). After addressing the specific aetiology, further treatment would be largely supportive (with awareness of effects on drug metabolism).

Discussion

 The college has cheated the candidate by not presenting them with a list of LFTs to analyse. With no information, the differentials (and thus the manaement options) are distrubingly broad.

One can work though this systematically.

The following tests will need to be ordered, in order of escalating expense, invasiveness and esotericims:

  • Albumin is a test of synthetic liver function, but is very nonspecific in critical illness.
  • Coags: APTT, PT, fibrinogen and mixing studies. These test the synthetic liver function. PT will be raised if the liver has stopped storing fat-soluble vitamins, and APTT will be raised if the synthetic function is so poor that clotting factor synthesis is impaired. Mixing studies help to demonstrate that the addition of healthy plasma corrects the factor deficiency.
  • Bilirubin differential (conjgated vs. unconjugated) helps discriminate biliary from nonbiliary causes of jaundice
  • Amylase and lipase (to exclude pancreatitis)
  • Ultrasound of the liver and biliary tree to rule out bile duct obstruction and any interruption of the hepatic vascular supply; and to look at the hepatic parenchymal texture (eg. fatty, cirrhotic, etc)
  • Hepatitis virus tests  to rule out acute hepatitis
  • Iron studies (to look for haemochromatosis)
  • Ceruloplasmin (if Wilson's disease is a realistic possibility)
  • Anti-smooth muscle antibodies (primary sclerosing cholangitis)
  • Anti-liver microsomal antibodies (autoimmune hepatitis)
  • Serum α-1 antitrypsin level (for deficiency)
  • Liver biopsy (gold standard)

Differentials and their management

  • Poor hepatic blood flow
    • decrease the PEEP to improve viscera
  • Right heart failure
    • maintain cardiac output with inotropes and fluids
  • Generalised shock state
    • maintain normotension with fluids and vasopressors
  • Idiopathic drug reaction
    • change the offending drug to an analogue
  • Hepatic vein thrombosis
    • anticoagulation
  • Hepatic infarction
    • anticoagulation
  • Infectious cause
    • viral serology
    • blood cultures

In addition, one would need to adjust drug doses and dosing intervals to allow for changes in hepatic clearance.

References

Question 28 - 2005, Paper 1

These are  the biochemical  results  taken  from a  50-year-old woman, missing from an alcohol rehabilitation  programme, who was found in her home by police three days since she was last seen.  Blood was drawn for investigation.

Na

126

mmol/l

138 - 145

K

3.5

mmol/l

3.6 - 5.2

Cr

0.25

mmol/l

0.04 - 0.1

Urea

7.0

mmol/l

3.1 - 7.5

Bilirubin (Total)

509

micromol/l

2 - 22

Protein (Total)

40

g/l

65 - 85

Albumin

20

g/l

38 - 48

ALP

153

IU/L

40 - 100

GGT

459

IU/L

0 - 50

ALT

336

IU/L

0 - 45

CK

400

IU/L

30 - 180

TroponinT

0.1

mcg/l

0.00 - 0.03

Glucose

3.2

mmol/l

3.5 - 5.6

Ammonia

342

micromol/l

0 - 50

Lactate

3.7

mmol/l

0.6 - 2.4

Based on these results, what is the most likely cause of her reduced conscious state?  Give reasons.   What  other  simple  blood  test  would  support  this  diagnosis?  What  is  the significance of the high plasma creatinine but normal urea concentrations?

College Answer

Most likely cause is hepatic encephalopathy, but many other conditions would be excluded as part of her work up.  She has obvious liver dysfunction (GGT, ALT, bilirubin), supported by a low albumin and a very high ammonia level. Other results (eg. Na, Cr/urea, glucose) are not as extreme and less likely to contribute to her reduced conscious state.

An additional assessment of the synthetic function of the liver would support the diagnosis(eg. prothrombin time, which is a marker of severity and should be prolonged).

The high plasma creatinine probably reflects significant renal impairment (not rhabdomyolysis as CK only mildly elevated).   The urea value is probably a reflection of decreased production and a nutritional deficiency.  A normal value makes gastrointestinal bleeding and severe hypovolaemia unlikely as precipitants for the encephalopathy.

Discussion

This question closely resembles (but is not identical to) Question 29.2 from the second paper of 2011. The key difference is that in 2011, it was a 48 yr old male who escaped from the alcohol rehab camp. However, the bloods were identical.

In contrast to the 2011 question, this time the examiners are asking us for ONE diagnosis.

So, if the candidate were to put all their money on one pony, it would be hepatic encephalopathy. The ammonia, bilirubin, LFTs and background history all point to this. The one test which the college has not provided us with is the coags- coagulopathy would be informative as a part of the staging process for this condition, particularly the prothrombin time.

The significance of the creatitine and urea disparity is probably an issue of dehydration. The patient, haveing collapsed some time ago, has spent some hours/days slowly dehydrating. However, owing to the greatly diminished oral intake and muscle mass, the patient probably has a very slow rate of urea production. The absence of CK demonstrates the fact that rhabdomyolysis has no role to play in this process.

References

Question 1 - 2006, Paper 2

A 60 year old woman has a right hemi-hepatectomy for invasive cholangio- carcinoma. She has been admitted  to the Intensive Care Unit for postoperative care.

List the problems she may develop in the first 48 hours.

College Answer

The perioperative complications could be classified into (1) that of any major upper abdominal surgery and (2) specifically that of a hemi-hepatectomy for cholangiocarcinoma; or divided into various systems, i.e.

(1) Respiratory:                     Inadequate or excessive analgesia, pulmonary oedema from fluid overload, R. haemothorax, R. pneumothorax, R diaphragmatic dysfunction, V/Q mismatch from hepatic failure, aspiration and possibly early pulmonary infection or thromboembolism. Very rarely, intraoperative air embolism ®ARDS.

(2) Cardiovascular:                Hypotension   from   bleeding,   epidural   block,   perioperative myocardial ischaemia / infarction, Arrhythmias associated with electrolyte abnormalities.

(3) GI failure:                          Prolonged ileus, pseudo-obstruction, ascites, G I haemorrhage

(4) Renal:                                                Hepatorenal syndrome, acute tubular necrosis, oliguria.

(5) Hepatic:                             Cholangitis, hepatic failure, encephalopathy, coagulopathy,

(6) CNS:                                                Encephalopathy.

(7) Metabolic:                        hyperlactataemia, low Na+, high K+, hypoglycaemia.

(8) Premorbid condition possible ulcerative colitis/primary sclerosing cholangitis: Therefore, medication issues i.e. steroids, immune state, nutritional status etc.

Discussion

This is a question which benefits from a systematic approach. The college answer has already made this attempt.

Thus: a table of Problems and Solutions:

Post-operative Complications of Liver Surgery:

A Table of Problems and their Solutions

Problems Solutions
Airway issues Extubate them in ICU (no difference in duration of ICU stay, regardless of where they are extubated)
(Neelakanta et al, 1997).
Atelectasis Use NIV (reintubation rates will be improved- Narita et al, 2010)
Bleeding Use a low CVP strategy (2-5mmHg)
Intraoperatively, insist on occlusive manoeuvres (eg. Pringle manoeuvre)
Analgesia Remember the impaired clearance. Avoid benzodiazepines and long-acting opiates.
Epidural seems to increase fluid requirements: use PCA instead.
Delirium Hepatic encephalopathy may develop if the patient had abnormal liver function preoperatively. One is referred to the chapter on hepatic encephalopathy for details of its management (spoiler: a lot of lactulose is involved)
High lactate Expect it. Unlikely to be related to real shock (more a reflection of poor residual liver function)
Observe it.
Low phosphate Expect it. Replace it. The phosphate is being absorbed by the regenerating liver.
Renal failure In advanced cirrhosis, may represent hepatorenal syndrome.
In other situations, it may be pre-renal (i.e. due to inadequate fluid resuscitation) or due to intraoperative renal vascular or ureteric injury.
Fluid overload Use concentrated colloids to maintain intravascular volume (eg. 20% albumin).
Hypercatabolic state Early enteral nutrition (not much benefit from TPN - Hotta et al, 2002)
Optimal pre-operative nutrition is important.
Branched-chain amino acids (BCAAs) should be mentioned, in spite of the fact that tey are probably pointless in this setting.
Hypoglycaemia Attentive BSL monitoring
Coagulopathy Attentive coag monitoring; likely no need for correction unless there is active bleeding
Infection Mainly in the setting of bile leaks, abdominal collections, VAP or line-related sepsis. In any case, broad-spectrum cover will be deployed, some combination of an extended-spectrum β-lactam and lactamase inhibitor, eg. Tazocin.

References

Jarnagin, William R., et al. "Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade." Annals of surgery 236.4 (2002): 397-407.

Page, Andrew J., and David A. Kooby. "Perioperative management of hepatic resection." Journal of gastrointestinal oncology 3.1 (2012): 19-27.

Wrighton, Lindsay J., et al. "Postoperative management after hepatic resection." Journal of gastrointestinal oncology 3.1 (2012): 41-47.

Thorat, Ashok, and Wei-Chen Lee. Critical Care Issues After Major Hepatic Surgery. INTECH Open Access Publisher, 2013.

Pagano, Duilio, et al. "The unreliability of continuous postoperative lactate monitoring after extended hepatectomies: single center experience." Updates in surgery 67.1 (2015): 33-37.

Ciuni, Roberto, et al. "Nutritional aspects in patient undergoing liver resection." Updates in surgery 63.4 (2011): 249-252.

Hotta, Tsukasa, et al. "Evaluation of postoperative nutritional state after hepatectomy for hepatocellular carcinoma." Hepato-gastroenterology 50.53 (2002): 1511-1516.

Richter, B., et al. "Nutritional support after open liver resection: a systematic review." Digestive surgery 23.3 (2006): 139-145.

Marchesini, Giulio, et al. "Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial." Gastroenterology 124.7 (2003): 1792-1801.

Kim, Say-June, Dong-Goo Kim, and Myung Duk Lee. "Effects of branched-chain amino acid infusions on liver regeneration and plasma amino acid patterns in partially hepatectomized rats." Hepato-gastroenterology 58.109 (2010): 1280-1285.

Neelakanta, Gundappa, et al. "Early tracheal extubation after liver transplantation." Journal of cardiothoracic and vascular anesthesia 11.2 (1997): 165-167.

Narita, Masato, et al. "Noninvasive ventilation improves the outcome of pulmonary complications after liver resection." Internal Medicine 49.15 (2010): 1501-1507.

Question 8 - 2007, Paper 1

A 62-year-old man presents to ICU with progressive oliguria and shortness of breath. He had been admitted to the ward a week before because of jaundice. His previous medical history is unremarkable, except for heavy alcohol consumption. There is no history of gastrointestinal bleeding or ingestion of nephrotoxic drugs. There is no past history of renal dysfunction. Clinical 
examination reveals a blood pressure of 124/60 mm Hg, jaundice, oedema and a distended non-tender abdomen. Cardiovascular examination is normal.

Investigations reveal: 
Ultrasound abdomen: Nodular cirrhosis of liver, ascites and normal sized, regular shaped kidneys.


Urinalysis:

No proteinuria, White cell count <10 X 1~6/L (Normal< 10) 

Ascitic tap

White cell count <10 X 10 6 /L (Normal< 10) 
Red cell count <10 X 10 6 /L (Normal< 10), 
No organisms on Gram stain.

On admission to hospital

On admission to
ICU (7 days later)

Na   (135-145 mmol/L)

139

123

K     (3.5-5.0 mmol/L)

4.1

5.1

Creatinine (0.06-0.14
mmol/L)

0.06

0.340

Urea       (4-6 mmol/L)

3.8

22

Bilirubin (0-20 J!mol/L )

34

48

ALT  (<40  U/L)

180

600

AST(<50 U/L)

340

870

Hb  (120-1500/L)

134

104

wcc (4-11 x 1011/L)

14.4

16.1

a)  What is the most likely cause of the renal deterioration? Give reasons.

List 4 important management measures specifically for the treatment of this patient's renal dysfunction.

College Answer

a)  What is the most likely cause of the renal deterioration? Give reasons.

Hepatorenal syndrome .
Reasons: Fulfils criteria for Type 1 HRS -(Acute deterioration, absent renal parenchymal disease, absent proteinuria, no shock and no history of nephrotoxic drugs)

List 4 important management measures specifically for the treatment of this patient's renal dysfunction.
Management of complications of renal dysfunction- hyperbilirubinaemia
Albumin administration
Terlipressin Midodrine/ Octreotide
TIPS 
Consideration for liver transplantation

Discussion

Hepatorenal syndrome is discussed in greater detail in the answer to Question 13 from the first paper of 2001, and in a chapter or rambling digressions.

This case fits the criteria for diagnosis, which are as follows:

  • Cirrhosis
  • Ascites
  • Creatinine level over 150mmol/L
    • failure of this to improve after 2 days of fluid replacement
  • Absence of other causes of renal failure, such as nephrotoxic drugs or some sort of serious parenchymal renal disease (eg. glomerulonephritis)

i.e. it is renal failure in a patient with coexisting liver failure and no other good reason to have renal failure. "Absence of proteinuria" promotes a view that this is a purely pre-renal disease, with no glomerular damage.

Type 1 hepatorenal syndrome is an acute episode, whereas Type 2 is gradual in onset.

As for "4 important management measures"...

  • Albumin and fluid resuscitation:
    • On its own, the effect from this is minimal; mortality is ~ 70%
  • Terlipressin
    • Improves mortality to from 70% to 50%
    • Thought to improve renal perfusion by decreasing the tension within the ascites compartment.
  • Noradrenaline
    • The idea is to increase renal perfusion by increasing the MAP by about 10mmHg
  • Octreotide
    • potent agent of splanchnic vasoconstriction
    • Mortality perhaps 60% 

If all else fails, TIPS procedure may be appropriate. As this disorder has an abysmal survival rate, those who qualify for transplant should be worked up for one.

The college examiners prescriptively asked for "management measures specifically for the treatment of this patient's renal dysfunction", but in their answer gave a generic support strategy ("Management of complications of renal dysfunction- hyperbilirubinaemia"). This answer is puzzling on several levels, and probably had no value in terms of marks for the actual trainees, revealing more information about the CICM quality control process than about hepatorenal syndrome.

References

UpToDate has an excellent synopsis of hepatorenal syndrome.

 

Salerno, Francesco, et al. "Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis." Postgraduate medical journal 84.998 (2008): 662-670.

 

Solà, Elsa, Mónica Guevara, and Pere Ginès. "Current treatment strategies for hepatorenal syndrome." Clinical Liver Disease 2.3 (2013): 136-139.

 

Arroyo, Vicente, et al. "Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis." Hepatology 23.1 (1996): 164-176.

 

Velez, Juan Carlos Q., and Paul J. Nietert. "Therapeutic response to vasoconstrictors in hepatorenal syndrome parallels increase in mean arterial pressure: a pooled analysis of clinical trials." American Journal of Kidney Diseases 58.6 (2011): 928-938.

 

Gluud, L. L., M. S. Kjaer, and E. Christensen. "Terlipressin for hepatorenal syndrome." Cochrane Database Syst Rev 4 (2006).

 

Kalambokis, Georgios, et al. "The effects of chronic treatment with octreotide versus octreotide plus midodrine on systemic hemodynamics and renal hemodynamics and function in nonazotemic cirrhotic patients with ascites."The American journal of gastroenterology 100.4 (2005): 879-885.

 

Rössle, Martin, and Alexander L. Gerbes. "TIPS for the treatment of refractory ascites, hepatorenal syndrome and hepatic hydrothorax: a critical update." Gut59.7 (2010): 988-1000.

 

Malinchoc, Michael, et al. "A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts." Hepatology 31.4 (2000): 864-871.

Question 7.3 - 2008, Paper 2

A patient presented with massive abdominal distension. On examination, a fluid thrill was present. List three clinical diagnoses, which may produce these findings

College Answer

.

Candidates listing 3 correct differentials for a fluid thrill (see a-c below) or providing 3 conditions which may result in massive ascites (see d-f below) were awarded  full marks.

a)  Massive ascites
b)  Massive ovarian cyst
c)  Pregnancy with hydramnios

d)  Severe liver disease
e)  Budd-Chiari syndrome
f)   Severe right heart failure or pericardial constriction

g)  Abdominal malignancy.

Discussion

This question asks for a fairly random detail from Talley and O'Connor.

The "fluid thrill" is one of the tests for ascites; however it will be positive in any condition where a major part of the abdomen is taken up by a big lake of sloshing fluid. Essentially, it consists of somebody (possibly the patient) pressing down on the middle of their abdomen, and the physician percussing one side while feeling for the percussion wave in the other side. A big sloshy lake of fluid will allow the percussion wave to transmit across, whereas bowel gas or stool will transmit nothing.

This generally held to be pretty unreliable sign of ascites, as it requires the ascites to be massive, and under tension.

In either case, the college was fairly non-specific in their expected answer. They would have been happy to hear several different explanations for abdominal fluid (cysts of all sorts, ascites or massive hydramnios are all valid causes). They were equally happy about three different reasons for massive ascites (which leaves the answer pretty well open to any suggestion.. Budd-Chiari? Liver cirrhosis? Severe right heart failure?).

References

A good description of the fluid thrill test can be found at the website of the University of California, San Diego.

Question 28.3 - 2008, Paper 2

List 4 causes of an elevated serum ammonia concentration in critically ill patients

College Answer

Hepatic failure
Inherited disorders of urea cycle
Drugs: Valproate, glycine, carbamezapine
Porta-systemic shunts
Increased protein load: GI bleed, TPN,
Infection with urease splitting organisms – proteus Gastric bypass, urinary diversion procedures Cancers – myeloma
Chemotherapy.

Discussion

This question closely resembles, though is not identical to, Question 14 from the second paper of 2012. There, one may find a discussion of the usefulness of the serum ammonia levels in critical illness.

Here, one is merely expected to regurgitate a series of differentials.

Using a familiar template, an easily remembered list would look like this:

  • Hepatic vascular insufficiency, eg. hepatic necrosis due to ischaemia
  • Hepatic failure
  • Portosystemic shunts
  • Infection with urea splitting organisms eg. Proteus mirabilis, H.pylori
  • Multiple myeloma
  • Drugs - eg. valproate, carbamazepine
  • Congential disorders of urea cycle
  • Increased protein catabolism, eg. chemotherapy, starvation, GI bleeding, or TPN

More detail, you beg? Impossibly large tables, useless for the purpose of rapid revision?

Causes of Hyperammonaemia, Arranged by Aetiology

Vascular and cardiac causes

  • Ischaemic hepatitis
  • Portal vein thrombosis
  • Portosystemic shunts

Infections

  • Hepatitis (viral)
  • Liver abscess
  • Urease producing bacteria (eg. Proteus, Klebsiella)
  • Herpes virus

Neoplasms

  • Hepatocellular carcinoma
  • Metastatic disease
  • AML
  • Multiple myeloma
  • Post bone marrow transplant

Drugs

  • Ammonium chloride
  • Basically, any drug which causes fulminant hepatotoxicity. Some examples:
    • Halothane and enflurane
    • Paracetamol
  • Also, drugs which affect the urea cycle:
    • Sodium Valproate
    • 5-fluorouracil
    • Asparginase
    • Insulin overdose
    • Glycine (in TURP syndrome)
    • Carbamazepine
    • Salicylates
    • Sulfadiazine
    • Pyrimethamine

Pre-analytical error

  • Prolonged pre-transport time
  • Room temperature storage of sample

Congenital causes

  • Inherited ura cycle defects
  • Organic aciduria
  • Fatty acid oxidation defects

Autoimmune causes

  • Fulminant autoimmune hepatitis

Urinary and renal causes

  • Distal renal tubular acidosis
  • Ureteric diversion
  • Urinary tract infections
  • Vesicoureteric reflux
  • Bladder perforation
  • Glycine (in TURP syndrome)

Endocrine and Metabolic causes

  • Parenteral nutrition
  • Reye's syndrome
  • Primary dietary carnitine deficiency
  • Deficiency of essential amino acids (with resulting increase in protein catabolism
  • Increased protein load
  • Increased protein catabolism, eg. steroids
  • Severe exercise (muscle protein catabolism)
  • Gastric bypass

Another method of arranging the differentials, according to the physiological mechanism:

Causes of Hyperammonaemia, Arranged by Physiology

Pre-analytical error

  • Prolonged pre-transport time
  • Room temperature storage of sample

Increased substrate for ammoniagenesis

  • Excess protein catabolism:
    • Essential amino acid deficiency
    • Primary dietary carnitine deficiency
    • Steroids
    • Immobility
    • Severe exercise
    • Increased tissue turnover, eg haematological malignancy
  • Excess protein intake:
    • Weird diet
    • Parenteral nutrition

Bypass of normal metabolism

  • TIPS procedure
  • Portosystemic shunts

Acquired urea cycle defects

  • Fulminant hepatitis of any cause
  • Reye's syndrome
  • Drugs, eg. glycine or valproate

Congenital urea cycle defects

  • Inherited ura cycle defects
  • Organic aciduria
  • Fatty acid oxidation defects

Excess of exogenous ammonia

  • Ammonium chloride therapy
  • Excess generation of ammonia:
    • Gastric bypass
    • Urease-producing organisms
    • UTI

Reabsorption of excreted ammonia

  • Distal renal tubular acidosis
  • Ureteric diversion
  • Urinary tract infections
  • Vesicoureteric reflux
  • Bladder perforation

References

Conway, Edward Joseph, and Robert Cooke. "Blood ammonia." Biochemical Journal 33.4 (1939): 457.

Shambaugh, G. E. "Urea biosynthesis I. The urea cycle and relationships to the citric acid cycle.The American journal of clinical nutrition 30.12 (1977): 2083-2087.

McDermott Jr, William V., Raymond D. Adams, and Athol G. Riddell. "Ammonia metabolism in man." Annals of surgery 140.4 (1954): 539.

Vince, Angela, et al. "Ammonia production by intestinal bacteria." Gut 14.3 (1973): 171-177.

Vince, Angela J., and Sigrid M. Burridge. "Ammonia production by intestinal bacteria: the effects of lactose, lactulose and glucose." Journal of medical microbiology 13.2 (1980): 177-191.

Dohrenwend, Paul, and Richard D. Shih. "Glycine Induced Hyperammonemia After Bladder Rupture During Transurethral Resection of a Bladder Tumor." Journal of Medical Cases 4.4 (2013): 250-253.

Felipo, Vicente, and Roger F. Butterworth. "Neurobiology of ammonia." Progress in neurobiology 67.4 (2002): 259-279.

Hashim, Ibrahim A., and Jennifer A. Cuthbert. "Elevated ammonia concentrations: Potential for pre-analytical and analytical contributing factors." Clinical biochemistry 47.16 (2014): 233-236.

Clay, Alison S., and Bryan E. Hainline. "Hyperammonemia in the ICU." CHEST Journal 132.4 (2007): 1368-1378.

Weng, Te-I., Frank Fuh-Yuan Shih, and Wen-Jone Chen. "Unusual causes of hyperammonemia in the ED." The American journal of emergency medicine 22.2 (2004): 105-107.

Hawkes, N. D., et al. "Non-hepatic hyperammonaemia: an important, potentially reversible cause of encephalopathy." Postgraduate medical journal 77.913 (2001): 717-722.

Question 23 - 2009, paper 1

A 54 year old woman was referred to the emergency department by her GP with a 3 day history of vomiting accompanied by upper abdominal pain. On examination she was obese, appeared restless and confused, GCS 13, febrile 38.6 C, heart rate of 100 /min, BP 90/40 mm Hg. She has Spo2 of 88% on oxygen via a non-rebreather bag.  There was diffuse abdominal tenderness on palpation in particular in the upper abdomen.   Bowel sounds were sluggish. Blood tests taken in a private laboratory the preceding day had revealed a lipase of 400 U/l (normal < 70).

23.1) What are the differential diagnoses of this patient’s  presentation?

23.2) What are the causes of hypotension in acute pancreatitis?

23.3) List 3 causes of a raised A-a gradient in acute pancreatitis?

23.4) What do you understand is the role for prophylactic antimicrobial therapy in sterile pancreatic necrosis?

College Answer

23.1) What are the differential diagnoses of this patient’s  presentation?

1)  Pancreatitis
2)  Perf DU
3)  Intestinal obstruction
4)  Acute cholecystitis with sepsis
5)  Aspiration and sepsis
6)  Gut ischaemia

23.2) What are the causes of hypotension in acute pancreatitis?

a) sequestration (3rd spacing) of protein rich fluids in and around the pancreas and abbdominal cavity, retroperitoneum
b) compounded by pre existing fluid depletion.

c) direct myocardial depression
d) SIRS / sepsis
e) Intra-abd hypertension

f) Bleeding

23.3) List 3 causes of a raised A-a gradient in acute pancreatitis?

Pulmonary dysfunction - Aspiration, pleural effusions, ARDS, atelectasis.

23.4) What do you understand is the role for prophylactic antimicrobial therapy in sterile pancreatic necrosis?

a) Antibiotic use in SAP without overt infection controversial and trial data are conflicting.

b) Antibiotics have been given either IV or IV plus orally/rectally via SDD.
c) Early trials - underpowered, mostly non blinded and included patients with differing disease severity suggested a reduction in both infections and improved outcome with early use of prophylactic antibiotics (Cefuroxime and imipenem) in necrotising SAP when compared with placebo. Subsequent meta analyses including a Cochrane review also suggested that antibiotics reduced infections and mortality and need for surgery in necrotic pancreatitis.
d) 2 recent RCTs (Isenmann 2004 and Dellinger 2007) have however demonstrated no effect on outcome or infection rate when prophylactic antibiotics were used in necrotic pancreatitis. The SCCM (2004) consensus conference on severe pancreatitis recommends against the use of routine prophylactic antibiotics.

Discussion

23.1) What are the differential diagnoses of this patient’s  presentation?

An obese hypoxic woman presents in a state of shock, febrile, and with this story of vomiting and abdominal pain. A systematic approach is called for, even though the lipase is high and the obvious single diagnosis is pancreatitis.

Vascular causes:

  • acute mesenteric vasculitis
  • mesenteric ischaemia, embolic or otherwise

Infectious causes: sepsis from any origin, but more likely the gut,

  • biliary sepsis
  • colitis

Neoplastic causes

  • perforated colorectal mass
  • SIRS due to a systemic cytokine release, due to lymphoma or leukaemia

Drug-induced causes

  • Drug-induced pancreatitis or hepatitis

Autoimmune causes eg. inflammatory bowel disease with perforation

Traumatic causes eg. Boerhaave's syndrome due to excessive vomiting

Endocrinological cause of abdo pain and SIRS, eg. pacreatitis due to any number of causes

23.2) What are the causes of hypotension in acute pancreatitis?

Again, there are several mechanisms:

  • "Third space losses" due to capillary leak, particularly sequestration in the abdomen
  • Systemic inflammatory response due to cytokine release
  • Gastrointestinal losses due to vomiting, diarrhoea, decreased oral intake, and gastric bleeding
  • Retroperitoeal hematoma (maybe from a ruptured splenic artery aneurysm)
  • Decreased preload due to abdominal compartment syndrome
  • Cardiac ouput decrease due to acidosis and SIRS-associated cardiomyopathy

23.3) List 3 causes of a raised A-a gradient in acute pancreatitis?

  • ARDS due to systemic cytokine release
  • Pleural effusions due to third space fluid mobilisation and aggressive fluid resuscitation
  • Pulmonary oedema due to decreased cardiac contractility and depressed systolic function
  • Aspiration pneumonia given that the patient has a decreased level of consciousness and presents with a history of vomiting

23.4) What do you understand is the role for prophylactic antimicrobial therapy in sterile pancreatic necrosis?

  • Short answer: there is no role for antibiotics in acute pancreatitis.
  • In the 1990s, authors were fond of using prophylactic antibiotics because small-scale trials demonstrated a benefit.
  • These days the evidence does not support the use of antibiotics
  • Cochrane has an even more recent review which agrees that there does not appear to be any benefit, even on the basis of studies which were not adequately powered to detect a subtle benefit
  • For some reason, imipenem seems to stand out as an antibiotic which on its own prevents pancreatic necrosis infections. This, again, was the result of an inadequately powered trial.

Again, thank you to Rajkumar (you know who you are) for pointing out the error in this answer. There was a duplication of content from Question 22 of the same paper. Well spotted!

References

Pederzoli, Paolo, et al. "A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem." Surgery, gynecology & obstetrics 176.5 (1993): 480-483.

Wilmer, Alexander. "ICU management of severe acute pancreatitis." European journal of internal medicine 15.5 (2004): 274-280.

Villatoro, Eduardo, Mubashir Mulla, and Mike Larvin. "Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis."Cochrane Database Syst Rev 5.5 (2010).

Question 12.2 - 2009, Paper 2

List 4 clinical signs of portal hypertension.

College Answer

1. Splenomegaly
2. Ascites
3. Caput medusae
4. Haemorrhoids

Discussion

This question is identical to Question 5.1 from the second paper of 2010.

 

References

Question 5.1 - 2010, Paper 2

List 4 clinical signs of portal hypertension.

College Answer

List 4 clinical signs of portal hypertension.

•     Splenomegaly
•    Caput medusae
•     Ascites
•    Haemorrhoids on rectal examination
•    Haematemesis? Melaena

Discussion

This is fairly straightforward.

  • Ascites
  • Caput medusae
  • Hepatomegaly and splenomegaly
  • Haemorrhoids
  • Oesophageal varices (and thus haematemesis)

References

Escorsell, Angels, Joan Carles García-Pagán, and Jaume Bosch. "Assessment of portal hypertension in humans." Clinics in liver disease 5.3 (2001): 575-589.

 

de Franchis, Roberto. "Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension." Journal of hepatology 53.4 (2010): 762-768.

Question 30 - 2010, Paper 2

A  26  year  old  female  presents  to the  Emergency  Department  having  been found at home confused and jaundiced by her GP.

Her GCS is E3V5M5

She has a temperature of 38 ˚C, BP 90/60, HR 90 and SpO2  94% on 4 litres/min O2.

Her plasma biochemistry is as follows:

Test

Value

Normal Range

Sodium

137 mmol/L

(135 – 145)

Potassium

4.1 mmol/L

(3.5 – 5.0)

Total bilirubin*

200 micromol/L

(0 – 25)

AST*

4000 U/L

(<40)

GGT*

500 U/L

(<40)

ALT*

3000 U/L

(<40)

Urea

4.2 mmol/L

(4 – 6)

Coagulation profile:

Test

Value

Normal Range

INR*

2.6

(0.8 – 1.2)

a)  Based on the above information, what do you think this woman is suffering from?

b)  List 5 important aetiologies which could result in this presentation.

c)  List 4 important complications (apart from respiratory failure) she is at risk of developing.

d)  List 4 reasons why this woman might progress  to developing  respiratory failure.

College Answer

a)  Based on the above information, what do you think this woman is suffering from?

Acute liver failure (without more detail it is hard to say, hyperacute, acute, subacute or chronic)

b)  List 5 important aetiologies which could result in this presentation.

•     Sepsis
•    Viral hepatitis – Hep B/C/D, CMV/EBV
•    Drug induced
•     Poisoning
•    Miscellaneous  (wilson’s disease, acute fatty liver of pregnancy, ischaemic necrosis, Budd-Chiari, complications of hepatic surgery)
•     Idiopathic
•    Pregnancy related

c)  List 4 important complications (apart from respiratory failure) she is at risk of developing.

•    Cerebral oedema and herniation
•     Coagulopathy
•    GI bleed
•     Sepsis
•    Renal failure

d)  List 4 reasons why this woman might progress  to developing  respiratory failure.

•    Impaired ventilation because of coma
•    Pleural effusions
•    ARDS
•    Intra-pulmonary shunts
•    Aspiration pneumonia
•    Sepsis- pulmonary or extrapulmonary

Discussion

a)  Based on the above information, what do you think this woman is suffering from?

With the transaminases in their thousands, a raised bilirubin, coagulopathy and fever, one might assume that this lady has some sort of acute hepatitis. As the college rightly points out, "acute hepatic failure" is the only description one can make without any further history.

b)  List 5 important aetiologies which could result in this presentation.

  • Vascular causes, eg. acute hepatic artery thrombosis or ischaemic hepatic injury
  • Infectious causes, eg. acute viral hepatitis or liver abscess
  • Neoplastic causes, eg. decompensation due to hepatocellular carcinoma
  • Drug-induced hepatitis eg. paracetamol overdose
  • Exacerbation of congenital disorder, eg. Wilson's disease
  • Autummune hepatitis, eg. cryptogenic cirrhosis or idiopathic autoimmune hepatitis (IAIH)
  • Traumatic hepatic injury

c)  List 4 important complications (apart from respiratory failure) she is at risk of developing.

There is a brilliant article on this subject which outlines all the possible and impossible complications of acute hepatic failure. I will summarise their Panel 1:

Complications of acute liver failure

  1. Unprotected airway due to obtundation
    Potential for aspiration due to nausea and vomiting
  2. Acute lung injury and ARDS (due to SIRS)
  3. Systemic inflammatory response.
    Vasodilated shock with hyperdynamic circulation
  4. Hyperammonaemic encephaloparthy
    Increased intracranial pressure (cerebral oedema)
  5. Decreased lactate clearance and metabolic acidosis
  6. Renal failure (hepatorenal syndome)
  7. Hypercatabolic state
    Hypoglycaemia
  8. Coagulopathy
    Thrombocytopenia
    Bone marrow suppression
  9. Increased susceptibility to sepsis
    Decreased complement synthesis

d)  List 4 reasons why this woman might progress  to developing  respiratory failure.

This answer calls for differentials of respiratory failure in a semiconscious shocked woman with fever.

  • ARDS due to SIRS
  • Aspiration pneumonia
  • Decreased respiratory drive due to decreased level of consciousness
  • Pleural effusions due to hypoalbuminaemia / ascites
  • Intrapulmonary shunts - the so-called "hepatopulmonary syndrome" (very interesting to read about)

References

Bernal, William, et al. "Acute liver failure." The Lancet 376.9736 (2010): 190-201.

 

Fallon, Michael B., and Gary A. Abrams. "Pulmonary dysfunction in chronic liver disease." Hepatology 32.4 (2000): 859-865.

Question 2 - 2011, Paper 1

Answer the following questions about transjugular intrahepatic portosystemic shunts (TIPS):

a) What is a TIPS procedure and why is it used in patients with portal hypertension?

b) What are 2 recognised indications for this procedure?

c) Excluding mortality list 5 COMMON complications of TIPS procedure

d) Describe  one  classification  system  used  in assessing  severity  of chronic  liver disease and outline its utility.

College Answer

a) What is a TIPS procedure and why is it used in patients with portal hypertension?

The hepatic vein is accessed via the internal jugular vein and IVC. A needle is then passed to connect the hepatic vein with the large portal vein near the centre of the liver, the needle tract  dilated  and  a stent  inserted  to maintain  the tract and form  the shunt  between  the higher pressure portal vein and the lower pressure hepatic vein.   This reduces portal hypertension.

b) What are 2 recognised indications for this procedure?

a)     Variceal bleeding that has failed endoscopic and pharmacological treatment. b)  Refractory ascites

c) Excluding mortality list 5 COMMON complications of TIPS procedure

•   thrombosis
•   occlusion of the stent
•   capsular puncture
•   bleeding
•   encephalopathy
•   stent migration

d) Describe  one  classification  system  used  in assessing  severity  of chronic  liver disease and outline its utility.

Either: Childs-Pugh score
Classified A,B or C by a composite of Total bilirubin, albumin, INR, ascites and hepatic encephalopathy.  Originally  used for prognostication  for surgery  – also used for prognostication  in  chronic  liver  disease  and  prediction  of  likelihood  of  complications  of cirrhosis

Or: MELD score severity scoring system for assessing severity of chronic liver that uses the serum  bilirubin,  creatinine  and INR. Initially developed  to predict  three month survival  in patients post TIPS. Now used for prognosis of liver disease and prioritizing liver transplant recipients

Discussion

The first 3 parts of this question are reasonably straightforward.

  • TIPS is the transjugular intrahepatic portosystemic shunt, a conduit for portal venous blood to bypass the ineffective liver and thereby relieve portal hypertension.

Indications for TIPS:

Technical complications of TIPS:

  • Vascular access complications
  • Hepatic damage (through-and-through puncture): risk of intraperitoneal haemorrhage is 1-2%
  • Haemobilia (damage to the biliary tree)
  • Shunt stenosis or thrombosis (it happens in up to 70%)
  • Shunt migration
  • Hepatic vein stenosis (this can sabotage a future transplant)

Complications from portal venous shunting:

  • Worsening hepatic encephalopathy
  • Bilirubin rise: the diseased liver doesn't even get a chance to metabolise it
  • Ischaemic hepatitis: the liver gets much of its oxygen from the portal vein, and even in spite of the hepatic arterial buffer response there is a risk of ischaemic hepatitis.
  • Tricuspid endocarditis (organisms may now travel directly from the leaky gut into the systemic circulation)
  • Haemolysis (due to the direct shearing effect of being in contact with the shunt)
  • "Unmasked" cardiomyopathy: the TIPS returns splanchnic blood to the heart and acts as a volume challenge, and if there was pre-existing cardiomyopathy, it may be dramatically revealed in this manner.

The last part of the question is far from straightforward. How does one "briefly outline the utility" of something like the Childs-Pugh scoring system?

The system itself has existed since the 1970s, and it includes in its assessment the albumin level, the prothrombin time, the bilirubin, the presence of encephalopathy and the presence of ascites.

It seems the main point is prognosis. The utility of the scoring systems in general has been to estimate the expected lifespan of a cirrhosis patient, which has implications for liver transplantation. However, in the ICU, the overall mortality for cirrhosis patients is about 43%, irrespective of Childs-Pugh score. In general, SOFA and APACHE are better systems for predicting in-ICU mortality than the liver-specific scoring systems.

Thus, the answer to the "briefly outline utility" question should look like this:

Classification system:

  • Childs-Pugh scoring system for cirrhosis
  • Uses bilirubin, albumin, ascites, encephalopathy and INR to stratify the severity of cirrhosis according to risk of mortality and morbidity, particularly in the context of preoperative assessment

Its utility, briefly:

  • Pre-transplant risk stratification
  • Pre-TIPS risk stratification
  • Helps estimate prognosis in untreated liver disease
  • Does not discriminate survivors and non-survivors among cirrhosis patients admitted to ICU.

References

Ochs, Andreas, et al.New England Journal of Medicine 332.18 (1995): 1192-1197."The transjugular intrahepatic portosystemic stent–shunt procedure for refractory ascites." 

Guevara, Mónica, et al. "Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and vasoactive systems."Hepatology 28.2 (1998): 416-422.

Papatheodoridis, George V., et al. "Transjugular intrahepatic portosystemic shunt compared with endoscopic treatment for prevention of variceal rebleeding: A meta‐analysis." Hepatology 30.3 (1999): 612-622.

Azoulay, D., et al. "Transjugular intrahepatic portosystemic shunt (TIPS) for severe veno-occlusive disease of the liver following bone marrow transplantation." Bone marrow transplantation 25.9 (2000).

Ganger, Daniel R., et al. "Transjugular intrahepatic portosystemic shunt (TIPS) for Budd-Chiari syndrome or portal vein thrombosis." The American journal of gastroenterology 94.3 (1999): 603-608.

Freedman, A. M., et al. "Complications of transjugular intrahepatic portosystemic shunt: a comprehensive review." Radiographics 13.6 (1993): 1185-1210.

Angermayr, B., et al. "Child-Pugh versus MELD score in predicting survival in patients undergoing transjugular intrahepatic portosystemic shunt." Gut 52.6 (2003): 879-885.

Bazarah, Salem M., et al. "Utility of MELD and Child-Turcotte-Pugh scores and the Canadian waitlisting algorithm in predicting short-term survival after liver transplant." Clinical and investigative medicine 27 (2004): 162-167.

Singh, Nina, et al. "Outcome of patients with cirrhosis requiring intensive care unit support: prospective assessment of predictors of mortality." Journal of gastroenterology 33.1 (1998): 73-79.

Levesque, Eric, et al. "Prospective evaluation of the prognostic scores for cirrhotic patients admitted to an intensive care unit." Journal of hepatology 56.1 (2012): 95-102.

Question 29.2 - 2011, Paper 2

These are the biochemical results taken from a 48-year-old man, missing from an alcohol rehabilitation program and found in his home comatose by police three days from the time he was last seen.

Parameter

Patient Value

Normal Range

Sodium

126* mmol/l

138 – 145

Potassium

3.5 mmol/l

3.5 – 5.2

Creatinine

250*µmol/l

40– 100

Urea

7.0 mmol/l

3.1– 7.5

Bilirubin (total)

509*µmol/l

2–22

Protein (total)

40* g/l

65– 85

Albumin

20* g/l

38– 48

ALP

153* IU/l

40– 100

GGT

459* IU/l

0–50

ALT

336* IU/l

0 - 45

CK

400* IU/l

30– 180

Troponin

0.1 µg/l

0–0.3

Glucose

3.2* mmol/l

3.5– 4.6

Ammonia

342*µmol/l

0–50

Lactate

3.7* mmol/l

0.6– 2.4

a)  Given this presentation, list 3 possible causes of his altered conscious state?

b)  Interpret the biochemical abnormalities

College Answer

a)  Given this presentation, list 3 possible causes of his altered conscious state?

Alcohol intoxication

Hepatic encephalopathy 
Drug ingestion 
GI bleed

Sepsis 
Intracranial bleed

b)  Interpret the biochemical abnormalities

Liver dysfunction as demonstrated by elevated enzymes, reduced albumin, hypoglycaemia with decompensation indicated by marked elevation of ammonia. Hyponatraemia in keeping with cirrhosis. Raised lactate as a result of liver dysfunction / alcoholic ketoacidosis / sepsis / thiamine deficiency Raised creatinine indicates renal dysfunction and urea may be apparently “normal” because of decreased hepatic dysfunction and possible nutritional deficiencies. Urea:creatine ratio suggests that GI bleed and/or dehydration are unlikely

 

Discussion

This question interrogates the candidate's ability to generate a list of differential causes for a decreased level of consciousness in a person with chronic liver disease.

a)

Ok, the college has given us an alcoholic and put 342 µmol/l of ammonia into him.

Thus one of the differentials would have to be hepatic encephalopathy.

Given the extent of the other liver function abnormalities, and of course the borderline BSL, one could surmise that hypoglycaemia is another valid differential.

Being a drunk, alcohol intoxication is not out of the question.

One might wish to use the VINDICATE acronym to come up with some differentials.

  • V- Stroke
  • I- Sepsis
  • N- Seizures; hepatic encephalopathy
  • D- Drug intoxication (including alcohol)
  • I -
  • C-
  • A-
  • T- Intracerebral bleed, GI bleed
  • E- hyponatremia, hypoglycaemia

Fortunately, the college only asks for three answers. Hepatic encephalopathy, alcohol intoxication and sepsis seem the most likely, given the bloods.

b)  Interpret the biochemical abnormalities

  • Sodium is low due to the hypervolemic hyponatremia of cirrhosis
  • Creatinine is high potentially due to dehydration or hepatorenal syndrome.
  • Urea is normal likely due to nutritional deficiency or failure of the urea cycle. (so its probably not a GI bleed)
  • The LFTs are deranged in keeeping with a history of chronic liver disease, featuring a degree of synthetic failure (albumin of only 20) and hypoglycaemia.
  • The CK is only slightly elevated, suggesting seziures were probably not taking place before the police arrived
  • The lactate is raised, and there could be numerous reasons for this - but its likely either increased production due to sepsis or thiamine deficiency, combined with a decreased hepatic clearance.

There is some good material out there on the biochemical abnormalities of chronic liver disease, and their interpretation.

References

Chung, Raymond T., David L. Jaffe, and Lawrence S. Friedman. "Complications of chronic liver disease." Critical care clinics 11.2 (1995): 431-463.

 

Heidelbaugh, Joel J., and Michael Bruderly. "Cirrhosis and chronic liver failure: part II. Complications and treatment." American family physician 74.5 (2006).

Question 27 - 2012, Paper 1

A 40-year-old woman presents 7 days after a pan-colectomy for Crohn’s disease. She has a past history of antithrombin III deficiency. She has increasing abdominal pain and vomiting. There is marked tenderness in the right upper quadrant. An abdominal CT scan is performed.

  • What does the CT scan show?
  • What is the most likely cause for the appearances seen in the CT?
  • What are the causes of anti-thrombin III deficiency?
  • What further investigations would you order to help manage this lady’s condition?
  • What treatment would you order for this lady’s condition?

College Answer

a) CT Scan:

    • Extensive hypodense areas in liver consistent with hepatic infarction
    • Splenomegaly
    • Hypodense areas in spleen consistent with splenic infarcts
    • Free fluid in abdomen

b) Cause:

•  Portal venous thrombosis

c) Causes of anti-thrombin III deficiency:

•   Hereditary

•   Acquired

o Post-operative state

o Liver disease

o Disseminated intravascular coagulation

o Nephrotic syndrome

o Vasculitis

  • Further investigations:
    • Ultrasound of hepatic/abdominal vasculature.
    • ATIII activity on blood sample … Prothombotic screen also acceptable

e) Treatment:

    • Heparinisation
    • If there is heparin resistance or low ATIII activity, either antithrombin III concentrate or fresh frozen plasma.
    • Referral for advice regarding surgical (endovascular Vs open) options

Discussion

The CT scan I used was mined shamelessly from Google Images. It is not the one which appeared in the paper.

The first two parts of this question are straightforward.

The CT features of portal vein thrombosis are as follows:

  • Direct visualisation of the clot:
    • Usually seen as a hypodense filling defect in the portal vein lumen
    • The decreased density inside the portal vessels is best seen in the contrast phase
    • Non-contract CT will not pick this up: you need portal venous phase contrast enhanced studies.
    • You can also sometimes see enhancement of the walls of the portal vein, which is either dilated vasa vasorum or a thin film of contrast flowing around the obstruction
    • The thrombus itself should not enhance with contrast. If there is enhancement, particularly in the arterial phase, the thrombus is probably malignant in origin (i.e a HCC has eroded into the lumen).
  • Sequelae of portal vein obstruction:
    • Venous infarcts of the liver and spleen
    • Cavernous transformation of the portal vein (looks like a varicocele!)
    • Posrtosystemic collateral vessels and arterioportal shunts
    • Gut ischaemia
    • Ascites

The second half of the question requires detailed knowledge of AT-III deficiency. One can arrive at at least half of a sensible answer by logically asking why AT-III might not be present in sufficient quantities. Either you hereditarily fail to synthesise enough of it, or your liver is so damaged that it cannot produce enough. Or, it has been used up somehow, eg. in the context of DIC, MAHA, or in a bypass circuit. Lastly, it is possible that you are losing it along with other proteins via your leaky nephrotic kidneys.

The chapter which discusses thrombophilia screening tests contains within it this table, which lists the causes of AT-III deficiency with greater granularity.

Causes of Antithrombin III Deficiency

Inherited AT-III defects

  • Type I (reduced level)
  • Type II (functionally defective AT-III)
    • Reactive site defect
    • Heparin binding site defect
    • Pleiotropic effect mutations

Acquired 

Reduced production

  • Liver disease
  • Asparginase therapy (for ALL)
  • Oral contraceptive use
  • Preeclampsia or eclampsia

Loss of protein

  • Nephrotic syndrome
  • Plasmapheresis, replaced with albumin
  • Major surgery with extensive blood loss 
  • Heparin therapy (by increasing AT clearance)- however, this does not pose an increased thrombotic risk - only a false positive result on the thrombophilia screen

Increased consumption

  • Disseminated intravascular coagulation (DIC)
  • Acute thrombosis, eg. lage PE
  • Extracorporeal circuits, eg. ECMO and CRRT

The management of AT-III deficiency is, predictably, supplementation with AT-III. If the expensive purified factor is not available, FFP will suffice. Heparinisation for thrombosis actually will not work unless there is some antithrombin for the heparin to act upon.

Management options for PVT include the following:

  • Do nothing:  If the patient is asymptomatic, or if significant risks are associated with anticoagulation (eg. bleeding varices), one may also rely on portal cavernous transformation to divert venous flow around the thrombus. However, rate of spontaneous resolution is low (~ 17%).
  • Anticoagulate with heparin, LMWH or warfarin: Ideally, anticoagulation should be started in the first week (according to Basit et al, "Rate of recanalization is 69% if anticoagulation is started in the first week, but 25% if anticoagulation is started in second week").
  • Control portal venous hypertension: 
    • β-blockers, eg. propanolol
    • Diuretics, eg. spironolactone
    • TIPS procedure
    • Intraportal thrombolysis
    • Surgical thrombectomy

References

UpToDate offers a good article about Antithrombin III deficiency, for a price.

Beresford, C. H. "Antithrombin III deficiency." Blood reviews 2.4 (1988): 239-250.

Mathieu, Didier, Norbert Vasile, and P. Grenier. "Portal thrombosis: dynamic CT features and course." Radiology 154.3 (1985): 737-741.

Lee, Hae-Kyung, et al. "Portal vein thrombosis: CT features." Abdominal imaging 33.1 (2008): 72-79.

Denninger, Marie‐Hélène, et al. "Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors." Hepatology31.3 (2000): 587-591.\

Valla, Dominique-Charles, and Bertrand Condat. "Portal vein thrombosis in adults: pathophysiology, pathogenesis and management.Journal of hepatology 32.5 (2000): 865-871.

Boyer, Thomas D. "Management of portal vein thrombosis."Gastroenterology & hepatology 4.10 (2008): 699.

Basit, Syed Abdul, Christian D. Stone, and Robert Gish. "Portal vein thrombosis." Clinics in liver disease 19.1 (2015): 199-221.

Question 11 - 2012, Paper 2

A 42-year-old male is admitted to ICU following a cadaveric orthotopic liver transplant for end-stage liver disease secondary to alcohol-induced cirrhosis.

  • List the important management principles for the first 24 hours specific to this patient.
  • Despite weaning sedation he remains unresponsive 12 hours after ICU admission. What are the possible causes?
 

College Answer

a)

Haemodynamic stabilization – optimize cardiac output and tissue perfusion and avoid fluid overload as ventricular function may be impaired. Close haemodynamic monitoring. Vaso-active agents as indicated.

Correction of anaemia and coagulopathy – maintain haemocrit 0.25 – 0.3 to keep blood viscosity low. INR £2, APTT £50 secs, Fibrinogen above 0.5 g/L and Platelets above 30 x 109/L.

Fluid and electrolyte management – appropriate negative fluid balance day 1 decreases risk of pulmonary complications. Fluid overload may aggravate graft congestion and oedema caused by ischaemic-reperfusion. Electrolyte imbalances are common and need to be corrected.

Correction of metabolic abnormalities – hypoglycaemia is an ominous sign of compromised liver recovery, hyperglycaemia also may occur, acid-base abnormalities also occur

Early weaning from mechanical ventilation – associated with better outcome but not feasible in patients with respiratory failure, haemodynamic instability, pulmonary oedema, primary graft dysfunction, encephalopathy etc. Unsucessful early extubation may result in impaired oxygen delivery to transplanted liver

Monitoring of graft function LFTs, lactate, BSL, coagulation, hepatic artery doppler

Early detection of surgical complications - bleeding

Immunosuppressants

Infection prophylaxis

Housekeeping including analgesia (PCA) and appropriate nutrition plan

Other – ICP monitoring if decompensated CLD pre-op

b)

Delayed metabolism of sedative / anaesthetic drugs

Metabolic derangements – hypoglycaemia, hyponatraemia, hyperosmolar syndrome

Hepatic encephalopathy

Hypoxic-ischaemic cerebral injury

Seizures

Intracerebral haemorrhage

Discussion

This is a delicate topic for anybody who has not had the privilege of working in one of the sandstone centres of excellence, where liver transplants for the rich and famous serve as a constant source of private funding and media attention.

Thus, let there be a brief digression into the specifics of managing a post-op orthotopic liver transplant patient in the ICU.

(Incidentally, for those like me who were unsure precisely what the long words mean, "orthotopic" transplantation is the total removal of the old diseased liver, and the implantation of the donated organ into the same anatomical position).

The above link points to a scanned document from the Atlas of Organ Transplantation, which deals extensively with the pre-operative and peri-operative management of liver transplantation, detailing such interesting time intervals as "the Anhepatic stage". It however, is more aimed at the surgeons. Because the quality of the scanner leaves much to be desired, the gory pictures of open livers are just black-and-white blurs.

However, there is plenty of literature regarding the critical care management of liver transplant recipients.

Let us approach this answer systematically.

  • Airway:
    • Historically these patients tend to remain intubated for the first 12-24 hours, although there is good evidence that early extubation (eg. in theatre) has no adverse effects.
  • Breathing:
    • In order for the graft to survive normoxia must be established
    • The general "word of mouth" advice in these situations is to minimise the PEEP. In order for the anastomoses to remain intact, PEEP should be minimised, as it will increase the CVP and thus compromise the venous vascular anastomotic sites. However, some studies have reported no significant change to the hepatic venous flow even with PEEP as high as 15cm H2O.
    • Positive pressure ventilation in general is a bad idea, as organ perfusion is decreased by positive pressure, and perfusion of the donated liver is very important in the early stages.
    • Thus, early weaning from invasive ventilation is one of the major goals
  • Circulation
    • There is likely to be a degree of shock. Given that fluid management must remain relatively conservative, vasopressors and inotropes must be deployed liberally. After all, the graft needs to remain perfused.
    • Hepatic oedema due to over-resuscitation should be avoided.
    • Arbitrarily, the CVP should remain within the range of 6-10.
    • Observe for reactive vasoconstriction
      • These patients, with heir dead livers, have been in a vasodilated state, associated with nitric oxide synthase hyperactivity.
      • Now, with their new livers, normal vascular tone will return.
      • This might mean a sudden massive increase in the afterload.
      • Thus, their left ventricles, which are chronically deconditioned, might decompensate when faced with such demands.
      • Thus, GTN or nitroprusside infusions should be used liberally in these people.
    • The need for RF and LV functional assessment as well as pulmonary arterial pressure measurements and
  • Neurology and sedation
    • No specific recommendations can be made, rather than to say that both hepatic and renal dysfunction in the post-operative period is to be anticipated, and thus drugs which do not rely on organ metabolism should be used. Remifentanyl and propofol spring to mind.
  • Fluids and electrolytes
    • There is some "magical" preload at which the CVP is reasonable, preload adequate, and cardiac output satisfactory. Finding this magic preload is something of an art.
    • Initially, fluid resuscitation should take place, but the fluid of choice should not be Hartmanns because the new liver will probably not be able to metabolise the lactate.
    • After the initial post-operative resuscitation phase is over, a negative fluid balance should be pursued; generating a lower pressure in the right side of the thoracic circulation will serve to draw blood from the graft, and thus theoretically should improve graft perfusion.
    • Renal function needs to be watched closely - renal failure is associated with poor graft survival.
  • Graft function
    • There is a phase of "preservation injury" with very high LFTs but this tends to disappear over the first 3-4 days. Thereafter, synthetic function should be restored.
    • Monitoring of the graft consist of several sequential assessments:
      • Hepatic arterial Doppler
      • BSL
      • Lactate
      • Bilirubin
    • Typically, 1-9% of liver transplants fail within hours of surgery.
  • Surveillance for abdominal compartment syndrome
    • Due to the extensive nature of the procedure and due to the preexisting portal venous pathology, this issue (with pressure over 25mmHg) is fairly common.
    • Abdominal girth values are required as sequential measurements.
  • Nutritional support
    • There is no string reason to recommend TPN here. Like in most other situation, nasogastric enteral feeding is probably best. A degree of ileus is to be expected, and usually resolves
  • Hematological support
    • This consists of the replacement of missing blood products and blood cells.
    • Essentially, there is no specific hemoglobin goal, and what you are trying to do is prevent bleeding from the anastomotic sites.
    • Its probably OK to be slightly coagulopathic, because you don't want to develop a hepatic arterial thrombus.
  • Immune suppression
    • I will not litter this summary with discussion of the relative merits of each class of antirejection drug. Suffice to say, cyclosporin tacrolimus and mycophenolate are gradually giving way to monoclonal antibodies and other immunomodulator drugs which have slightly less devastating organ system effects.
  • Antibiotics and sepsis surveillance
    • Many of these patients die from postoperative infectious complications
    • 48 hrs of IV antibiotics are typically administered
    • The Sanford Guide recommends linezolid, ciprofloxacin and fluconazole.
    • The belowlinked article from 2011 also suggests 14 days of aciclovir, given the propensity for embarrassing HSV reactivation.

The second part of this question is far less interesting, and refers mainly to the candidate's ability to generate differentials for a decreased level of consciousness.

Using a usual template, one can arrive at a series of differential easily:

  • Vascular causes, eg. stroke or hypoxic brain injury
  • Infectious causes, eg. reactivated HSV or CMV encephalitis
  • Drug-related causes, eg. slow metabolism of anaesthetic drugs reliant on hepatic clearance
  • Hepatic encephalopathy
  • Haematological, eg. intracranial bleeding due to coagulopathy
  • Electrolyte disturbances, for instance cerebral oedema due to hyponatremia
  • Endocrine disturbance eg. hypoglycaemia

References

The best, most comprehensive source is this article:

Feltracco, Paolo, et al. "Intensive care management of liver transplanted patients." World journal of hepatology 3.3 (2011): 61.

The rest are also helpful.

Stieber, Andrei C., R. D. Gordon, and J. R. Galloway. "Orthotopic liver transplantation." Hepatology. A text book of liver disease. WB Saunders, Philadelphia (1996): 1759-1780.

Mazariegos, George V., Ernesto P. Molmenti, and David J. Kramer. "Early complications after orthotopic liver transplantation." Surgical Clinics of North America 79.1 (1999): 109-129.

Razonable, Raymund R., et al. "Critical care issues in patients after liver transplantation." Liver Transplantation 17.5 (2011): 511.

Mandell, M. Susan, et al. "Reduced use of intensive care after liver transplantation: influence of early extubation." Liver Transplantation 8.8 (2002): 676-681.

Question 14 - 2012, Paper 2

Critically evaluate the role of the following investigations in the critically ill patient:

  1. Serum ammonia
  2. B-type natriuretic peptide (BNP)
 

College Answer

  • Serum Ammonia
    • Used as an indicator of hepatic encephalopathy
    • Normal values do not rule out encephalopathy – therefore of limited utility in patients with known chronic liver disease
    • Not useful as a monitor during therapy
    • Very high levels may indicate cerebral herniation
    • May be useful to indicate undiagnosed cirrhosis in patients presenting with altered mental status
    • May also be elevated in: TPN, GI Bleed and steroid use, portosytemic shunts and inborn errors of metabolism.
  • B-type natriuretic peptide (BNP)
    • Released from cardiac cells in response to ventricular wall distension
    • Elevated in heart failure
    • Can be used as a diagnostic marker in patients presenting with dyspnoea to emergency department, and can be useful prognostically and to guide therapy in heart failure
    • May be elevated in many other conditions in critical care, including sepsis, acute lung injury, PE and intracranial bleed
    • Interpretation of BNP in ICU patients is therefore complex and while it may have a role in prognosis and response to therapy in future its current place is unclear.

Discussion

This question was quite arbitrarily placed into the gastroenterology section, on no grounds other than the interesting association of ammonia with various metabolic disturbances, versus the rather boring association of BNP with heart failure.

The question asks us to "critically evaluate", which means a certain systematic approach. I note that this approach was not used in the college answer.

The use of ammonia levels in critical care:

  • Introduction:
    • Ammonia is a metabolic byproduct of amino acid catabolism; there has been interest in measuring ammonia levels and making attempts to associate them with various forms of pathology.
  • Rationale:
    • The most prolific site of production of ammonia ions is in the gut, where amino acids are converted into ammonia by gut microflora. The ammonia is then absorbed into the portal circulation and converted into urea in the hepatic urea cycle.
    • Hepatic damage and the failure of the urea cycle is therefore usually associated with a rise in the serum ammonia levels
    • The normal compensatory responses to raised serum ammonia (eg. conversion into glutamine) can give rise to cerebral oedema and thus is thought to play some role in the pathogenesis of hepatic encephalopathy
    • Other causes of raised ammonia levels include
      • Increased rates of protein catabolism, eg. extreme starvation or hematological malignancy
      • TPN
      • Inherited errors of metabolism
  • Evidence:
  • Summary:
    • The use of ammonia to assess the severity of hepatic encephalopathy is still controversial
    • a raised ammonia level may point to an undiagnosed error of metabolism in a patient with an otherwise unexplainable loss of consciousness

The use of BNP levels in critical care:

  • Introduction:
    • BNP is a peptide released by stressed atria which has been a tempting target of laboratory analysis in determining the aetiology of breathlessness in the acutely distressed patient
  • Rationale
    • BNP (brain natriuretic peptide) is a 32-amino acid peptide released by the human atria and ventricles in response to distending pressure. In spite of its name, its presence in the human brain is rather minimal- it was first identified in porcine brain tissue, where for some reason it is concentrated. BNP is a peptide which has natriuretic and diuretic actions in the renal tubule, and is though to be a part of the natural homeostatic mechanisms which work in defence of normal intravascular volume.
    • Thus, a raised BNP, suggesting increased atrial stretch, may be a serum marker which may differentiate cardiac failure and pulmonary oedema from respiratory infection in situations when both are equally likely on the basis of history and examination.
    • The classical patient for such serology would be the elderly lady or gentleman with severe COPD and CCF, who presents to the ED with shortness of breath, wheeze, fever, and clinical features of fluid overload.
    • It may also be a useful serum marker to guide the management of heart failure
  • Evidence:
  • Summary:
    • BNP is a non-specific marker of atrial and ventricular strain, and has limited diagnostic utility. Its role in treatment monitoring and risk stratification remains to be established.

References

Clay, Alison S., and Bryan E. Hainline. "Hyperammonemia in the ICU." CHEST Journal 132.4 (2007): 1368-1378.

Ong, Janus P., et al. "Correlation between ammonia levels and the severity of hepatic encephalopathy." The American journal of medicine 114.3 (2003): 188-193.

McKinney, A. M., et al. "Acute hepatic (or hyperammonemic) encephalopathy: diffuse cortical injury and the significance of ammonia." American Journal of Neuroradiology 32.7 (2011): E142-E142.

Richter, Derek, and Rex MC Dawson. "The ammonia and glutamine content of the brain." Journal of Biological Chemistry 176.3 (1948): 1199-1210.

Summar, Marshall L., et al. "Unmasked adult-onset urea cycle disorders in the critical care setting." Critical care clinics 21.4 (2005): S1-S8.

Troughton, Richard W., et al. "Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations." The Lancet355.9210 (2000): 1126-1130.

McCullough, Peter A., et al. "B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure analysis from Breathing Not Properly (BNP) multinational study."  Circulation 106.4 (2002): 416-422.

Hall, Christian. "Essential biochemistry and physiology of (NT-pro) BNP."European Journal of Heart Failure 6.3 (2004): 257-260.

Silver, Marc A., et al. "BNP Consensus Panel 2004: A clinical approach for the diagnostic, prognostic, screening, treatment monitoring, and therapeutic roles of natriuretic peptides in cardiovascular diseases." Congestive Heart Failure 10.s5 (2004): 1-30.

Jefic, Dane, et al. "Utility of B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide in evaluation of respiratory failure in critically ill patients."CHEST Journal 128.1 (2005): 288-295.

Karmpaliotis, Dimitri, et al. "Diagnostic and prognostic utility of brain natriuretic Peptide in subjects admitted to the ICU with hypoxic respiratory failure due to noncardiogenic and cardiogenic pulmonary edema." CHEST Journal 131.4 (2007): 964-971.

Demir, Ali, et al. "The value of Serum BNP for diagnosis of intracranial injury in minor head trauma." World journal of emergency surgery 9.1 (2014): 16.

Li, Nan, et al. "BNP and NT-proBNP levels in patients with sepsis.Ront Biosei18 (2013): 1237-1243.

Mitaka, Chieko, et al. "Increased plasma concentrations of brain natriuretic peptide in patients with acute lung injury." Journal of critical care 12.2 (1997): 66-71.

Kucher, Nils, Gert Printzen, and Samuel Z. Goldhaber. "Prognostic role of brain natriuretic peptide in acute pulmonary embolism." Circulation 107.20 (2003): 2545-2547.

Meyer, Brigitte, et al. "511: Nt-Pro-Bnp Is A Strong Predictor of Outcome in Critically Ill Patients Admitted to the Icu After Cardiac Surgery." Critical Care Medicine 39.12 (2011): 141.

Yardan, T., et al. "B-type natriuretic peptide as an indicator of right ventricular dysfunction in acute pulmonary embolism." International journal of clinical practice 62.8 (2008): 1177-1182.

Question 10.2 - 2014, paper 2

These are the biochemical results taken from a 48-year-old male, missing from an alcohol rehabilitation program and found in his home, comatose, by police, three days from the time he was last seen.

Parameter Patient Value Normal Adult Range
Sodium 126 mmol/L* 138 – 145
Potassium 3.5 mmol/L 3.5 – 5.0
Creatinine 250 μmol/L* 40 – 100
Urea 7.0 mmol/L 3.1 – 7.5
Bilirubin (total) 509 μmol/L * 2.0 – 22.0
Protein (total) 40 g/L* 65 – 85
Albumin 20 g/L* 38 – 48
Alkaline phosphatase (ALP) 153 IU/L* 40 – 100
Gamma glutamyl transferase (GGT) 459 IU/L* 0 – 50
Alanine aminotransferase (ALT) 336 IU/L* 0 – 45
Creatine kinase (CK) 400 IU/L* 30 – 180
Glucose 3.2 mmol/L* 3.5 – 4.6
Ammonia 342 μmol/L 0 – 50
Lactate 3.7 mmol/L* 0.6 – 2.4

a) Comment, with explanation, on each of the biochemical abnormalities.

b) List three possible causes of his altered conscious state.

College Answer

a) Comment, with explanation, on each of the biochemical abnormalities.

Liver dysfunction as demonstrated by elevated enzymes, reduced albumin. Hypoglycaemia with decompensation indicated by marked elevation of ammonia. Hyponatraemia in keeping with cirrhosis.

Raised lactate as a result of liver dysfunction / alcoholic ketoacidosis / sepsis / thiamine deficiency
Raised creatinine indicates renal dysfunction and urea may be apparently “normal” because of
decreased hepatic dysfunction and possible nutritional deficiencies. Urea:creatinine ratio suggests
that GI bleed and/or dehydration are unlikely

b) List three possible causes of his altered conscious state.

  • Alcohol intoxication
  • Hepatic encephalopathy
  • Drug ingestion
  • Sepsis
  • Intracranial bleed
  • Wernickes encephalopathy

Discussion

This question is nearly identical to Question 29.2 from the second paper of 2011. The answer to that question is also duplicated here, to simplify revision

The following is a list of biochemical abnormalities and plausible explanations for them:

  • Sodium is low due to the hypervolemic hyponatremia of cirrhosis
  • Creatinine is high potentially due to dehydration or hepatorenal syndrome.
  • Urea is normal likely due to nutritional deficiency or failure of the urea cycle. (so its probably not a GI bleed)
  • The LFTs are deranged in keeeping with a history of chronic liver disease, featuring a degree of synthetic failure (albumin of only 20) and hypoglycaemia.
  • Features of synthetic liver failure are present:
    • Ammonia is elevated.
    • Albumin is low.
    • Total protein is low.
    • Bilirubin is high
  • The CK is only slightly elevated, suggesting seziures were probably not taking place before the police arrived
  • The lactate is raised, and there could be numerous reasons for this - but its likely either increased production due to sepsis or thiamine deficiency, combined with a decreased hepatic clearance.
 

The college asks for three possible causes of unconsciousness in this comatose drunk. Three only. The most relevant ones would have to be

  • Hepatic encephalopathy
  • Alcohol intoxication
  • Sepsis

A possible list of differentials would have to also include the following:

  • V- Stroke
  • I- Septic encephalopathy
  • N- Seizures
  • D- Drug intoxication
  • I -
  • C-
  • A-
  • T- Intracerebral bleed, GI bleed
  • E- hyponatremia, hypoglycaemia

References

Johnston, David E. "Special considerations in interpreting liver function tests." American family physician 59 (1999): 2223-2232.

Limdi, J. K., and G. M. Hyde. "Evaluation of abnormal liver function tests." Postgraduate medical journal 79.932 (2003): 307-312.

Hoekstra, Lisette T., et al. "Physiological and biochemical basis of clinical liver function tests: a review." Annals of surgery 257.1 (2013): 27-36.

Giannini, Edoardo G., Roberto Testa, and Vincenzo Savarino. "Liver enzyme alteration: a guide for clinicians." Canadian medical association journal 172.3 (2005): 367-379.

Kim, W., et al. "Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease." Hepatology 47.4 (2008): 1363-1370.

Pratt, Daniel S., and Marshall M. Kaplan. "Evaluation of abnormal liver-enzyme results in asymptomatic patients." New England Journal of Medicine 342.17 (2000): 1266-1271.

Whitfield, J. B. "Gamma glutamyl transferase." Critical reviews in clinical laboratory sciences 38.4 (2001): 263-355.

Balistreri, William F., et al. "Intrahepatic cholestasis: Summary of an American Association for the Study of Liver Diseases single‐topic conference." Hepatology 42.1 (2005): 222-235.

Assy, N., et al. "Diagnostic approach to patients with cholestatic jaundice." World journal of gastroenterology 5.3 (1999): 252-262.

Stellpflug, Samuel J. "Transaminitis: The Lab Test That Has Inflammation…." Journal of Medical Toxicology 7.3 (2011): 252-253.

Question 14 - 2014, paper 2

A 43-year-old female with a history of paranoid schizophrenia and multiple episodes of selfharm, presented to the Emergency Department with decreased conscious state. She had been seen three days earlier for possible worsening of her psychosis and discharged home.

Her haematology and biochemistry results at both presentations are as follows:

Parameter Patient Value Normal Adult Range
1st Presentation 2nd Presentation
Haemoglobin  134 g/L 135 g/L 115 – 160
White cell count  12.6 x 109 /L* 7.5 x 109/L 4.0 – 11.0
Platelet count  250 x 1012/L 76 x 1012/L* 150 – 400
Prothrombin time    40.0 seconds* 12.3 – 16.6
International Normalised Ratio (INR)   4.1* 0.9 – 1.3
Activated partial thromboplastin time (APTT)    35.0 seconds 27.0 – 38.5
Fibrinogen    1.8 g/L* 2.0 – 4.0
 
Sodium  139 mmol/L 136 mmol/L 134 – 146
Potassium  3.6 mmol/L 4.6 mmol/L 3.4 – 5.0
Bicarbonate 18 mmol/L* 21 mmol/L* 22 – 32
Urea 5.0 mmol/L 18.9 mmol/L* 3.0 – 8.0
Creatinine  56 µmol/L 448 µmol/L* 45 – 90
Bilirubin total  6.0 µmol/L 81 µmol/L* < 20
Alanine aminotransferase (ALT)  31 U/L 11700 U/L* < 35
Alkaline phosphatase (ALP)  88 U/L 245 U/L* 35 – 135
Gamma glutamyl transferase (GGT)  13 U/L 104 U/L* < 40
Lactate    4 mmol/L < 1.5
 
Paracetamol    < 10 mg/L 10 mg/L
Urine Ethanol    Not detected  
Urine Amphetamines    Not detected  
Urine Benzodiazepines    Detected  
Urine Cannabinoids    Not detected  
Urine Opiates   Not detected  

a) What is the underlying diagnosis?

b) List the possible causes in this patient.

c) Outline your immediate management.

College Answer

a) What is the underlying diagnosis?

Hyperacute (fulminant) hepatic failure

b) List the possible causes in this patient.

Paracetamol
Idiosyncratic drug reaction
Other toxin e.g. Amanita phalloides
Viral (hepatitis A and E as hyperacute consider B, CMV, Epstein Barr)
Ischaemic hepatitis
Budd-Chiari

c) Outline your immediate management.

Concurrent resuscitation and institution of supportive care and monitoring with focussed assessment
to identify underlying cause and definitive management as indicated.

Airway management and oxygen – likely to need intubation and mechanical ventilation with
ARDSNet targets and PCO2 32-38 mmHg

Haemodynamic support for adequate MAP and CPP >60 and appropriate monitoring (A-line,
PAC/PiCCO, bedside echo etc.). Avoid fluid overload

Strategies to offset cerebral oedema (head-up, neutral position, sedation, PCO2 targets, Na 145-155
etc.) 

ICP monitoring controversial

Consider renal replacement therapy
Extracorporeal albumin dialysis therapies (SPAD, MARS and Prometheus) have limited evidence to
support use

Monitoring of coagulopathy using TEG/ROTEM to guide correction. Correction to cover invasive
procedures or if bleeding otherwise not.

Monitor blood glucose

Screening for infection and antibiotics as indicated +/- empiric broad spectrum cover including antifungal

Stress ulcer prophylaxis

Nutrition

Specific 
NAC
Lactulose / Neomycin / Rifaximin controversial and use varies from unit to unit

Investigations including liver USS, viral screen

Discussion with liver transplant team / transfer to ICU with liver unit (does not currently meet
transplantation criteria)

Discussion

The diagnosis is clearly liver failure. The college further qualify their description as "fulminant". That term is very 1990s. What makes a liver failure fulminate? Well, apparently that just means it is acute (see Sass et al, 2005). The term was originally applied to patients in whom encephalopathy developed within two weeks of the development of jaundice. These days, the terminology we use is hyparcute (0-7 days), acute (8-28 days) and subacute  (29 days to 8 weeks). The disorders were redefined by Williams et al in 1993, on the basis of the fact that they correlate better with survival statistics (paradoxically, the hyperacute ones do much better).

Possible categories of the causes:

Vascular:

  • Right heart failure
  • Hepatic arterial ischaemia (eg. due to either global ischaemia, or due to an embolic event)
  • Hepatic venous insufficiency (Budd-Chiari syndrome)
  • Veno-occlusive disease (eg. post bone marrow transplant)

Infectious:

  • Hepatitis A, B and C
  • Hepres simlex
  • Cytomegalovirus
  • Varicella

Neoplastic:

  • Colonic carcinoma metastases
  • Hepatocellular carcinoma
  • Lymphoma

Drug-induced:

  • Paracetamol
  • Alcohol
  • Kava-kava
  • Tuberculosis antibiotics
  • Amanita phalloides mushroom
  • Cocaine (by ischaemia)
  • Solvents: xylene, chloroform, trichloroethylene, carbon tetrachloride
  • MDMA

Idiopathic: idiosyncratic drug reactions:

  • Anticonvulsants
  • NSAIDs
  • Aspirin in children (Reye's syndrome)

Congenital:

  • Wilson's disease

Autoimmune:

  • Haemophagocytic syndrome
  • Vasculitic hepatitis

Traumatic:

  • Crush injury to the liver
  • Capsular hematoma
  • Disruption of hepatic vessels
  • Hyperthermia-induced liver injury

Endocrine/metabolic:

  • Acute fatty liver of pregnancy
  • HELLP syndrome
  • Pregnancy-associated liver rupture

Of these, the following short list is relevant. However, it must be added that the college did not specify how many differentials they wanted. You could have brought up your various azathiprine-induced hepatitis and Amanita phalloides mushrooms.

Thus:

  • Hepatic ischaemia
  • Acute viral hepatitis or liver abscess
  • Acute right heart failure due to PE
  • Drug-induced hepatitis eg. paracetamol overdose (or Amanita)
  • Autummune hepatitis, eg. cryptogenic cirrhosis or idiopathic autoimmune hepatitis (IAIH)
  • Traumatic hepatic injury due to fall

Management

As with most things, management falls into the category of specific management and supportive management. Specific management may be viewed as a series of antidotes or proven solutions tailored to specific causes of the liver failure.

Paracetamol overdose

N-acetylcystine

Wilson's disease (chronic)

Copper chelating agents

Hepatic vein thrombosis

Thrombolysis / clot retrieval;

TIPS procedure

Hepatitis viruses

Antiviral drugs

Autoimmune hepatitis

Steroids may be helpful... or may be harmful.

Alcoholic hepatitis

Steroids are probably helpful

Valproate overdose

L-carnitine, and probably also dialysis to extract the excess ammonia

Amanita phalloides

Haemopherfusion may remove the phallotoxins

A discussion of supportive management might take the following shape:

  1.  Intubate the patient for airway protection, as they will be obtunded (and to control the CO2)
  2. Hyperventilation to low-normal PaCO2 (35 mmHg)
  3. Maintain haemodynamic stability using noradrenaline preferentially.
  4. Use propofol instead of benzodiazepines, and avoid long-acting opiates.
    Consider an ICP monitor
  5. Hypothermia to a temperature of 32-33°
    Hypernatremia (to control ICP, with hypertonic saline) to achieve a sodium of 145-155 mmol/L
  6. Haemodiafiltration - continuously - to remove ammonia
  7. Anticipate hypoglycaemia.
  8. Anticipate coagulopathy.
    Administer Vitamin K empirically.
    Consider blood products, but view complete correction as unobtainable.
  9. Vigilant surveillance for sepsis: they are prone to it, and it makes the encephalopathy worse

References

​Sass, David A., and A. Obaid Shakil. "Fulminant hepatic failure." Liver Transplantation 11.6 (2005): 594-605.

Williams, R., S. W. Schalm, and J. G. O'Grady. "Acute liver failure: redefining the syndromes." The Lancet 342.8866 (1993): 273-275.

Chapter 44   (pp. 501) Liver  failure by Christopher  Willars  and  Julia  Wendon

Daly, Frank FS, et al. "Guidelines for the management of paracetamol poisoning in Australia and New Zealand-explanation and elaboration." Medical journal of Australia 188.5 (2008): 296.

Bailey, Benoit, René Blais, and Anne Letarte. "Status epilepticus after a massive intravenous N-acetylcysteine overdose leading to intracranial hypertension and death." Annals of emergency medicine 44.4 (2004): 401-406.

Parsons-Smith, B. G., et al. "The electroencephalograph in liver disease." The Lancet 270.7001 (1957): 867-871.

Ramos, Juan Francisco Rivera, and Celina Rodríguez Leal. "Review of the final report of the 1998 Working Party on definition, nomenclature and diagnosis of hepatic encephalopathy." Ann Hepatol 10 (2011): S36-S39.

Walsh, Timothy S., et al. "Energy expenditure in acetaminophen-induced fulminant hepatic failure." Critical care medicine 28.3 (2000): 649-654.

Ichai, Philippe, et al. "Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis." Liver transplantation 13.7 (2007): 996-1003.

O’Grady, John G., et al. "Early indicators of prognosis in fulminant hepatic failure." Gastroenterology 97.2 (1989): 439-445.

Dhiman, Radha K., et al. "Early indicators of prognosis in fulminant hepatic failure: An assessment of the Model for End‐Stage Liver Disease (MELD) and King's College Hospital Criteria." Liver transplantation 13.6 (2007): 814-821.

Yantorno, Silvina E., et al. "MELD is superior to King's college and Clichy's criteria to assess prognosis in fulminant hepatic failure." Liver transplantation13.6 (2007): 822-828.

Wiesner, Russell, et al. "Model for end-stage liver disease (MELD) and allocation of donor livers." Gastroenterology 124.1 (2003): 91-96.

Gleisner, Ana L., et al. "Survival benefit of liver transplantation and the effect of underlying liver disease." Surgery 147.3 (2010): 392-404.

Ding, G. K. A., and N. A. Buckley. "Evidence and consequences of spectrum bias in studies of criteria for liver transplant in paracetamol hepatotoxicity." QJM101.9 (2008): 723-729.

Lee, William M., R. Todd Stravitz, and Anne M. Larson. "Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011." Hepatology 55.3 (2012): 965-967.

McPhail, Mark JW, Julia A. Wendon, and William Bernal. "Meta-analysis of performance of Kings’s College Hospital Criteria in prediction of outcome in non-paracetamol-induced acute liver failure." Journal of hepatology 53.3 (2010): 492-499.

Stravitz, R. Todd, et al. "Intensive care of patients with acute liver failure: recommendations of the US Acute Liver Failure Study Group." Critical care medicine 35.11 (2007): 2498-2508.

Warrillow, S. J., and R. Bellomo. "Preventing cerebral oedema in acute liver failure: the case for quadruple-H therapy." Anaesthesia and intensive care 42.1 (2014): 78.

Question 3.1 - 2015, Paper 2

A 35-year-old female with no known previous medical history presents to the emergency department with a decreased conscious level.

The following results are obtained

Venous Biochemistry

Parameter

Patient Value

Normal Adult Range

Sodium

144 mmol/L

135 – 145

Potassium

4.0 mmol/L

3.5 – 4.5

Chloride

100 mmol/L

95

105

Bicarbonate

14 mmol/L*

22

26

Glucose

1.1mmol/L*

3.5 – 6.1

Urea

2.7 mmol/L

2.9 – 8.2

Creatinine

120 μmol/L

70

120

Albumin

46 g/L

35

55

Total bilirubin

90 μmol/L*

< 20

Alkaline phosphatase (ALP)

131 U/L*

36

92

Aspartate aminotransferase (AST)

2450 U/L*

< 40

Gamma glutamyl transferase (GGT)

50 U/L*

< 30

Alanine aminotransferase  (ALT)

2750 U/L*

< 35

Coagulation Tests

Parameter

Patient Value

Normal Adult Range

PT

45 sec*

12

16

APTT

46 sec*

25.0

– 37.0

Fibrinogen

0.2 g/ L*

2.20

– 4.30

a)  Give one diagnosis which will explain the clinical and laboratory findings.    (10% marks)
b)  List six possible aetiologies.                    (20% marks)

College Answer

a)    

  • Acute liver failure

b)

  • Toxins – paracetamol, alcohol, mushrooms. Viral hepatitis – hep A,B,C,D,E, EBV,CMV
  • Idiosyncratic drug reaction
  • Ischaemic hepatitis due to shock – cardiogenic, septic. Acute fatty liver of pregnancy.
  • Congenital/genetic - Wilson’s disease. Hyperthermia - Heat stroke.
  • Autoimmune hepatitis. Budd-chiari syndrome.
  • Malignant hepatic infiltrations – breast cancer, lung cancer, melanoma, lymphoma, myeloma.

Discussion

Well, you can't call it "acute liver failure" or "hyper-acute" or subacute" because these have specific time intervals as definitions. All you can really say is that there is liver failure. The college gives malingant infiltration as a differential, which gives one the impression that they would be willing to consider the more insidious causes of liver damage.

Possible categories of the causes:

Vascular:

  • Right heart failure
  • Hepatic arterial ischaemia (eg. due to either global ischaemia, or due to an embolic event)
  • Hepatic venous insufficiency (Budd-Chiari syndrome)
  • Veno-occlusive disease (eg. post bone marrow transplant)

Infectious:

  • Hepatitis A, B and C
  • Hepres simlex
  • Cytomegalovirus
  • Varicella

Neoplastic:

  • Colonic carcinoma metastases
  • Hepatocellular carcinoma
  • Lymphoma

Drug-induced:

  • Paracetamol
  • Alcohol
  • Kava-kava
  • Tuberculosis antibiotics
  • Amanita phalloides mushroom
  • Cocaine (by ischaemia)
  • Solvents: xylene, chloroform, trichloroethylene, carbon tetrachloride
  • MDMA

Idiopathic: idiosyncratic drug reactions:

  • Anticonvulsants
  • NSAIDs
  • Aspirin in children (Reye's syndrome)

Congenital:

  • Wilson's disease

Autoimmune:

  • Haemophagocytic syndrome
  • Vasculitic hepatitis

Traumatic:

  • Crush injury to the liver
  • Capsular hematoma
  • Disruption of hepatic vessels
  • Hyperthermia-induced liver injury

Endocrine/metabolic:

  • Acute fatty liver of pregnancy
  • HELLP syndrome
  • Pregnancy-associated liver rupture

References

Question 9 - 2015, Paper 2

A 42-year-old male is admitted to ICU following a cadaveric orthotopic liver transplant for end-stage liver disease secondary to alcohol-induced cirrhosis.

a)    List the important management principles for the first 24 hours specific to this patient. (70% marks)

b)    Despite weaning sedation he remains unresponsive 12 hours after ICU admission. What are the possible causes? (30% marks)

College Answer

a)

Haemodynamic stabilization – optimize cardiac output and tissue perfusion and avoid fluid overload as ventricular function may be impaired. Close haemodynamic monitoring. Vaso-active agents as indicated.

Correction of anaemia and coagulopathy – maintain haemocrit 0.25 – 0.3 to keep blood viscosity low. INR 2, APTT 50 secs, Fibrinogen above 0.5 g/L and Platelets above 30 x 109/L.

Fluid and electrolyte management – appropriate negative fluid balance day 1 decreases risk of pulmonary complications. Fluid overload may aggravate graft congestion and oedema caused by ischaemic-reperfusion. Electrolyte imbalances are common and need to be corrected.

Correction of metabolic abnormalities – hypoglycaemia is an ominous sign of compromised liver recovery, hyperglycaemia also may occur, acid-base abnormalities also occur

Early weaning from mechanical ventilation – associated with better outcome but not feasible in patients with respiratory failure, haemodynamic instability, pulmonary oedema, primary graft dysfunction, encephalopathy etc. Unsuccessful early extubation may result in impaired oxygen delivery to transplanted liver

Monitoring of graft function LFTs, lactate, BSL, coagulation, hepatic artery doppler

Early detection of surgical complications - bleeding

Immunosuppressants

Infection prophylaxis

Housekeeping including analgesia (PCA) and appropriate nutrition plan

Other – ICP monitoring if decompensated CLD pre-op

b)

Delayed metabolism of sedative / anaesthetic drugs

Metabolic derangements – hypoglycaemia, hyponatraemia, hyperosmolar syndrome Hepatic encephalopathy

Hypoxic-ischaemic cerebral injury

Seizures

Intracerebral haemorrhage

Discussion

This question is essentially identical to Question 11 from the second paper of 2012. The answer has been reproduced below, in the face of goof SEO but in the interest of siplified revision.

There is also plenty of literature regarding the critical care management of liver transplant recipients.

Let us approach this answer systematically.
The following management steps may be followed in the first 24 hour period:

  • Airway:
    • Historically these patients tend to remain intubated for the first 12-24 hours, although there is good evidence that early extubation (eg. in theatre) has no adverse effects.
  • Breathing:
    • In order for the graft to survive normoxia must be established
    • The general "word of mouth" advice in these situations is to minimise the PEEP. In order for the anastomoses to remain intact, PEEP should be minimised, as it will increase the CVP and thus compromise the venous vascular anastomotic sites. However, some studies have reported no significant change to the hepatic venous flow even with PEEP as high as 15cm H2O.
    • Positive pressure ventilation in general is a bad idea, as organ perfusion is decreased by positive pressure, and perfusion of the donated liver is very important in the early stages.
    • Thus, early weaning from invasive ventilation is one of the major goals
  • Circulation
    • There is likely to be a degree of shock. Given that fluid management must remain relatively conservative, vasopressors and inotropes must be deployed liberally. After all, the graft needs to remain perfused.
    • Hepatic oedema due to over-resuscitation should be avoided.
    • Arbitrarily, the CVP should remain within the range of 6-10.
    • Observe for reactive vasoconstriction
      • These patients, with heir dead livers, have been in a vasodilated state, associated with nitric oxide synthase hyperactivity.
      • Now, with their new livers, normal vascular tone will return.
      • This might mean a sudden massive increase in the afterload.
      • Thus, their left ventricles, which are chronically deconditioned, might decompensate when faced with such demands.
      • Thus, GTN or nitroprusside infusions should be used liberally in these people.
    • The need for RF and LV functional assessment as well as pulmonary arterial pressure measurements and
  • Neurology and sedation
    • No specific recommendations can be made, rather than to say that both hepatic and renal dysfunction in the post-operative period is to be anticipated, and thus drugs which do not rely on organ metabolism should be used. Remifentanyl and propofol spring to mind.
  • Fluids and electrolytes
    • There is some "magical" preload at which the CVP is reasonable, preload adequate, and cardiac output satisfactory. Finding this magic preload is something of an art.
    • Initially, fluid resuscitation should take place, but the fluid of choice should not be Hartmanns because the new liver will probably not be able to metabolise the lactate.
    • After the initial post-operative resuscitation phase is over, a negative fluid balance should be pursued; generating a lower pressure in the right side of the thoracic circulation will serve to draw blood from the graft, and thus theoretically should improve graft perfusion.
    • Renal function needs to be watched closely - renal failure is associated with poor graft survival.
  • Graft function
    • There is a phase of "preservation injury" with very high LFTs but this tends to disappear over the first 3-4 days. Thereafter, synthetic function should be restored.
    • Monitoring of the graft consist of several sequential assessments:
      • Hepatic arterial Doppler
      • BSL
      • Lactate
      • Bilirubin
    • Typically, 1-9% of liver transplants fail within hours of surgery.
  • Surveillance for abdominal compartment syndrome
    • Due to the extensive nature of the procedure and due to the preexisting portal venous pathology, this issue (with pressure over 25mmHg) is fairly common.
    • Abdominal girth values are required as sequential measurements.
  • Nutritional support
    • There is no string reason to recommend TPN here. Like in most other situation, nasogastric enteral feeding is probably best. A degree of ileus is to be expected, and usually resolves
  • Hematological support
    • This consists of the replacement of missing blood products and blood cells.
    • Essentially, there is no specific hemoglobin goal, and what you are trying to do is prevent bleeding from the anastomotic sites.
    • Its probably OK to be slightly coagulopathic, because you don't want to develop a hepatic arterial thrombus.
  • Immune suppression
    • I will not litter this summary with discussion of the relative merits of each class of antirejection drug. Suffice to say, cyclosporin tacrolimus and mycophenolate are gradually giving way to monoclonal antibodies and other immunomodulator drugs which have slightly less devastating organ system effects.
  • Antibiotics and sepsis surveillance
    • Many of these patients die from postoperative infectious complications
    • 48 hrs of IV antibiotics are typically administered
    • The Sanford Guide recommends linezolid, ciprofloxacin and fluconazole.
    • The belowlinked article from 2011 also suggests 14 days of aciclovir, given the propensity for embarrassing HSV reactivation.

The second part of this question is far less interesting, and refers mainly to the candidate's ability to generate differentials for a decreased level of consciousness.

Using a usual template, one can arrive at a series of differential easily:

  • Vascular causes, eg. stroke or hypoxic brain injury
  • Infectious causes, eg. reactivated HSV or CMV encephalitis
  • Drug-related causes, eg. slow metabolism of anaesthetic drugs reliant on hepatic clearance
  • Hepatic encephalopathy
  • Haematological, eg. intracranial bleeding due to coagulopathy
  • Electrolyte disturbances, for instance cerebral oedema due to hyponatremia
  • Endocrine disturbance eg. hypoglycaemia

References

The best, most comprehensive source is this article:

Feltracco, Paolo, et al. "Intensive care management of liver transplanted patients." World journal of hepatology 3.3 (2011): 61.

The rest are also helpful.

Stieber, Andrei C., R. D. Gordon, and J. R. Galloway. "Orthotopic liver transplantation." Hepatology. A text book of liver disease. WB Saunders, Philadelphia (1996): 1759-1780.

Mazariegos, George V., Ernesto P. Molmenti, and David J. Kramer. "Early complications after orthotopic liver transplantation." Surgical Clinics of North America 79.1 (1999): 109-129.

Razonable, Raymund R., et al. "Critical care issues in patients after liver transplantation." Liver Transplantation 17.5 (2011): 511.

Mandell, M. Susan, et al. "Reduced use of intensive care after liver transplantation: influence of early extubation." Liver Transplantation 8.8 (2002): 676-681.

Question 23.2 - 2015, Paper 2

A 70-year-old male presents to the ED with a 2-week history of increasing dyspnoea, cough with altered sputum and fever. Past history includes chronic obstructive airways disease (COPD), lung cancer seven years ago treated with chemotherapy and radiation therapy with no sign of recurrence since.

Examination findings included RR 30 breaths/min, BP 110/70mmHg, HR 145 bpm, Temp 37.4ºC, anxious and distress but tired and peripherally cold and cyanosed.

CXR shows findings consistent with COPD and right lower lobe infiltrate.

The following arterial blood gas is taken one hour after receiving 2 litres of fluid resuscitation, antibiotics and bi-level non-invasive ventilation (NIV), at FiO2 = 1.0.

(This blood gas is discussed in Question 23.1 )

Parameter

Patient Value

   

Normal Adult Range

FiO2

1.0

       

pH

7.16*

7.35

– 7.45

 

PCO2

33 mmHg* (4.3 kPa)*

35

45 (4.6 – 6.0)

 

PO2

272 mmHg (38.5 kPa)

       

Bicarbonate

11 mmol/L*

22

30

 

Base Excess

-17 mmol/L*

-3 – +3

 

Sodium

138 mmol/L

135 – 145

 

Potassium

4.3 mmol/L

3.5 – 5.0

 

Chloride

121 mmol/L*

95

110

 

Glucose

13.1 mmol/L*

3.5 – 7.8

 

Lactate

6.4 mmol/L*

0.6 – 2.4

 

Haemoglobin

131 g/L*

135 – 175

 

Creatinine

150 micromol/L*

70

120

 

Six hours later the patient remains on NIV, is conscious, reports feeling slightly better, feet remain cyanosed, BP 105/72 mmHg, HR 108 bpm, RR 30 breaths/min, urine output 10 – 20 mL/hr and the following biochemistry profile is obtained:

Parameter

Patient Value

Normal Adult Range

Sodium

139 mmol/L

135 – 145

Potassium

5.5 mmol/L*

3.5 – 5.2

Chloride

110 mmol/L

95

– 110

Bicarbonate

12 mmol/L*

22

– 32

Urea

20.0 mmol/L*

2.7 – 7.8

Creatinine

220 μmol/L*

70

– 120

Estimated glomerular filtration rate (eGFR)

25 mL/min/1.73 m2*

> 90

Anion gap

22 mmol/L*

8 – 18

Total protein

57 g/L*

60

– 80

Albumin

27 g/L*

35

– 50

Total bilirubin

24.9 μmol/L

< 25

Alkaline phosphatase (ALP)

81 IU/L

30

– 110

Alanine transaminase (ALT)

6138 IU/L*

< 65

Aspartate transaminase (AST)

10122 IU/L*

< 50

g-Glutamyl transferase (GGT)

88 IU/L

< 90

C-reactive protein (CRP)

22.5 mg/L*

< 8

b)  Give your interpretation of these findings. Include likely aetiologies.            (40% marks)

College Answer

Increasing anion gap due to worsening renal impairment and possibly increasing lactate.

LFTs deranged with predominant finding of transaminitis. (This is likely to be associated with an increase in lactate).

Aetiologies

  • Liver ischaemia due to hypoperfusion
  • cardiac failure (poor output +/- liver congestion) severe sepsis with profound hypotension
  • other shock states e.g. obstructive thrombo-embolic disease
  • Drug related e.g. paracetamol (inadvertent or deliberate)
  • (NB Acute alcoholic hepatitis is unlikely with such a high AST)

Discussion

The following biochemical abnormalities are present in the second set of results:

  • High anion gap metabolic acidosis
  • Renal impairment (raised urea and creatinine)
  • Hypoalbuminaemia
  • Borderline raised bilirubin
  • Trivially elevated cholestatic liver enzymes
  • Massively elevated hepatic transaminases
  • A high AST to ALT ratio
  • Trivially elevated inflammatory markers

The raised transaminases are described as a "transaminitis" by the college, a term which has been in use since 1977, in spite of some authors referring to it as "made up and improper" (Stellpflug, 2011). The previous set of results from Question 23.1 demonstrated a raised lactate and severe acidaemia wioth a normal glucose and normal haemoglobin. From the list of causes of elevated transaminases, the following are relevant diferentials, and parenthesised comments as to why they are relevant:

  • Congestive heart failure (he has COPD: maybe the right heart?)
  • Portal vein thrombosis (past history of cancer)
  • Malignant infiltration (past history of cancer)
  • Drug overdose (this is always an option)
  • Viral hepatitis (this is always an option)
  • Fatty liver or NASH
  • Liver abscess (right lower lobe "infiltrate" may be sympathetic effusion)
  • α1-antitrypsin deficiency (the college has given a history of COPD, implying emphysema, but no history of any actual smoking)
  • Poor liver perfusion and ischaemia ("shock liver") - however, no history of profound hypotension

And then those things which this is not:

  • Alcoholic hepatitis (unlikely: no history of drinking and GGT is not elevated)
  • Pancreatitis (not a cholestatic picture)
  • Traumatic causes (no history of trauma)
  • Congenital issues, haemochromatosis, Wilson's disease (he's 70)

References

Stellpflug, Samuel J. "Transaminitis: The Lab Test That Has Inflammation…." Journal of Medical Toxicology 7.3 (2011): 252-253.

Johnston, David E. "Special considerations in interpreting liver function tests." American family physician 59 (1999): 2223-2232.

Limdi, J. K., and G. M. Hyde. "Evaluation of abnormal liver function tests." Postgraduate medical journal 79.932 (2003): 307-312.

Hoekstra, Lisette T., et al. "Physiological and biochemical basis of clinical liver function tests: a review." Annals of surgery 257.1 (2013): 27-36.

Question 17 - 2016, Paper 1

Outline the risk factors and your management strategies for constipation in the critically ill.

College Answer

Risk factors

  • Constipation usually results from multiple interacting causative factors:
  • Decreased gastrointestinal motility secondary to:  sepsis, 
  • electrolyte abnormalities  drugs e.g. opiates
  • spinal injury
  • neuromuscular conditions such as Parkinsons long-term laxative abuse
  • Immobility due to illness, injury or sedation. Bed rest or a period of immobility is thought to result in a weakening of the abdominal wall muscles leading to difficulty in raising the intraabdominal pressure sufficiently for defecation to occur.
  • Stool quality, which may be affected by lack of fluid and fibre
  • Lack of access to appropriate toilet facilities and lack of privacy
  • Unconscious patients may not feel the need to defecate and cannot express this need
  • Using a bedpan increases the likelihood of constipation. Intra-abdominal pressure needs to be raised for successful defecation and this is impaired while lying on a bedpan. 
  • Increased incidence in the elderly and nursing home residents

Management Strategies

  • May benefit from routine Bowel Management Protocol. 
  • Routine laxatives for all, upgraded to stronger agents/enemas if no bowel action after 2 days.
  • AXR if no successful bowel movements after 3-4 days.
  • Consider surgical/mechanical cause for constipation and rule out with surgical review / AXR / CT.
  • Consideration of neostigmine infusion if pseudo obstruction (rule out mechanical obstruction first – CT abdomen transition point).

Non-pharmacological Interventions:

  • Sedation breaks to allow assessment of need
  • Stop medications that cause constipation
  • Normal enteral diet (high fibre feed)
  • Availability of commodes/toilets near to patient area for ambulant patients
  • Minimisation of opiate analgesia as able (consideration of Targin)
  • Mobilisation / free patient from unnecessary lines/tubes etc.
  • Adequate oral hydration
  • Normalise electrolytes

Pharmacological Interventions:

  • Bulk forming laxatives
  • Osmotic laxatives
  • Enemas
  • Contact laxatives
  • Prokinetics
  • Neostigmine for pseudo-obstruction

Discussion

Risk factors for constipation in the critically ill:

Modifiable ICU-related risk factors

  • Delayed enteral nutrition (delayed for longer than 24 hrs) - although early enteral nutrition has also been blamed, and in fact in ICU patients nasogastric nutritional formula is at least as likely to cause constipation as diarrhoea ( Montejo et al, 1999).
  • Reduced mobility
  • Deep sedation
  • Heavy opiate use
  • Anticholinergic drug side effects
  • Calcium channel blockers
  • The use of paralysing infusions
  • Electrolyte disturbance, eg.hypokalemia hypercalcemia and hypomagnesemia
  • Dehydration, inadequate fluid resuscitation (or excess diuresis)
  • Hypotension (SBP under 90mmHg - Gacouin et al, 2010)
  • Hypoxia (P/F ratio under 150 - also Gacouin et al)

Non-modifiable disease risk factors

  • Abdominal surgery
  • Severe illness
  • Paralysis (eg. spinal cord injury) 
  • Prior alcohol or cannabis use

Management strategies for constipation in the critically ill

Tier one therapies and investigations:

  • Abdominal X-ray to exclude "true" bowel obstruction"
  • Electrolytes and biochemistry to rule out and correct any electrolyte disturbance
  • Fluid management review to ensure euvolaemia and adequate hydration
  • Attention to primary pathology (eg. shock, hypoxic respiratory failure) - if this is being treated well and is getting better, patience may be all that is required.
  • Drug chart audit to ensure exposure to opiates, anticholinergics and calcium channel blockers is minimised
  • Mobility: physiotherapy for limbs, sit out of bed in a chair, etc
  • Stool softeners, stimulants and bulk-forming laxatives:
    • Docusate
    • Sennocot
    • Soluble fibre

Tier two therapies and investigations: Assuming bowel obstruction and megacolon are ruled out

  • Osmotic laxatives:
    • Lactulose
    • Polyethylene glycol
  • PR examination:  this may have a therapeutic effect
  • Enema
  • Prokinetics, eg. erythromycin
  • Opiate antagonists, eg. methylnaltrexone

Tier three therapies and investigations: assuming all of the above are ineffective, or mpossible to implement

  • Abdominal CT  to investigate for possible abdominal pathology unseen on AXR
  • Neostigmine infusion
  • Manual disimpaction
  • Surgical decompression

References

Mostafa, S. M., et al. "Constipation and its implications in the critically ill patient†." British journal of anaesthesia 91.6 (2003): 815-819.

Nassar, Antonio Paulo, Fernanda Maria Queiroz da Silva, and Roberto de Cleva. "Constipation in intensive care unit: incidence and risk factors." Journal of critical care 24.4 (2009): 630-e9.

Blaser, Annika Reintam, et al. "Gastrointestinal function in intensive care patients: terminology, definitions and management. Recommendations of the ESICM Working Group on Abdominal Problems." Intensive care medicine 38.3 (2012): 384-394.

Artinyan, Avo, et al. "Prolonged postoperative ileus—definition, risk factors, and predictors after surgery." World journal of surgery 32.7 (2008): 1495-1500.

Nadrowski, L. "Paralytic ileus: recent advances in pathophysiology and treatment." Current surgery 40.4 (1982): 260-273.

Smonig, Roland, et al. "Constipation is independently associated with delirium in critically ill ventilated patients." Intensive Care Medicine 42.1 (2016): 126-127.

Patanwala, Asad E., et al. "Pharmacologic management of constipation in the critically ill patient." Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 26.7 (2006): 896-902.

Gacouin, Arnaud, et al. "Constipation in long-term ventilated patients: associated factors and impact on intensive care unit outcomes." Critical care medicine 38.10 (2010): 1933-1938.

Azevedo, Rodrigo Palácio de, and Flávia Ribeiro Machado. "Constipation in critically ill patients: much more than we imagine." Revista Brasileira de terapia intensiva 25.2 (2013): 73-74.

de Souza Guerra, Tatiana Lopes, Simone Sotero, and Norma Guimarães Marshall Mendonça. "Incidência de constipação intestinal em uma unidade de terapia intensiva." Rev Bras Ter Intensiva 25.2 (2013): 87-92.

Question 12 - 2017, Paper 1

Outline the pathophysiology, diagnosis and treatment of mesenteric ischaemia.

College answer

Mesenteric ischaemia occurs when blood flow is inadequate to meet the metabolic demands of the small bowel or colon.

Pathophysiology

  • Occlusion of the arterial supply leads to ischaemia of the mucosa, before progressing to full thickness ischaemia and infarction with subsequent bacterial translocation leading to localised abscess formation, peritonitis and systemic sepsis depending of the extent of ischaemia.
  • Arterial embolism – generally originates from atrial thrombi and therefore tends to occur with tachyarrhythmias, cardiac failure or rheumatic heart disease
  • Arterial thrombosis – occlusion of atherosclerotic mesenteric vessel
    • Dissection of the aorta
    • Torsion
    • Closed loop bowel obstruction (intraluminal pressure > arterial pressure)
    • Surgical misadventure
  • Venous thrombosis – venous occlusion generally in prothrombotic state e.g.: factor deficiency, malignancy, abdominal trauma, closed loop obstruction
  • Mesenteric ischaemia may also occur as a near terminal event in low cardiac output states with poor global oxygen delivery
     

Diagnosis

  • History:
    • Acute onset of central colicky or constant abdominal pain, often associated with nausea, vomiting, and constipation
    • May have history of pre-disposing condition e.g.
      • Atrial fibrillation
      • Mechanical cardiac valve
      • Predisposing conditions for atherosclerosis
      • Previous bowel surgery
  • Examination:
    • General
      • Often look unwell, tachycardiac (?AF) tachypnoiec (related to metabolic acidosis), hypotensive
    • Abdomen
      • At first may be soft and non-tender in spite of quite severe pain (while only mucosa is ischaemic) progressing then to localised or generalised peritonism
  • Investigations:
    • Laboratory
      • Lactate is often raised but may be normal
      • Non-specific markers of inflammation
    • Plain AXR -Riegler’s sign (gas on both sides of bowel wall), thickening of bowel wall
    • Ultrasound
      • May detect proximal vessel occlusion/narrowing
      • Images often inadequate due to pain, bowel gas, obesity etc.
    • CT
      • CT Angiography – information on vasculature as well indication of bowel injury (stranding, lack of enhancement, free air etc.)
      • Two phase imaging(contrast) for optimal venous images
      • Poor sensitivity
    • MRI
      • Good vascular images, but often unacceptable delay in image acquisition
    • Endoscopy
      • May identify ischaemic changes in bowel and rectum
    • Diagnostic surgery
      • May be only way to confirm diagnosis

Treatment

  • General resuscitative
    • Fluid resuscitation and judicious vasoactive support
    • Anticoagulation – generally with heparin
    • Antibiotics – controversial but often given as gut translocation and perforation common
  • Disease specific
    • Arterial thrombus/embolism
      • Reperfusion
      • Endovascular – mechanical thrombectomy, angioplasty and stenting or thrombolysis
        • Requires close monitoring and often require laparotomy for peritonitis and bowel resection
    • Open
      • Revascularisation – thrombectomy and or arterial bypass
      • Assessment of bowel viability
      • Resection of necrotic bowel
      • Often require “second look” operation
    • Venous thrombosis
      • Systemic anticoagulation
      • Consider percutaneous thrombectomy
      • Laparotomy for complications – peritonitis
    • Low output state
      • Optimise haemodynamic stability
      • Minimising vasoconstrictors controversial
      • Laparotomy for complications – peritonitis

Additional Examiners’ Comments:

The template above is only a guide to the expected answer.Important points sought by the Examiners were: the different categories of mesenteric ischaemia, comments about importance of history, examination and suspicion; it was essential to mention surgery as a diagnostic tool.

Discussion

The template below is also only a guide.

Pathophysiology

  • Acute mesenteric ischaemia
    • Arterial embolism (40% of cases)
    • Arterial thrombosis from ruptured atheroma (20-35% of cases)
    • Arterial dissection (<5% of cases)
    • Non-occlusive mesenteric hypoperfusion (10-15% of cases)
    • Venous infarction (5-15% of cases)
  • Chronic mesenteric ischaemia
    • Gradual onset of arterial insufficiency due to atherosclerosis

History

  • History of atherosclerosis
  • Hypercoagulable background
  • AF
  • Vasculitis
  • Recent abdominal surgery
  • Historical features associated with chornic mesenteri ischaemia, eg:
    • Postprandial pain ("mesenteric angina"), 30-60 minutes after eating
    • Weight loss
    • Diarrhoea or constipation
    • Early satiety

Examination

  • Classic “pain out of proportion to examination”
  • Epigastric bruit
  • Peritonism
  • Clinical features of shock

Biochemistry

  • Features of organ system dysfunction, eg. rising creatinine
  • Raised lactate
  • Neutrophilia

Imaging

  • Doppler ultrasound of the mesenteric vessels
  • CT with IV contrast, two-phase to detect venous thrombosis
  • Catheter angiography (also allows thrombolysis)
  • Diagnostic laparotomy (the college felt this was an essential part of the answer)

Specific management

  • Aggressive:
    • Endovascular repair
    • Open repair with or without vascular bypass
    • Catheter-directed clot aspiration or  thrombolysis
    • Stenting of dissected segments
  • Conservative:
    • Heparin infusion (this is probably the only therapy required for venous mesenteric ischaemia)

Supportive management

  • Airway protection may be required (high risk of aspiration)
  • Mechnical ventilation (increased work of breathing due to acidosis)
  • Circulatory support (vasodilated shock state)
  • Analgesia and anaesthesia (opiates may actually be preferred, as they "rest the gut" by paralysing its motility)
  • Neuromuscular junction blockers may help organ perfusion by their effect on abdominal compartment pressure
  • Electrolyte correction (particularly correction of acdi-base balance)
  • Fluid resuscitation (extensive third-space losses are to be expected)
  • Abdominal compartment pressure - serial measurements 
  • Parenteral nutrition (the patient should remain fasted)
  • Antibiotics of a broad spectrum, eg. piperacillin/tazobactam or meropenem

References

Acosta, Stefan, and Martin Björck. "Modern treatment of acute mesenteric ischaemia." British Journal of Surgery 101.1 (2014).

Schofield, Nick, et al. "Acute mesenteric ischaemia." Journal of the Intensive Care Society 15.3 (2014): 226-230.

Clair, Daniel G., and Jocelyn M. Beach. "Mesenteric ischemia." New England Journal of Medicine 374.10 (2016): 959-968. (pdf)

Pecoraro, Felice, et al. "Chronic mesenteric ischemia: critical review and guidelines for management." Annals of vascular surgery 27.1 (2013): 113-122.

Question 1 - 2017, Paper 1

A 45-year-old male with a background of chronic liver disease is admitted to the Emergency Depattment (ED) with massive haematemesis secondary to gastric varices. He is managed with endoscopy and sclerotherapy.

List four other causes for massive haematemesis.    (10% marks)

List the clinical indicators for risk of re-bleeding from the gastric varices.  (20% marks)

List the pharmacological agents that may reduce the risk of a re-bleed.     (20% marks)

Following initial stabilisation and control of bleeding, he deteriorates with a variceal re-bleed.

List the options for controlling the re-bleed AND, where appropriate, the relative advantages and disadvantages of these.          (50% marks)

College answer

a) Causes
• Gastric or duodenal ulcer with bleeding visible vessel
• Dieulafoy's lesion (large exposed arteriole within gastric wall)
• Tear at gastro-oesophageal junction (Mallory Weiss)
• Aorto-duodenal fistula
• Eroding cancer into vessel (short gastric artery, splenic artery)

b) Rebleed likely if:
• Advanced age
• Unable to band all varices
• Gastric > oesophageal varices
• Severe coagulopathy due to liver disease or massive transfusion
• Severity of portal hypertension or liver disease
• Size of varices – larger higher risk
• Presence of red signs (localised reddish spots on the mucosal surface of the varix)

c) Drugs to reduce risk of re-bleed
• Octreotide/somatostatin
• Vasopressin / terlipressin +/- venodilator
• Tranexamic acid
• Oral Sucralfate (local anti-fibrinolytic effect)
• PPI infusion if concomitant ulcer bleeding
• Beta blockers e.g. propranolol if haemodynamics permit
• Short-term prophylactic antibiotics

d) Options for re-bleeding:
• Measure and fix coagulation, ongoing resuscitation


• Repeat endoscopy
   o Can be done in ICU although may be more appropriate in the operating theatre
   o Requires airway protection
   o Allows endoscopic variceal obturation or endoscopic variceal ligation


• TIPS to reduce portal pressure; risks of encephalopathy
   o Strategy of choice with initial treatment failure
   o May be contra-indicated in high MELD score
   o Complications of shunting blood away from liver and increased hepatic encephalopathy


• Balloon tamponade (Sengstaken, Minnesota)
   o Only useful in varices in the oesophagus or GO junction; not useful for gastric
   o Requires airway protection
   o Mucosal injury and necrosis


• Surgery
   o Ligation and resection of gastric vessels
   o Oesophageal venous ligation
      ▪ Requires luminal incision; high risk of breakdown in context of liver disease
      ▪ May not be available depending on local resources


• Balloon-occluded retrograde transverse obliteration (BRTO)
   o New technique and still undergoing evaluation
   o Increases portal hepatic blood flow and may be alternative for patients who may not tolerate TIPS
   o Obliterates spontaneous porto-systemic shunts and may aggravate portal hypertension
• Activated factor 7
   o Questionable efficacy
   o Highly pro-coagulant
   o May have a role in buying time to allow retrieval to a more specialised centre

Discussion

a) Other causes of haematemesis could include a whole range of differentials. Owing to the author's shameful obsession with structured classifications, this range can be divided into "blood is coming from the gut" and "blood is not coming from the gut but somehow has ended up in the gut". This was generated with the use of Oh's Manual, but contains conditions which are not listed in the canonic Chapter 42  (pp. 487,  "Acute  gastrointestinal  bleeding"  by Joseph  JY  Sung).

Bleeding of gastrointestinal origin 

  • Oesophageal sources:
    • Oesophageal varices (90% of varices)
    • Mallory-Weiss tears or Boerhaave's syndrome
    • Oesophagitis
  • Gastric sources
    • Gastric varices (10% of varices)
    • Peptic ulcers (75% of bleeding ulcers)
    • Portal hypertensive gastropathy
    • Gastritis
  • Duodenal sources
    • Duodenal ulcers (25% of bleeding ulcers)
    • Duodenitis
  • Anywhere
    • Arterio-venous malformation
    • Dieulafoy lesion 
    • Trauma, eg. swallowed sharp object
    • Iatrogenic, eg. following sphincterotomy or duodenal polypectomy
    • Malignancy

Bleeding of non-gastrointestinal origin 

  • Swallowed blood
    • Epistaxis
    • Haemoptysis
    • Blood swallowed during delivery (neonates)
    • Haemorrhage following dental surgery or facial trauma
  • Exotic causes
    • Innomino-oesophageal fistula or aorto-duodenal fistula

b) The college have listed causes of rebleeding which seem fairly logical, eg. "unable band everything" and "still coagulopathic". To this list, one might also add gastroenterological lazyness (delayed endoscopy increases re-bleeding risk  according to Chen et al, 2012). From Augustine et al (2010), there are several features found to be strongly associated with "five-day failure", a composite endpoint consisting of re-bleeding and five-day mortality. All of these have been combined into this list:

  • Uncontrolled bleeding
    • Ongoing acute bleeding, or failure to control bleeding at initial endoscopy ("unable to band all varices")
    • Delay in the procedure
    • Number of bands which were used - according to Xu et al (2011), more than 6 bands is a bad sign
  • Severe liver disease
    • Severity of liver disease: Child-Pugh and MELD scores (even their individual components!)
    • A hepatic venous pressure gradient (HVPG) in excess of 20mmHg
    • Aetiology of cirrhosis (apparently some causes are associated with greater risk of rebleeding)
    • Portal vein thrombosis
  • Severe initial haemorrhage
    • High transfusion needs
    • Shock state
  • Endoscopic features
  • Laboratory features
    • Haematocrit
    • Platelet count
    • Coagulopathy (prolonged PT)

c) Pharmacological agents which can decrease the risk of rebleeding:

  • Terlipressin (has been shown to decrease mortality)
  • Octreotide ( the next best choice after terlipressin)
  • Propanolol (might be helpful but the jury is still out).
  • Antibiotics - sepsis promotes the risk of variceal bleeding; literature demonstrates a benefit from antibiotics in this setting (the usual course is 7 days).
  • Tranexamic acid - mentioned by the college in their answer, but Tavakoli et al published on this in 2017 and they did not find any difference in rebleeding rate, nor any other outcome variable for that matter. The whole thing is very 80s. However, as the college answers are definitive, the savvy candidate would need to include this potentially pointless therapy in their answer.
  •  Proton pump inhibitors: but PPI infusion probably has no advantage over twice-daily dosing
  • Sucralfate is also mentioned by the college in their answer. The "local anti-fibrinolytic effect" is seen more in patients who have had sclerotherapy and then go on to bleed from post-sclerotherapy ulcers (i.e. no longer varices, but still technically a rebleed). This was reported upon by Brooks (1995). The specific benefit seems to be the result of sucralfate counteracting the pro-fibrinolytic effect of ethanolamine oleate, the specific sclerosant agent widely used in the 1990s. 

d) Options for controlling a re-bleed: whenever the college ask for something with a list of advantages and disadvantages, it is usually better to put it in a table. Thus:

Options for Controlling a Variceal Re-Bleed
Strategy Advantages Disadvantages
Medical resuscitation
  • It does not hurt to correct coagulopathy and resuscitate with fluid and blood products
  • If the venous pressure ends up too high, there will be more bleeding
Repeat endoscopy
  • May be able to control previously unseen varices, or use a different technique to the previous attempt
  • May be able to use several techniques simultaneously (eg. band ligation, sclerotherapy and electrocautery)
  • Risk of anaesthetic in an already unstable patient
  • If the first attempt did not succeed, what makes you think the subsequent attempt will be any more successful
Balloon tamponade
  • Should be able to control blood loss from otherwise uncontrollable variceal bleeding by applying enough direct pressure
  • Poorly tolerated by the conscious patient
  • Use by non-experts can produce terrible complications (eg. oesophageal rupture, aspiration, etc)
  • May exacerbate bleeding by dislodging variceal bands from previously well-controlled varices
TIPS
  • Decreases the chances of treatment failure in refractory variceal bleeding (in one study, the probability of remaining bleed-free was 97% in the TIPS group and 50% in the pharmacotherapy group)
  • No effect on long-term outcomes
  • Increases the risk of hepatic encephalopathy
  • Requires expertise which is becoming scarce
  • May be impossible in the coagulopathic volume-depleted patient
Surgical control
  • Allows direct control of bleeding, eg. resection of the bleeding varices, or the construction of some sort of surgical shunt, eg. the Warren distal splenorenal shunt.
  • Healing will be poor
  • Future liver transplantation will likely be technically difficult if not impossible
  • So far nobody has demonstrated any mortality benefit from this

Balloon-occluded retrograde transverse obliteration (BRTO)

  • Destroys shunts, and thus increases portal venous pressure
  • Sclerosant used in this procedure may cause renal failure, anaphylaxis and pulmonary oedema
     
     

Factor VIIa is also mentioned by the college in their answer, though they themselves moderate their enthusiasm by pointing out that it has "questionable efficacy". If one reads the papers (eg. Bosch et al, 2008) this would certainly seem correct (there was no effect on any primary endpoints). The mention of this option in the college answer is itself questionable, as it is promoted as an option for controlling a re-bleed even when trial results "do not support the routine use of rFVIIa in this setting". In protest, I did not add it to my table.

References

Oh's Intensive Care manual: Chapter 42  (pp. 487)  Acute  gastrointestinal  bleeding  by Joseph  JY  Sung

arcia-Tsao, Guadalupe, and Jaime Bosch. "Management of varices and variceal hemorrhage in cirrhosis." New England Journal of Medicine 362.9 (2010): 823-832.

García-Pagán, Juan Carlos, et al. "Early use of TIPS in patients with cirrhosis and variceal bleeding." New England Journal of Medicine 362.25 (2010): 2370-2379.

Vlavianos, P., et al. "Balloon tamponade in variceal bleeding: use and misuse."BMJ: British Medical Journal 298.6681 (1989): 1158.

Reverter, Enric, and Juan Carlos García‐Pagán. "Management of an acute variceal bleeding episode." Clinical Liver Disease 1.5 (2012): 151-154.

Ioannou, G. N., J. Doust, and D. C. Rockey. "Terlipressin in acute oesophageal variceal haemorrhage." Alimentary pharmacology & therapeutics 17.1 (2003): 53-64.

Corley, Douglas A., et al. "Octreotide for acute esophageal variceal bleeding: a meta-analysis." Gastroenterology 120.4 (2001): 946-954.

Reiberger, Thomas, et al. "Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol." Gut62.11 (2013): 1634-1641.

Hou, Ming‐Chih, et al. "Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial." Hepatology 39.3 (2004): 746-753.

Augustin, Salvador, Antonio González, and Joan Genescà. "Acute esophageal variceal bleeding: Current strategies and new perspectives." World J Hepatol 2.7 (2010): 261-274.

Chen, Ping-Hsien, et al. "Delayed endoscopy increases re-bleeding and mortality in patients with hematemesis and active esophageal variceal bleeding: a cohort study." Journal of hepatology 57.6 (2012): 1207-1213.

Kleber, Gerhard, et al. "Prediction of variceal hemorrhage in cirrhosis: a prospective follow-up study.Gastroenterology 100.5 (1991): 1332-1337.

Question 9.1 - 2017, Paper 1

A 51 -year-old female presents with a decreased conscious state, Glasgow Coma Scale (GCS) 12, confusion and myoclonus. She is on treatment for a seizure disorder. Her CT brain scan shows no acute intracranial abnormality.

Her investigations are as follows:

Parameter

Patient Value

Adult Normal Range

Sodium

1 38 mmol/L

135-145

Potassium

4.1 mmollL

3.5 - 5.2

Bicarbonate

18 mmol/l_•

22 - 32

Urea

14.2 mmoVL•

3.0 - 8.0

Creatinine

210 mol/l_•

45 - 90

Bilirubin

54 mol/L*

< 20

Alanine transferase

2710

< 35

Aspartate transferase

1365

< 35

Alkaline phosphatase

103 Ull-

30- 110

Glutam transferase

67 U/L*

< 40

Albumin

37

35-50

Protein

61 IL

60 - 80

Ammonia

156

< 50

       

List  possible causes of the hyper-ammonaemia in this patient.  (40% marks)

College answer

  • Liver failure
  • Anti-epileptic drugs – Sodium valproate and Carbamazepine
  • Other drugs / toxins eg paracetamol, salicylates, mushrooms
  • Urosepsis with urea-splitting organisms e.g. Klebsiella, Proteus
  • Urea-cycle disorders (Patients with high ammonia from drugs or urosepsis usually have undiagnosed mild disorders of urea-cycle metabolism)

Discussion

The patient; she is probably on valproate for her seizure disorder. Valproate overdose is a logical explanation for a decreased level of consciousness, myoclonus and high ammonia.

Causes of hyperammonaemia more broadly could be any of the following:

Pre-analytical error

  • Prolonged pre-transport time
  • Room temperature storage of sample

Increased substrate for ammoniagenesis

  • Excess protein catabolism:
    • Essential amino acid deficiency
    • Primary dietary carnitine deficiency
    • Steroids
    • Immobility
    • Severe exercise
    • Increased tissue turnover, eg haematological malignancy
  • Excess protein intake:
    • Weird diet
    • Parenteral nutrition

Bypass of normal metabolism

  • TIPS procedure
  • Portosystemic shunts
 

Acquired urea cycle defects

  • Fulminant hepatitis of any cause
  • Reye's syndrome
  • Drugs, eg. glycine or valproate

Congenital urea cycle defects

  • Inherited urea cycle defects
  • Organic aciduria
  • Fatty acid oxidation defects

Excess of exogenous ammonia

  • Ammonium chloride therapy
  • Excess generation of ammonia:
    • Gastric bypass
    • Urease-producing organisms
    • UTI

Reabsorption of excreted ammonia

  • Distal renal tubular acidosis
  • Ureteric diversion
  • Urinary tract infections
  • Vesicoureteric reflux
  • Bladder perforation

References

Conway, Edward Joseph, and Robert Cooke. "Blood ammonia." Biochemical Journal 33.4 (1939): 457.

Shambaugh, G. E. "Urea biosynthesis I. The urea cycle and relationships to the citric acid cycle.The American journal of clinical nutrition 30.12 (1977): 2083-2087.

McDermott Jr, William V., Raymond D. Adams, and Athol G. Riddell. "Ammonia metabolism in man." Annals of surgery 140.4 (1954): 539.

Vince, Angela, et al. "Ammonia production by intestinal bacteria." Gut 14.3 (1973): 171-177.

Vince, Angela J., and Sigrid M. Burridge. "Ammonia production by intestinal bacteria: the effects of lactose, lactulose and glucose." Journal of medical microbiology 13.2 (1980): 177-191.

Dohrenwend, Paul, and Richard D. Shih. "Glycine Induced Hyperammonemia After Bladder Rupture During Transurethral Resection of a Bladder Tumor." Journal of Medical Cases 4.4 (2013): 250-253.

Felipo, Vicente, and Roger F. Butterworth. "Neurobiology of ammonia." Progress in neurobiology 67.4 (2002): 259-279.

Hashim, Ibrahim A., and Jennifer A. Cuthbert. "Elevated ammonia concentrations: Potential for pre-analytical and analytical contributing factors." Clinical biochemistry 47.16 (2014): 233-236.

Clay, Alison S., and Bryan E. Hainline. "Hyperammonemia in the ICU." CHEST Journal 132.4 (2007): 1368-1378.

Weng, Te-I., Frank Fuh-Yuan Shih, and Wen-Jone Chen. "Unusual causes of hyperammonemia in the ED." The American journal of emergency medicine 22.2 (2004): 105-107.

Hawkes, N. D., et al. "Non-hepatic hyperammonaemia: an important, potentially reversible cause of encephalopathy." Postgraduate medical journal 77.913 (2001): 717-722.

Question 10 - 2017, Paper 2

You have been asked to review a 53-year-old female with known alcoholic liver disease. She has had a progressive fall in her conscious level over the last 24 hours and the medical team are concerned she is developing hepatic encephalopathy (HE). 

a) List four alternative diagnoses to HE that you would consider in this circumstance. (10% marks)

b) List six clinical signs that would be suggestive of HE. (30% marks)
c) Discuss the specific management of severe HE in this setting. (60% marks) 

College answer

    a.                                                         
•    Drug or alcohol effects 
•    Seizure disorder 
•    Traumatic injury 
•    Septic encephalopathy 
•    Hypoglycaemia and other electrolyte disorders 
•    Uraemia                                          
 
    b.                                                          
•    Asterixis 
•    Hypertonia 
•    Hyperreflexia 
•    Clonus           
•    Hippus 
•    Bradykinesia      
•    Nystagmus 
 

c.

c.                                                          
•    Basic principles of management include: 
 
Excluding other causes of altered mentation 
HE is a diagnosis of exclusion (part [a] of question 10). Serum ammonia levels should not be used as a diagnostic tool or to monitor response to treatment.
 
 
Identifying and treating precipitating cause 
•    Increased nitrogen load (GI bleed, excess protein intake, infection) 
•    Decreased toxin clearance (hypovolaemia, renal failure, constipation, port-systemic shunt, medication non-compliance, acute on chronic liver failure) 
•    Altered neurotransmission (sedating medications, alcohol, hypoxia, hypoglycaemia) 
 
Reducing nitrogen load in the gut/Ammonia formation 
First Line- 
•    Non-absorbable disaccharidases- Lactulose is metabolized by bacteria in the colon to acetic and lactic acid, which reduces colonic pH, decreases survival of urease producing bacteria in the gut, and facilitates conversion of ammonia (NH3) to ammonium (NH4+), which is less readily absorbed by the gut. The cathartic effect of these agents also increases faecal nitrogen waste.  
•    Antibiotics-Rifaximin is a minimally absorbed oral antibiotic with broad spectrum activity against gram-positive and gram-negative aerobic and anaerobic bacteria. Oral neomycin and metronidazole have been used to treat hepatic encephalopathy in the past but due to concerns of toxicity and side effects, rifaximin is now the preferred antibiotic.  
 
Second line- (all not required to score full marks) 
•    Probiotics- As gut bacteria play a central role in producing ammonia it has been theorized that altering gut flora using probiotics may be beneficial in HE.  
•    Polyethylene Glycol- Commonly used, safe and highly effective laxative that has recently been proposed as a possible agent for HE  
•    Flumazenil- benzodiazepine antagonist at GABA receptors. Can result in clinical improvement but no mortality benefit 
•    Ammonia scavengers- increase ammonia clearance and reduce systemic concentrations by providing an alternative pathway for renal ammonia clearance. 
•    L-ornithine l-aspartate (LOLA)- increases glutamine synthase and urea excretion. Similar clinical improvement when compared to lactulose. 
•    Zinc- Low zinc is associated with impairment of urea cycle enzymes leading to elevated ammonia levels.  
•    Porta-systemic shunts- Medically refractory HE should raise suspicion of a spontaneous splenorenal shunt and patients who have undergone TIPS should be considered for shunt reversal if severe HE persists 
 
Supportive care 
Management of cerebral oedema-Lactulose or rifaximin can be beneficial for the treatment of gradual-onset encephalopathy in patients with prior cirrhosis, but additional, aggressive treatment of brain edema with osmotic diuretics is required in new, fulminant forms to prevent secondary, permanent brain-stem damage and to sustain patients through liver transplantation.  
 
Nutrition - plays a key role in managing HE and preventing recurrence. Optimal daily energy intake should be 35 to 40 kcal/kg ideal body weight with daily protein intake of 1.2 to 1.5 g/kg ideal body weight.Multivitamin should be considered with the addition of specific treatments for clinically apparent vitamin deficiencies. 
 
Assessing the need for long term therapy and liver transplant evaluation 
Liver transplant evaluation should be considered in appropriate candidates once a diagnosis of overt hepatic encephalopathy is made 
 

Discussion

Possible causes of unconsciousness in the middle-aged alcoholic could be anything, considering also that we are not given any better description of it (i.e. it could represent merely confusion rather than coma). 

The top four would have to be:

  • Hypoglycaemia
  • Intracranial haemorrhage, eg. a subdural haematoma from a fall
  • Intoxication - i.e. this patient may have access to alcohol while in hospital, or may have drunk something which is not exactly ethanol (eg. chlorhexidine-based hand wash)
  • Seizures, eg. associated with withdrawal

Other possibilities include:

  • Stroke, including cerebral venous sinus thrombosis
  • CNS infection
  • Septic encephalopathy
  • Hyponatremia
  • Space-occupying lesion

Clinical signs which might suggest HE can be extracted from this ancient grading system which was developed by Conn and Lieberthal (1979)

Physical Signs in Hepatic Encephalopathy

Stage I

  • Metabolic tremor
  • Muscular incoordination
  • Impaired handwriting

Stage II

  • Slurred speech
  • Asterixis
  • Hypoactive reflexes
  • Ataxia

Stage III

  • Hyperactive reflexes
  • Nystagmus
  • Babinski’s sign
  • Clonus
  • Rigidity

Stage IV

  • Dilated pupils
  • Opisthotonus
  • Coma

Specific steps in the management of hepatic encephalopathy should consist of specific therapies targeted at reducing the hepatic toxin load and management of the precipitating cause. The excellent college answer offers some detailed discussion, which is difficult to improve upon.

  • Lactulose
  • Rifaximin
  • Avoidance of hyponatremia
  • Nutritional management:
    • Branched-chain amino acids (BCAAs) and a reduced amount of aromatic amino acids
    • High fiber diet
    • Pro-biotics (though their benefit is unclear)
  • Management of the precipitant:
    • Stop GI bleeding (endoscopy, banding, etc)
    • Antibiotics for SBP
    • Correct dehydration
    • Withdraw hepatotoxins

J.S. Bajaj (2010) offers a detailed exploration of the modern management of hepatic encephalopathy. Another excellent review is from Riggio et al (2015). From these, the following approach has been concocted, to easily recall and regurgitate in an exam setting:

Specific management of hepatic encephalopathy

  • Lactulose, or lactose if they are lactose-intolerant
  • Rifaximin
  • Avoidance of hyponatremia
  • Nutritional management:
    • Branched-chain amino acids (BCAAs) and a reduced amount of aromatic amino acids
    • High fiber diet
    • Pro-biotics (though their benefit is unclear)
    • Optimise nutrition (35-40kcal/kg/day)
    • High protein intake (1.2-1.5g/kg/day)

Management of the precipitating cause

  • Stop GI bleeding (endoscopy, banding, etc)
  • Antibiotics for SBP
  • Correct dehydration
  • Withdraw hepatotoxins

Supportive management of the encephalopathic patient

  1. Support the airway.  
  2. Wean ventilation to spontaneous mode as tolerated.
    Avoid NIV; abdominal distension and a fluctuating level of consciousness will likely result in aspiration. HFNP is ok.
  3. Support haemodynamically;
    noradrenaline +/- terlipressin may be appropriate if hepatorenal syndrome is suspected
    Albumin (20%) is a reasonable resuscitation fluid
  4. Avoid sedation. As needed, use drugs which do not depend on hepatic metabolism (eg. remifentanyl)
  5. Correct electrolyte derangement
  6. Monitor renal function (hepatorenal syndrome)
  7. Ensure BSL is monitored and supplemental glucose is made available
    Ensure thiamine is co-administered with glucose!
  8. Correct clinically significant anaemia. 
    Address haematinic factor deficiencies.
  9. Antibiotics as appropriate: ceftriaxone may be required if SBP is a real possibility.

References

Oh's Intensive Care manual:

Chapter 49   (pp. 549) Disorders  of  consciousness  by Balasubramanian  Venkatesh

Chapter 44   (pp. 501) Liver  failure by Christopher  Willars  and  Julia  Wendon

Blei, Andres T., and Juan Córdoba. "Hepatic encephalopathy." The American journal of gastroenterology 96.7 (2001): 1968-1976.

Ferenci, Peter, et al. "Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998." Hepatology 35.3 (2002): 716-721.

Prakash, Ravi, and Kevin D. Mullen. "Mechanisms, diagnosis and management of hepatic encephalopathy." Nature Reviews Gastroenterology and Hepatology7.9 (2010): 515-525.

Nabi, Eiman, and Jasmohan S. Bajaj. "Useful Tests for Hepatic Encephalopathy in Clinical Practice." Current gastroenterology reports 16.1 (2014): 1-8.

Guillén, Juan C. Quero, and Juan M. Herrerías Gutiérrez. "Diagnostic methods in hepatic encephalopathy." Clinica chimica acta 365.1 (2006): 1-8.

Shawcross, Debbie L., and Julia A. Wendon. "The neurological manifestations of acute liver failure." Neurochemistry international 60.7 (2012): 662-671.

Conn, Harold O., and Milton M. Lieberthal. The hepatic coma syndromes and lactulose. Williams & Wilkins, 1979. - this is a book, and not available for free online.

Question 16 - 2017, Paper 2

With respect to the management of patients presenting with acute pancreatitis, briefly discuss the following issues:


a) The optimal timing and method of delivery of nutrition.(40% marks)

b) The role of antimicrobials.(40% marks)

c) The role of endoscopic retrograde cholangio-pancreatography (ERCP).(20% marks) 
 

College answer

(a) Method of delivery of nutrition                                                                                                  

  • Mild pancreatitis – oral diet if tolerated. Commence at admission or within 24 hours.
    • No superiority of enteral over oral in this group (NEJM 2014)
  • If unable to tolerate oral intake
    • Enteral preferred to TPN
    • Cochrane 2010 – reduced mortality and other end-points (including infective, MOF)
  • Jejunal not shown to be superior to gastric feeding. Limited evidence (2 small metaanalyses). 
    • No evidence of benefit in delaying feeding awaiting jejunal tube placement – especially in light of apparent benefit of early feeding.
    • Gastric feeding succeeds in delivering nutritional targets in 90%
  • Commence enteral feeds within 48 hours of admission, TPN >5 days

        (b) Use of antimicrobials                                                                                                            

  • Prophylactic antibiotics not recommended o Not indicated for peripancreatic fluid collections or necrosis without clinical (or radiological) evidence of sepsis
    •  Number of meta-analyses – no improvement in mortality, rates of infected necrosis
  • If clinical suspicion of infected necrosis or peripancreatic collection – FNA with culture (high sensitivity)
  • Antibiotics if positive FNA result OR unstable and sepsis suspected while awaiting further investigation
  • If used – choose appropriate antibiotic(s) with GP and Gn cover. Consider antifungal agents.
  • Treatment of other infective complications – e.g. hospital-acquired pneumonia, line-related, urinary tract.

        (c) Role of ERCP                                                                                                                        

  • Not routinely indicated
  • May be cause
  • Should be performed early (24-48 hrs.) in acute gallstone pancreatitis associated with persistent biliary obstruction or cholangitis
    • May not be tolerated / safe in critically unwell patient – consider percutaneous drainage as alternative

Discussion

Nutrition in acute pancreatitis:

  • For mild or moderate pancreatitis:
    • Fast for the first 3-4 days? Oh's Manual suggests that these patients need no feeding whatsoever until the disease settles (i.e. for 5-7 days), but the 2017 college answer recommends immediate feeding. The college quote a study ("NEJM 2014") to support their answer, which presumably is the PYTHON trial by Bakker et al (2014). This was an RCT which compared immediate enteral feeding with oral diet initiated 72 hours after presentation, which is not exactly "commence at admission or within 24 hours" ​​​​​.​
    • Advance to normal oral diet before 72 hours. Bakker et al (2014) found that enteral nutrition is no better than oral.
    • No need to rush enteral nutrition. Only progress to enteral nutrition of the patient is not tolerating oral diet after 5-7 days
    • Avoid TPN. Only progress to TPN if enteral nutrition has been trialled and is clearly not tolerated. The college mention another study ("Cochrane 2010") to support their aversion to TPN,  presumably referring to the meta-analysis by Al-Omran et al (2010). After pruning the evidence tree the authors found only two trials to analyse, with a total of 70 patients. They were forced to conclude that the data were insufficient for any firm recommendation, but that the trend was in the direction of better outcomes with enteral nutrition. This vaguely reflects "reduced mortality and other end-points (including infective, MOF)" which is what the college examiners said about it.
  • For severe pancreatitis:
    • EN is preferable to PN (ASPEN and ESPEN agree on this)
    • EN should be started early.
    • Tube position does not matter (gastric vs jejunal). The college refer to "2 small metaanalyses" in support of their assertion, presumably referring to Chang et al (2013)  with 157 patients and Petrov et al (2008) with 92 patients. A mor recent addition is Zhu et al (2016) who brought the numbers up to 237.  None of these ever found any benefit in jejunal feeding unless you've got clearly demonstrated impaired gastric emptying, i.e. a gastric outlet obstruction. 
    • Elemental feeds are preferred (ASPEN)
    • Nutritional requirements should be:
      • 25-35 kcal/kg of total body weight per day
      • 1.2 to 1.5g/kg of protein
      • 3-6g/kg of carbohydrate
      • go easy on the lipids (up to 2g/kg)
    • When to use parentral nutrition? These guidelines are much less prescriptive than previous statements. "when EN is contraindicated or not well tolerated", they say.

Antibiotics in pancreatitis:

  • There is no role for prophylactic antibiotics in severe acute pancreatitis.
  • Up to 20% of these patients go on to develop extrapancreatic infections which require antibiotics.
  • Half of bacterial cultures of pancreatic necrosis are of non-enteric origin.
  • Of course clinically significant extrapancreatic infections should still be treated with antibiotics

The role of ERCP in pancreatitis:

"May be cause", the college say economically, as if to type a "the" into their answer would incur an intolerable time cost. 

  • ERCP specifically:
    • Diagnostic use:
      • To establish that there are gall stones in the common bile duct
      • To determine that the sphincter of Oddi is dysfunctional
      • To investigate pancreatic duct stenosis
      • To get biopsy samples of a neoplasm
      • To investigate any sort of anastomosis
      • To perform intra-ductal ultrasound
    • Therapeutic use:
      • Sphincterotomy, for stenosis or sphincter dysfunction
      • Stone extraction or fragmentation
      • Placement of a pancreatic duct or common bile duct stent
  • Endoscopy more generally adds a few strategies:
    • Placement of nasojejunal tubes
    • Transgastric drainage of pancreatic pseudocysts

References

ASPEN guidelines

Specifically, section L of the 2016 statement

ESPEN guidelines :
specifically,
MACFIE, J., and ESPEN CONSENSUS GROUP. "ESPEN guidelines on nutrition in acute pancreatitis." Clinical Nutrition 21.2 (2002): 173-183.

Eatock FC, Chong P, Menezes N, Murray L, McKay CJ, Carter CR, Imrie CW. A randomized study of early nasogastric versus nasojejunal feeding in severe acute pancreatitis. Am J Gastroenterol. 2005 Feb;100(2):432-9.

Windsor AC, Kanwar S, Li AG, et al. Compared with parenteral  nutrition, enteral feeding attenuates the acute phase response and improves disease severity in acute pancreatitis. Gut. 1998;42: 431-435.

Ragins H, Levenson SM, Signer R, Stamford W, Seifter E Intrajejunal administration of an elemental diet at neutral pH avoids pancreatic stimulation. Studies in dog and man. .Am J Surg. 1973 Nov;126(5):606-14.

B. W. M. Spanier,1, M. J. Bruno, E. M. H. Mathus-Vliegen Enteral Nutrition and Acute Pancreatitis: A Review Gastroenterol Res Pract. 2011; 2011: 857949. Published online 2010 August 3.

Casaer, Michael P., et al. "Early versus late parenteral nutrition in critically ill adults." N Engl J Med 365.6 (2011): 506-517.

Abou-Assi, Souheil, Kimberly Craig, and Stephen JD O’Keefe. "Hypocaloric jejunal feeding is better than total parenteral nutrition in acute pancreatitis: results of a randomized comparative study." The American journal of gastroenterology 97.9 (2002): 2255-2262.

Petrillo-Albarano, Toni, et al. "Use of a feeding protocol to improve nutritional support through early, aggressive, enteral nutrition in the pediatric intensive care unit*." Pediatric Critical Care Medicine 7.4 (2006): 340-344.

Mirtallo, Jay M., et al. "International consensus guidelines for nutrition therapy in pancreatitis." Journal of Parenteral and Enteral Nutrition (2012): 0148607112440823.

Al-Omran, Mohammed, Ala Groof, and Derek Wilke. "Enteral versus parenteral nutrition for acute pancreatitis." Cochrane Database Syst Rev 1.1 (2003).

Ho, Kwok M., Geoffrey J. Dobb, and Steven AR Webb. "A comparison of early gastric and post-pyloric feeding in critically ill patients: a meta-analysis." Intensive care medicine32.5 (2006): 639-649.

Chang, Yu-sui, et al. "Nasogastric or nasojejunal feeding in predicted severe acute pancreatitis: a meta-analysis." Critical Care 17.3 (2013): R118.

Petrov, Maxim S., M. Isabel TD Correia, and John A. Windsor. "Nasogastric tube feeding in predicted severe acute pancreatitis. A systematic review of the literature to determine safety and tolerance." JOP. Journal of the Pancreas (2008).

Vaughn, Valerie M., et al. "Early versus delayed feeding in patients with acute pancreatitis: a systematic review." Annals of Internal Medicine 166.12 (2017): 883-892.

Oh's Intensive Care manual: Chapter   43  (pp. 495)  Severe  acute  pancreatitis by Duncan  LA  Wyncoll

Heinrich, Stefan, et al. "Evidence-based treatment of acute pancreatitis: a look at established paradigms." Annals of surgery 243.2 (2006): 154-168.

Pederzoli, Paolo, et al. "A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem." Surgery, gynecology & obstetrics 176.5 (1993): 480-483.

Wilmer, Alexander. "ICU management of severe acute pancreatitis." European journal of internal medicine 15.5 (2004): 274-280.

Villatoro, Eduardo, Mubashir Mulla, and Mike Larvin. "Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis."Cochrane Database Syst Rev 5.5 (2010).

Mirtallo, Jay M., et al. "International consensus guidelines for nutrition therapy in pancreatitis." Journal of Parenteral and Enteral Nutrition 36.3 (2012): 284-291.

Baltatzis, Minas, et al. "Antibiotic use in acute pancreatitis: Global overview of compliance with international guidelines." Pancreatology (2016).

Tenner, Scott, et al. "American College of Gastroenterology guideline: management of acute pancreatitis." The American journal of gastroenterology 108.9 (2013): 1400-1415.

Gabbrielli, Armando, et al. "ERCP in acute pancreatitis: What takes place in routine clinical practice?." World journal of gastrointestinal endoscopy 2.9 (2010): 308.

Wu, Bechien U., and Peter A. Banks. "Clinical management of patients with acute pancreatitis." Gastroenterology 144.6 (2013): 1272-1281.

Cherian, Jijo V., et al. "ERCP in acute pancreatitis.Hepatobiliary Pancreat Dis Int 6.3 (2007): 233-240.

Zhu, Youfeng, et al. "Nasogastric nutrition versus nasojejunal nutrition in patients with severe acute pancreatitis: a meta-analysis of randomized controlled trials." Gastroenterology research and practice 2016 (2016).

Question 29 - 2018, Paper 1

You are tasked with developing a guideline for the post-operative ICU / HDU care of patients following bariatric surgery.
a)    How would you identify high risk patients who will require post-operative ICU / HDU admission? (30% marks)
b)    Discuss the important post-operative issues in these patients and their management.
(70% marks)

College answer

Pre-op risk assessment 

  • Respiratory system evaluation            
  • Pulmonary hypertension
  • Sleep apnoea
  • Cardio-vascular evaluation and optimisation                    
  • Functional capacity 
  • Other considerations of relevance          
    • Diabetes, renal insufficiency, hiatus hernia, chronic pain and opioid tolerance issues, extreme weight

b)

Post-operative ICU Management 

  • Monitored environment     
    • HDU, preferably in ICU with 1:1 nursing supervision 
    • Multi-specialty involvement with a shared mental model
  • Respiratory management      
    • Head end elevation and guard against aspiration
    • High risk of post-operative atelectasis
    • Extubation to NIPPV if appropriate
  • Fluid management       
    • Maintain intravascular volume fluid status while not causing edema of the anastomotic site due to excessive infusion, need for accurate monitoring of fluid status (invasive monitoring)
  • Renal issues     
    • Prone to rhabdomyolysis (prolonged surgery, steep trendelenberg position, high BMI)
    • High index of clinical suspicion (particularly if complaining of pain in the buttocks, hips or shoulders)
  • Hyper-coagulopathy and increased risk of venous thromboembolism    
  • Close monitoring of glycaemic status and variability (insulin resistance); thyroid profile     
  • Regular (rather than prn) anti emetics
  • analgesia – avoid opioids if possible
  • Early mobilisation and physiotherapy, close attention to ICU housekeeping issues (FASTHUGS etc.)     

Altered pharmacokinetic profile in morbidly obese patients needs careful consideration

Discussion

The phrase "multi-specialty involvement with a shared mental model" sounds like something the candidates should memorise and deploy alongside phrases like "therapeutic alliance" and "client-centered healthcare". It almost belongs on the glossy brochure of a private obesity clinic. Looking beyond nauseating corporate slogans, there is wisdom here: the involvement of multiple teams is required for these high-risk patients to thrive. The best single guideline statement to read for this answer was probably Mechanick et al (2013).

a)

Features of high-risk bariatric patients:  In discussing this, everybody seems to quote the 2010 study by Birkmeyer et al, who assessed the features associated with hospital complications of bariatric surgery among 15,275 Michigan residents. Another highly referenced publication is the LABS consortium paper in NEJM (2009). The following factors were found to be associated with an increased risk of serious complications:

  • Patient factors:
    • Cardiovascular disease (eg. ischaemic herat disease)
    • Smoking
    • Sleep apnoea
    • Age over 70 (though LABS did not find this was the case)
    • BMI over 70
    • Cirrhosis
    • End-stage renal failure
    • Immunosuppression
    • Impaired functional status
    • History of DVT or PE
  • Surgical factors:
    • Laparoscopic band patients are lower risk
    • Gastric bypass or sleeve gastrectomy patients were higher risk
      (all this may be because the laparoscopic surgery candidates had a lower BMI on average)

Pre-operative risk assessment for bariatric surgical patients should therefore consist of investigations which detect and (hopefully) modify some of these risks pre-operatively. Mechanick et al (2013) have an excellent preoperative checklist for this population (their Table 5), which is reproduced here with minimal modification:

  • Bloods: BSL, lipids, kidney function, liver profile, urine analysis, FBC, coags
  • Nutrient screening: iron studies, B12 and folic acid (RBC folate, homocysteine, methylmalonic acid optional), and 25‐vitamin D (vitamins A and E optional)
  • Cardiac evaluation: ECG, CXR, echocardiography, lower limb Dopplers 
  • GI evaluation: H.pylori screening, gallbladder evaluation, upper endoscopy if indicated
  • Endocrine evaluation: HBA1c, TSH, androgens with PCOS suspicion, cortisol levels (for Cushing disease)
  • Psychosocial‐behavioral evaluation: encourage patient to continue efforts for preoperative weight loss
  • Diabetes educator: optimize glycemic control
  • Smoking: cessation counseling
     

Post-operative management of bariatric surgery patients

An excellent article by Thornton et al (2017) is available for the paying customers of UpToDate. 

  • Disposition
    • 1:1  nursing is reasonable because:
      • the patient may still be ventilated
      • there may be unstable BSL which requires constant adjustment
      • there may be haemodynamic instability which requires constant vigilance
  • Extubation
    • ​​​​​​​One might summarise the extubation criteria for these patients as "crisp".  They need to be wide awake and completely cooperative, with full muscle power.
    • Re-intubation will be difficult due to what can be euphemistically be called "redundant oropharyngeal tissue". Approach to the cricothyroid membrane in an emergency may be impossible because of depth. 
  • Ventilation
    • ​​​​​​​Dose your tidal volumes to ideal body weight
    • Oesophageal manometry would be ideal to help quantify the contributions of the chest wall to total compliance, but it is unlikely to be available, particularly as the upper GI surgeon may be somewhat reluctant to place any devices in the recently instrumented upper GI tract.
    • The guidelines recommend something they describe as "aggressive perioperative pulmonary toilet", which sounds terrible but probably just means "frequent tracheal suctioning".
    • After extubation, a period of NIV may be useful
  • Vascular access and monitoring
    • PICC lines are usually suggested as a means of having convenient long-term IV access
    • Arterial lines are expected as a part of the management package, mainly because it is otherwise difficult to get blood from these people.
  • Sedation
    • ​​​​​​​No specific recommendations are available, but people seem to trend towards the use of dexmedetomidine as a co-analgesic and sedative
  • Analgesia
    • ​​​​​​​Because opiates are obviously bad for these people who are chronically at the brink of hypercapneic respiratory failure, generally regional techniques (such as thoracic epidural) are favoured
  • Electrolytes and endocronology
    • ​​​​​​​One should pay careful attention the the BSL of all ICU patients, and there is really nothing about these diabetics that might discriminate them from other critically ill diabetics.
    • If the patient has hypothyroidism, it is important to negotiate some strategy with the surgeon regarding oral thyroxine replacement (i.e. how long would they want the patient to remain fasted after the anastomosis).
  • Fluid management and renal monitoring
    • ​​​​​​​The college recommends caution with fluid resuscitation, so as to avoid making the anastomosis oedematous. This is of course completely at odds with the need to resuscitate them vigorously when you discover their rhabdomyolysis (Chakravartty et al, 2013). Older patients, those with long operations, high BMI, hypertension and those using statins are at higher risk. Apparently a CK rise over 1,000 IUs is relatively common, and is associated with an acute renal failure rate of 14%. If this develops, hospital mortality from this supposedly elective procedure increases to 25%. 
  • Diet and nutrition
    • ​​​​​​​Mechanick et al (2013) recommend a "low‐sugar clear liquid meal program" to commence after 24 hours, but this is obviously going to depend on the type of surgery and how many inadvertent enterotomies there were.
    • Vitamin supplementation should take place in patients with risky premorbid nutrition (i.e. just because they are obese does not mean they are not suffering from poor nutrition)
  • DVT prophylaxis
    • ​​​​​​​Low molecular weight heparin should probably be dosed to total body weight
  • Antibiotics
    • ​​​​​​​Are not indicated, except to prevent or manage recalcitrant thiamine deficiency (apparently upper GI bacterial overgrowth in these people can result in thiamine deficiency)

References

Bergeat, Damien, et al. "Postoperative outcomes of laparoscopic bariatric surgery in older obese patients: a matched case-control study." Obesity surgery 27.6 (2017): 1414-1422.

Birkmeyer, Nancy JO, et al. "Hospital complication rates with bariatric surgery in Michigan." Jama 304.4 (2010): 435-442.

Longitudinal Assessment of Bariatric Surgery (LABS) Consortium. "Perioperative safety in the longitudinal assessment of bariatric surgery." New England Journal of Medicine 361.5 (2009): 445-454.

Mechanick, Jeffrey I., et al. "Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient—2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery." Surgery for Obesity and Related Diseases 9.2 (2013): 159-191.

Thornton, Kevin, et al. "Bariatric surgery: Intensive care unit management of the complicated postoperative patient."

Chakravartty, Saurav, Diwakar R. Sarma, and Ameet G. Patel. "Rhabdomyolysis in bariatric surgery: a systematic review." Obesity surgery 23.8 (2013): 1333-1340.

Question 7 - 2018, Paper 1

a)    What are the radiological features of colonic pseudo-obstruction / Ogilvie's syndrome? (20% marks)
b)    List six conditions which are associated with colonic pseudo obstruction        (20% marks)
c)    Briefly outline your approach to management.  (60% marks)

College answer

a)

Plain films: - Identical to mechanical obstruction: dilated bowel loops: may have fluid levels CT demonstrates dilated large bowel without a clear transition point or obstructing lesion.

b)

Trauma, especially fractures 

Recent surgery, especially involving spinal anaesthesia 

Burns 

Diabetes Mellitus

Uraemia

Severe medical illness, such as pneumonia, myocardial infarction, or heart failure 

Neurologic conditions 

Chemotherapy (e.g., all-trans retinoic acid, methotrexate, vincristine) 

Retroperitoneal pathology, such as malignancy or haemorrhage 

Electrolyte disturbance 

Medication (e.g., narcotics, phenothiazine’s, calcium channel blockers, alpha-2-adrenergic agonists, epidural analgesics)  

c)

Initial management of acute colonic pseudo-obstruction consists of conservative therapy in patients without significant abdominal pain or signs of peritonitis and those who have one or more potential factors that are reversible.  

Treat underlying disease, stop aggravating drugs, avoid laxatives, and keep NPO. NG tube – encourage mobility. Consider opiate reversal agents e.g. GI naloxone or SC Naltrexone

If fail or progress consider neostigmine:  In patients with caecal diameter >12 cm (varies) or failure of 24 to 48 hours of conservative therapy. Up to 2 mg slow IV and repeat if needed. Lower doses may also be effective. Studies have shown high response rate with low rate of recurrence. Side effects include abdominal pain, hypersalivation, vomiting and bradycardia. Perforation may occur if there is unrecognised mechanical obstruction.

Colonoscopy decompression: Those patients who fail or who have contraindications to neostigmine. Technically difficult and perforation is a risk. No randomised trials.

Surgery: In the absence of a colonic perforation, cecostomy tube or a segmental or subtotal resection with primary anastomosis can be performed. In the patients with a colonic perforation, a total colectomy, ileostomy, and Hartmann procedure are performed to retain the option of future ileorectal anastomosis

Examiners Comments:

Management plan poorly structured in many cases. Overall reasonably well answered.

Discussion

a)

Radiological features of colonic pseudo-obstruction:

  • Plain radiography: findings identical to mechanical obstruction, i.e. dilated bowel loops
  • CT findings: gaseous dilatation of the colon with no stricture, mass or clear transition point. A "smooth transition" may be seen, which is a slight discrepancy in diameter between the proximal and distal bowel loops - less than 50% (Choi et al, 2008).

b)

The list of risk factors for colonic-pseudo-obstruction specifically is derived from Saunders et al (2005) and Wells et al (2017):

  • Surgical: Cardiac surgery, solid organ transplantation, major orthopaedic surgery, spine surgery
  • Cardiorespiratory    Shock, myocardial infarction, congestive heart failure, chronic obstructive pulmonary disease
  • Neurological    Dementia, Parkinson’s disease, Alzheimer’s disease, stroke, spinal cord injury
  • Metabolic    Electrolyte imbalance, diabetes, renal failure, hepatic failure
  • Medications    Opiates, anti-Parkinson agents, anticholinergics, antipsychotics, cytotoxic chemotherapy, clonidine
  • Obstetric/gynaecological    Caesarean section, normal vaginal delivery, instrumental delivery, preeclampsia, normal pregnancy, pelvic surgery
  • Infectious    Varicella-zoster virus, herpes virus, cytomegalovirus
  • Miscellaneous    Major burns/trauma, severe sepsis, idiopathic

For ileus and constipation in general, you would expect the following risk factors:

Modifiable ICU-related risk factors

  • Delayed enteral nutrition (delayed for longer than 24 hrs) - although early enteral nutrition has also been blamed, and in fact in ICU patients nasogastric nutritional formula is at least as likely to cause constipation as diarrhoea ( Montejo et al, 1999).
  • Reduced mobility
  • Deep sedation
  • Heavy opiate use
  • Anticholinergic drug side effects
  • Calcium channel blockers
  • The use of paralysing infusions
  • Electrolyte disturbance, eg.hypokalemia hypercalcemia and hypomagnesemia
  • Dehydration, inadequate fluid resuscitation (or excess diuresis)
  • Hypotension (SBP under 90mmHg - Gacouin et al, 2010)
  • Hypoxia (P/F ratio under 150 - also Gacouin et al)

Non-modifiable disease risk factors

  • Abdominal surgery
  • Severe illness
  • Paralysis (eg. spinal cord injury) 
  • Prior alcohol or cannabis use
  • Nicotine withdrawal

c)

Most of this comes from Saunders et al (2005). Options for management of colonic pseudo-obstruction can be divided into categories:

Supportive

  • Nil by mouth
  • Correct electrolytes
  • Ensure the patient is well-hydrated
  • Nasogastric tube on free drrainage or low wall suction
  • Rectal tube to gravity drainage
  • Limit anti-motility medications, such as opiates and anticholinergic agents
  • Mobilise the patient and sit them out ouf bed

Pharmacological (pro-motility) management

  • Oral or nasogastric naloxone
  • Methylnaltrexone
  • Enema
  • Erythromycin
  • Neostigmine

Interventional (decompressive) management

  • Sigmoidoscopy
  • Colonoscopy 
  • Surgical decompression
  • Caecostomy 
  • Colectomy, ileostomy, and Hartmann procedure

References

Ogilvie, Heneage. "Large-intestine colic due to sympathetic deprivation." British Medical Journal 2.4579 (1948): 671.

Choi, Ji Soo, et al. "Colonic pseudoobstruction: CT findings." American Journal of Roentgenology 190.6 (2008): 1521-1526.

Saunders, M. D., and M. B. Kimmey. "Systematic review: acute colonic pseudo‐obstruction.Alimentary pharmacology & therapeutics 22.10 (2005): 917-925.

Wells, Cameron I., Gregory O’Grady, and Ian P. Bissett. "Acute colonic pseudo-obstruction: A systematic review of aetiology and mechanisms." World journal of gastroenterology23.30 (2017): 5634.

Question 10 - 2018, Paper 1

With regard to gastric ulceration in the ICU:
a)    List five risk factors for developing stress related gastric ulceration in ICU patients.
(20% marks)
b)    Discuss briefly strategies for prevention of gastrointestinal bleeding resulting from stress ulcers among ICU patients. Include in your answer the available evidence for these. (80% marks)

College answer

a)

Risk factors 

  1. Coagulopathy, 
  2. Mechanical ventilation for >48 hours
  3. Renal failure
  4. Traumatic brain injury, spinal cord injury, or burn injury
  5. History of GI ulceration or bleeding within the past year
  6. Shock 
  7. An intensive care unit (ICU) stay more than one week, 
  8. Occult GI bleeding for six or more days 
  9. Glucocorticoid therapy.

b)

Strategies for prevention of GI bleeding resulting from stress ulcers among ICU patients. 

  • Prevent gastric ischemia
    • Treat underlying problem responsible for gut Ischemia.
    • Supportive ICU care
  • Reduce gastric acid injury
    • Decrease acid production (H2 Antagonist and PPI)
      • Advantages
        • Decreased risk of gastrointestinal bleeding
        • Decreased exposure to blood products, and associated risk related to transfusion
      • Disadvantages
        • Decreased gastric acidity, thus increased risk of non-sterile aspiration and development of nosocomial pneumonia.
        • Increased risk of gastrointestinal bacterial overgrowth and translocation
        • Increased risk of Clostridium difficile infections

H2 blockers: 

Inhibits histamine stimulated acid secretion and are better than placebo, antacid or sucralfate as stress ulcer prophylaxis. No evidence they are superior than PPI.

Tolerance, requires dose adjustment in renal failure; rarely causes thrombocytopenia. 

Proton pump inhibitors: 

Pantoprazole and omeprazole do seem to have some benefit in protecting patients from stress ulceration. In critically ill patients, proton pump inhibitors seem to be more effective than histamine 2 receptor antagonists in preventing clinically important and overt upper gastrointestinal bleeding. No clear evidence that one PPI is better than the other.

Meta-analysis of 13 RCTs; n = 1587 patients (H2 blockers versus PPI) Found less GI bleeding among those who received a PPI (1.3 versus 6.6 percent, odds ratio 0.30, 95% CI 0.17-0.54) no difference in mortality or the incidence of nosocomial pneumonia.  (Detail not required)

 Side effects include: Interstitial nephritis Clostridium difficile enterocolitis, GI upset and headaches. Long-term use associated with fractures, hypomagnesemia hypocalcemia.

Enteral feeding 

Observational studies data suggest that enteral nutrition may be adequate substitute for pharmacologic stress ulcer prophylaxis in ICU patients, however controlled trials are necessary for confirmation.  There appears to be no benefit for stress ulcer prophylaxis in patients who are tolerating enteral feeding, and in these patients stress ulcer prophylaxis may not be needed. However, it is still unclear if enteral feeding is alone sufficient in protection of stress ulcers in high risk patients. 

Examiners Comments:

 Generally, poorly answered. Superficial knowledge of pharmacology and evidence base. 

Discussion

a) 

According to Cook et al (1994), independent risk factors for stress ulceration are:

  • Respiratory failure with mechanical ventilation for >48 hrs
  • Coagulopathy or anticoagulant use
  • Hypotension, shock states of any sort
  • Liver failure
  • Renal failure
  • Fasting state (no enteral feeding)
  • Steroid use (especially dexamethasone)

b)

To "include in your answer the available evidence for these", this answer to Question 1 from the first paper of 2003 was updated with contemporary data.

  • Antacids - These were the mainstay of ulcer prophylaxis in the 1980s (see Gonzalez et al, 1985). They were given hourly, and required hourly gastric pH measurement to titrate (the usual goal was to aim for a gastric pH of > 5.0). The available agents tend to have nasty metallic ions eg. magnesium, aluminium, sodium. Also, one might develop some metabolic alkalosis, or worse yet a bowel obstruction.
  • Sucralfate - an aluminium salt of sucrose octasulphate - coats ulcers and increases mucus production, but does absolutely nothing for gastric pH. This may be an advantage, as the low pH can continue killing pathogenic organisms, while the mucosa is protected by a thick coat of nicely viscous mucus. Again, constipation is a major side-effect. Sucralfate can form a bezoar, clogging the gastric outlet, and it can prevent the absorption of nutrients by binding to the components of enteral feeds. It is also thought to have a tendency to absorb or adsorb useful medications. The popularity of sucralfate decreased in the late 1990s when a trial compared it unfavorably to ranitidine (Cook et al, 1998); in fact ranitidine was twice as good.
  • H2-receptor antagonists like ranitidine became popular in the wake of trials which favourable compared them to antacids and sucralfate. Unfortunately these drugs have a tendency towards tachyphylaxis after the first day of therapy. Their use has been largely superceded by PPIs; however their one major remaining advantage is cost. Wikipedia lists the wholesale price of one tablet as 0.01$ (US), making it attractive in the developing world
  • Proton pump inhibitors eg. pantoprazole and omeprazole became available in the nineties and have subsequently superceded the H2 receptor antagonists. The college answer refers to a meta-analysis -if you can call that "refers", as they do not give a proper reference. That meta-analysis is Barkun et al (2012). A more recent publication (Alshamsi et al, 2016) included 19 trials (2117 patients) and found that overall there was a reduction in the risk of clinically significant bleeding when compared to H2 receptor antagonists, but with a NNT of 37. There was no mortality benefit. Also, thus far nobody can tell which patients are at sufficiently high risk to benefit from them. Fortunately, detail not required.
  • Enteral nutrition buffers gastric pH and suppresses stress-induced vagal stimulation, while proving trophic and circulatory benefits to the gut mucosa, but is occasionally impractical (i.e. not always can you feed them). Furthermore, these benefits were demonstrated mainly in animal studies and retrospective audits (MacLaren, 2001). A more recent prospective RCT (El-Kersh, 2018) found no difference, but only 2 patients had GI bleeding in each group. Ultimately, the benefit of enteral nutrution as stress ulcer prophylaxis has been extrapolated from the finding that it is usually safe to withold PPIs from patients who are tolerating enteral nutrition, i.e. with no additional GI bleeding risk (Alhazzani et al, 2017).

References

Oh's Intensive Care manual: Chapter 42  (pp. 487)  Acute  gastrointestinal  bleeding  by Joseph  JY  Sung

Cook, Deborah J., et al. "Risk factors for gastrointestinal bleeding in critically ill patients." New England Journal of Medicine 330.6 (1994): 377-381.

Marik, Paul E., et al. "Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis." Crit Care Med 38.11 (2010): 2222-2228.

Krag, Mette, et al. "Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients." Intensive care medicine 40.1 (2014): 11-22.

Madsen, Kristian Rørbæk, et al. "Guideline for Stress Ulcer Prophylaxis in the Intensive Care Unit." Danish medical journal 61.3 (2014): 1-4.

Plummer, Mark P., Annika Reintam Blaser, and Adam M. Deane. "Stress ulceration: prevalence, pathology and association with adverse outcomes."Critical Care 18.2 (2014): 213.

Yearsley, K. A., et al. "Proton pump inhibitor therapy is a risk factor for Clostridium difficile‐associated diarrhoea." Alimentary pharmacology & therapeutics 24.4 (2006): 613-619.

Steinberg, Kenneth P. "Stress-related mucosal disease in the critically ill patient: risk factors and strategies to prevent stress-related bleeding in the intensive care unit." Critical care medicine 30.6 (2002): S362-S364.

Buendgens, Lukas, Alexander Koch, and Frank Tacke. "Prevention of stress-related ulcer bleeding at the intensive care unit: Risks and benefits of stress ulcer prophylaxis." World journal of critical care medicine 5.1 (2016): 57.

Gonzalez, Edgar R., and Anthony R. Morkunas. "Prophylaxis of stress ulcers: Antacid titration vs. histamine2-receptor blockade." Drug intelligence & clinical pharmacy 19.11 (1985): 807-811.

Cook, Deborah, et al. "A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation." New England Journal of Medicine 338.12 (1998): 791-797.

Oh's Intensive Care manual: Chapter 42  (pp. 487)  Acute  gastrointestinal  bleeding  by Joseph  JY  Sung

Cook, Deborah J., et al. "Risk factors for gastrointestinal bleeding in critically ill patients." New England Journal of Medicine 330.6 (1994): 377-381.

Marik, Paul E., et al. "Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis." Crit Care Med 38.11 (2010): 2222-2228.

Krag, Mette, et al. "Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients." Intensive care medicine 40.1 (2014): 11-22.

Madsen, Kristian Rørbæk, et al. "Guideline for Stress Ulcer Prophylaxis in the Intensive Care Unit." Danish medical journal 61.3 (2014): 1-4.

Plummer, Mark P., Annika Reintam Blaser, and Adam M. Deane. "Stress ulceration: prevalence, pathology and association with adverse outcomes."Critical Care 18.2 (2014): 213.

Yearsley, K. A., et al. "Proton pump inhibitor therapy is a risk factor for Clostridium difficile‐associated diarrhoea." Alimentary pharmacology & therapeutics 24.4 (2006): 613-619.

Steinberg, Kenneth P. "Stress-related mucosal disease in the critically ill patient: risk factors and strategies to prevent stress-related bleeding in the intensive care unit." Critical care medicine 30.6 (2002): S362-S364.

Buendgens, Lukas, Alexander Koch, and Frank Tacke. "Prevention of stress-related ulcer bleeding at the intensive care unit: Risks and benefits of stress ulcer prophylaxis." World journal of critical care medicine 5.1 (2016): 57.

Gonzalez, Edgar R., and Anthony R. Morkunas. "Prophylaxis of stress ulcers: Antacid titration vs. histamine2-receptor blockade." Drug intelligence & clinical pharmacy 19.11 (1985): 807-811.

Cook, Deborah, et al. "A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation." New England Journal of Medicine 338.12 (1998): 791-797.

MacLaren, Robert, Catherine L. Jarvis, and Douglas N. Fish. "Use of enteral nutrition for stress ulcer prophylaxis." Annals of Pharmacotherapy 35.12 (2001): 1614-1623.

El-Kersh, Karim, et al. "Enteral nutrition as stress ulcer prophylaxis in critically ill patients: A randomized controlled exploratory study." Journal of critical care 43 (2018): 108-113.

Alhazzani, Waleed, et al. "Withholding pantoprazole for stress ulcer prophylaxis in critically ill patients: a pilot randomized clinical trial and meta-analysis." Critical care medicine 45.7 (2017): 1121-1129.

Barkun, Alan N., et al. "Proton pump inhibitors vs. histamine 2 receptor antagonists for stress-related mucosal bleeding prophylaxis in critically ill patients: a meta-analysis." The American journal of gastroenterology 107.4 (2012): 507.

Question 16 - 2018, Paper 1

Outline the specific management issues to address in a patient during the first 24 hours following liver transplantation.

College answer

Initial detailed assessment and resuscitation as indicated 
Particular care regarding volume status and identification of bleeding and early graft function Adequate analgesia and sedation 
Protocolised care; close liaison between ICU and other teams involved e.g. surgeons and transplant physicians 
Enteral nutrition 
DVT prophylaxis; usually mechanical Early mobilisation 
Lines and access management: need to rationalise multiple access when stability achieved and coagulation profile acceptable 
Assess suitability for stepdown if no complications 
 
Cardiovascular 
Vasodilated state often requiring pressor support for adequate MAP 
Careful management of volume status and early recognition of bleeding important; large fluid shifts; drain losses may be large and require ongoing volume administration. Avoid elevated CVP 
 
Graft 
Assessment of function via monitoring of coagulation profile, lactate, acid base and transaminases. 
(frequent blood tests/QID) 
Ultrasound assessment of graft particularly hepatic artery / vein / portal vein patency and flow characteristics 
Primary graft nonfunction may be indicated by conventional signs of liver failure i.e. worsening coagulopathy, acidosis, encephalopathy, AKI, hypoglycaemia 
 
Respiratory 
Early extubation when stability ensured 
Patients with hepatopulmonary syndrome or portopulmonary hypertension may need prolongation of ventilation.  pHT may require perioperative management with chronic therapies as well as acute therapies to reduce congestion of graft 
 
Coagulation / Transfusion 
Coagulopathy monitored and indicator of graft function, viscoelastic tests 
Not corrected unless bleeding or severe coagulopathy due to risks vascular thrombosis Hb target above 70 but consideration venesection if Hb > 100g/l 
 
Immunosuppression 
Should be protocoled e.g.  Methylprednisolone / Azathioprine OR MMF / Tacrolimus OR Cyclosporin Variations may be institution based or patient factors e.g. Basiliximab may be given if renal dysfunction preoperatively in lieu of Calcineurin inhibitor 
 
Infection 
Routine postoperative antibiotics not necessary but will depend upon institutional protocols / intraoperative events and preoperative patient status 
Postoperative IV antifungals often given in high risk cases (higher CP or MELD status) 
CMV prophylaxis if CMV pos graft in CMV neg recipient 
Hep B Ig and ongoing antivirals if Hep B patients 
Cytotoxic precautions
 

Renal 
Oliguria likely indicator of hypovolaemia; assess for bleeding 
Consider intraabdominal hypertension 
 
Examiner Comments: 
 
Generally, well answered. Candidates that did poorly made generic comments about post-operative care without specific issues related to liver transplantation or lacked detail in their answers. 

 

Discussion

This is another permutation of the liver transplant SAQ, which in its other incarnations has also included some questions about why the post-transplant patient might be still unconscious after 12 hours. This time,  the college asked about "specific management issues", which is ironically much less specific than the previous questions on this topic. The discussion section for the old SAQs (Question 9 from the second paper of 2015 and Question 11 from the second paper of 2012) was sufficiently detailed that it can also cover this question, and is therefore reproduced here with minimal modification. Furthermore it is worth pointing out that the college model answer to this SAQ is far better than the previous model answers.

The following management steps may be followed in the first 24 hour period:

  • Airway:
    • Historically these patients tend to remain intubated for the first 12-24 hours, although there is good evidence that early extubation (eg. in theatre) has no adverse effects.
  • Breathing:
    • In order for the graft to survive normoxia must be established
    • The general "word of mouth" advice in these situations is to minimise the PEEP. In order for the anastomoses to remain intact, PEEP should be minimised, as it will increase the CVP and thus compromise the venous vascular anastomotic sites. However, some studies have reported no significant change to the hepatic venous flow even with PEEP as high as 15cm H2O.
    • Positive pressure ventilation in general is a bad idea, as organ perfusion is decreased by positive pressure, and perfusion of the donated liver is very important in the early stages.
    • Thus, early weaning from invasive ventilation is one of the major goals
  • Circulation
    • There is likely to be a degree of shock. Given that fluid management must remain relatively conservative, vasopressors and inotropes must be deployed liberally. After all, the graft needs to remain perfused.
    • Hepatic oedema due to over-resuscitation should be avoided.
    • Arbitrarily, the CVP should remain within the range of 6-10.
    • Observe for reactive vasoconstriction
      • These patients, with heir dead livers, have been in a vasodilated state, associated with nitric oxide synthase hyperactivity.
      • Now, with their new livers, normal vascular tone will return.
      • This might mean a sudden massive increase in the afterload.
      • Thus, their left ventricles, which are chronically deconditioned, might decompensate when faced with such demands.
      • Thus, GTN or nitroprusside infusions should be used liberally in these people.
    • The need for RF and LV functional assessment as well as pulmonary arterial pressure measurements and
  • Neurology and sedation
    • No specific recommendations can be made, rather than to say that both hepatic and renal dysfunction in the post-operative period is to be anticipated, and thus drugs which do not rely on organ metabolism should be used. Remifentanyl and propofol spring to mind.
  • Fluids and electrolytes
    • There is some "magical" preload at which the CVP is reasonable, preload adequate, and cardiac output satisfactory. Finding this magic preload is something of an art.
    • Initially, fluid resuscitation should take place, but the fluid of choice should not be Hartmanns because the new liver will probably not be able to metabolise the lactate.
    • After the initial post-operative resuscitation phase is over, a negative fluid balance should be pursued; generating a lower pressure in the right side of the thoracic circulation will serve to draw blood from the graft, and thus theoretically should improve graft perfusion.
    • Renal function needs to be watched closely - renal failure is associated with poor graft survival.
  • Graft function
    • There is a phase of "preservation injury" with very high LFTs but this tends to disappear over the first 3-4 days. Thereafter, synthetic function should be restored.
    • Monitoring of the graft consist of several sequential assessments:
      • Hepatic arterial Doppler
      • BSL
      • Lactate
      • Bilirubin
    • Typically, 1-9% of liver transplants fail within hours of surgery.
  • Surveillance for abdominal compartment syndrome
    • Due to the extensive nature of the procedure and due to the preexisting portal venous pathology, this issue (with pressure over 25mmHg) is fairly common.
    • Abdominal girth values are required as sequential measurements.
  • Nutritional support
    • There is no string reason to recommend TPN here. Like in most other situation, nasogastric enteral feeding is probably best. A degree of ileus is to be expected, and usually resolves
  • Hematological support
    • This consists of the replacement of missing blood products and blood cells.
    • Essentially, there is no specific hemoglobin goal, and what you are trying to do is prevent bleeding from the anastomotic sites.
    • Its probably OK to be slightly coagulopathic, because you don't want to develop a hepatic arterial thrombus.
  • Immune suppression
    • I will not litter this summary with discussion of the relative merits of each class of antirejection drug. Suffice to say, cyclosporin tacrolimus and mycophenolate are gradually giving way to monoclonal antibodies and other immunomodulator drugs which have slightly less devastating organ system effects.
  • Antibiotics and sepsis surveillance
    • Many of these patients die from postoperative infectious complications
    • 48 hrs of IV antibiotics are typically administered
    • The Sanford Guide recommends linezolid, ciprofloxacin and fluconazole.
    • The belowlinked article from 2011 also suggests 14 days of aciclovir, given the propensity for embarrassing HSV reactivation.

References

Chapter 101  (pp. 1040)  Liver  transplantation by Anish  Gupta,  Simon  Cottam  and  Julia  Wendon

Roberts, Mark S., et al. "Survival after liver transplantation in the United States: a disease‐specific analysis of the UNOS database." Liver transplantation 10.7 (2004): 886-897.

Onaca, Nicholas N., et al. "A correlation between the pretransplantation MELD score and mortality in the first two years after liver transplantation." Liver transplantation 9.2 (2003): 117-123.

Vaid, Arjun, et al. "Molecular adsorbent recirculating system as artificial support therapy for liver failure: a meta-analysis." ASAIO Journal 58.1 (2012): 51-59.

Bañares, Rafael, et al. "Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute‐on‐chronic liver failure: The RELIEF trial." Hepatology 57.3 (2013): 1153-1162.

Schroeder, Rebecca A., et al. "Intraoperative fluid management during orthotopic liver transplantation." Journal of cardiothoracic and vascular anesthesia 18.4 (2004): 438-441.

Kirby, R. M., et al. "Orthotopic liver transplantation: postoperative complications and their management." British journal of surgery 74.1 (1987): 3-11.

Hannaman, Michael J., and Zoltan G. Hevesi. "Anesthesia care for liver transplantation."  Transplantation Reviews 25.1 (2011): 36-43.

Moreno, Rosalba, and Marina Berenguer. "Post-liver transplantation medical complications."  Ann Hepatol 5.2 (2006): 77-85.

McCaughan, Geoffrey W., and Stephen R. Munn. "Liver transplantation in Australia and New Zealand." Liver Transplantation 22.6 (2016): 830-838.

Question 22 - 2018, Paper 1

A 34-year-old male has been in the ICU for almost three weeks and has undergone several laparotomies following complex abdominal trauma. He appears to have nasogastric feed emanating from his dehisced laparotomy wound and has developed a vasopressor requirement.
Give the likely diagnosis, and outline the principles of its management.

College answer

Enterocutaneous fistula (ECF) with inadequate source control

Or ECF with undrained collection

Or ECF with septic shock

  • Management
    • Fluid and electrolyte
      • Match losses with crystalloid replacement
      • High sodium loss in high output fistulae
      • Supplement magnesium, phosphate and potassium
    • Sepsis management
      • Source control
      • Target antibiotics, antifungal
  • Surgical or percutaneous drainage of associated collections
  • Definitive surgical management may be delayed 
  • Rule out other sources of infection
     
  • Nutrition
    • TPN often required particularly if proximal fistulae
    • Enteral intake may not be possible if < 75cm bowel remaining
    • Trial elemental feed if intolerant or increased output with polymeric feed
    • Role of zinc and vitamin supplement controversial
  • Wound management and effluent control
    • Principle is effective drainage allowing wound healing
    • Ostomy appliance 
    • VAC dressing controversial as may cause harm, but can be very effective in effluent management of high output fistula
  • Reducing fistulae output
    • Reduce enteral intake and/or consider elemental feed
    • Antidiarrheal – loperamide
    • Somatostatin analogues – octreotide
  • Definition of fistulae anatomy
    • Often difficult to define single source
    • Define and/or exclude distal obstruction
    • CT, fistulography etc

Definitive surgery - may be much later

Examiner Comments:

Not well answered. Many candidates described a generic approach to intra-abdominal sepsis without considering the specific issues related to enterocutaneous fistulae.

Discussion

An approach more directly relevant to enterocutaneous fistulae is described by Cohen et al (2016) Lundy & Fischer (2010) and Evenson (2016).

  • Stabilisation where you resuscitate the septic shock
    • Fluid resuscitation should be conservative to prevent intestinal oedema
    • Vasopressor support should be careful to prevent intestinal ischaemia
  • Diagnosis where you confirm the location and extent of the fistula, by:
    • Methylene blue dyed feeds
    • Contrast "fistulogram" using water-soluble contrast and plain films or fluoroscopy (contrsat both rectal and oral)
    • Contrast CT, which has largely surpassed the fistulogram
  • Evaluation for spontaneous resolution where you decide whether this needs to go to theatre urgently, or whether you can sit on it for a month. Apart from imaging and historicla features, this includes
    • Nutritional assessment, incl. prealbumin, transferrin and clinical assessment
    • Attempted early surgery if you think you can't wait for it to get better on its own (and if the patient is likely to survive)
  • Trial of non-operative management if the impression is that surgery can be delayed
  • Management of infectious complications during conservative management:
    • Intra-abdominal faecal contamination initially - managed with broad-spectrum antibiotics (eg. peperacillin/tazobactam) as well as an antifungal if there are risk factors (malignancy, re-laparotomy, long term antibiotics)
    • Abdominal collections after a prolonged course of systemic antibiotics
  • Management of non-infectious complications during conservative management: 
    • Fluid losses particularly of high-output fistulas: strategies to decrease output include
      • avoidance of vac dressings
      • TPN
      • Octreotide, l​​​​​operamide, opiates
      • Diverting proximal stoma
      • Relief of distal bowel obstruction
    • Malnutrition: TPN and vitamin supplementation
    • Gut atrophy: low volume enteral feeds, or enteral nutrition given via the fistula
    • Electrolyte disturbance resulting from high stoma output (management of this depends mainly on vigilant replacement)
    • Skin excoriation due to spills (management of this requires a dedicated stoma service, or plastic surgical input to deal with tissue loss)
  • Definitive surgical management; or, when it becomes clear that this is not an option,
  • Palliative care

References

Cohen, Wess A., et al. "The complex surgical abdomen: What the nonsurgeon intensivist needs to know." Journal of intensive care medicine 31.4 (2016): 237-242.

Edmunds Jr, L. Henry, G. M. Williams, and Claude E. Welch. "External fistulas arising from the gastro-intestinal tract." Annals of surgery 152.3 (1960): 445.

Lundy, Jonathan B., and Josef E. Fischer. "Historical perspectives in the care of patients with enterocutaneous fistula." Clinics in colon and rectal surgery 23.3 (2010): 133.

Chapman, Richard, Robert Foran, and J. Englebert Dunphy. "Management of intestinal fistulas." The American Journal of Surgery 108.2 (1964): 157-164.

Evenson, Amy R., and Josef E. Fischer. "Current management of enterocutaneous fistula.Journal of gastrointestinal surgery 10.3 (2006): 455-464.

Gribovskaja-Rupp, Irena, and Genevieve B. Melton. "Enterocutaneous fistula: proven strategies and updates." Clinics in colon and rectal surgery 29.2 (2016): 130.

Hutchins, Robert R., et al. "Relaparotomy for suspected intraperitoneal sepsis after abdominal surgery." World journal of surgery 28.2 (2004): 137-141.

Green, Gemma, et al. "Emergency laparotomy in octogenarians: A 5-year study of morbidity and mortality." World journal of gastrointestinal surgery 5.7 (2013): 216.

Solomkin, Joseph S., et al. "Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections." Clinical Infectious Diseases 37.8 (2003): 997-1005.

Montravers, P., et al. "Emergence of antibiotic-resistant bacteria in cases of peritonitis after intraabdominal surgery affects the efficacy of empirical antimicrobial therapy." Clinical Infectious Diseases 23.3 (1996): 486-494.

Latifi, R., et al. "Enterocutaneous fistulas and a hostile abdomen: reoperative surgical approaches." World journal of surgery 36.3 (2012): 516-523.

Galie, Kathryn L., and Charles B. Whitlow. "Postoperative enterocutaneous fistula: when to reoperate and how to succeed." Clinics in colon and rectal surgery 19.4 (2006): 237.

Question 23.2 - 2018, Paper 2

A 45-year-old male with a history of alcohol abuse has been intubated and ventilated following an out of hospital cardiac arrest. Forty-eight hours after admission the following results were obtained:

Parameter

Patient Value

Adult Normal Range

Sodium 

134 mmol/L*

135 – 145 

Potassium  

3.3 mmol/L*

3.5 – 5.0 

Chloride 

107 mmol/L*

95 – 105 

Bicarbonate 

19.0 mmol/L*

22.0 – 26.0 

Glucose 

6.7 mmol/L*

3.5 – 6.0 

Urea 

5.9  mmol/L

3.0 – 8.0 

Creatinine  

59  μmol/L

45 – 90   

Magnesium

0.79  mmol/L

0.75 – 0.95 

Albumin 

20 g/L*

35 – 50 

Protein 

54 g/L*

60 – 80 

Total bilirubin 

82 μmol/L* 

< 26 

Aspartate aminotransferase (AST)

249 U/L* 

< 35 

Alanine aminotransferase (ALT)

41 U/L* 

< 35 

Alkaline phosphatase (ALP)

124 U/L* 

30 – 110 

-Glutamyl transferase (GGT)

481 U/L* 

< 55 

Calcium corrected 

2.26  mmol/L

2.12 – 2.62 

Phosphate 

0.49 mmol/L* 

0.80 – 1.50 

Creatinine Kinase 

114  U/L

46 – 171 

Lipase

19 U/L

< 60 

        a) Give a rationale for the results observed.                                                                       (50% marks)

College answer

Mild hyponatraemia and hypokalemia may be secondary to fluid therapy or diuretic treatment. Mild acidosis may be secondary to initial ischaemic insult, or hyperchloraemic in the setting of fluid resuscitation. 
Low phosphate and protein may indicate pre-existing malnutrition: risk of refeeding. 
Features of liver impairment or failure with elevated total bilirubin, GGT, AST and ALT.  
High AST to ALT ratio is associated with cirrhosis. rhabdomyolysis (unlikely as CK normal). 
In this context both ischaemic liver damage (from out of hospital cardiac arrest) and alcoholic liver damage should be considered. However, the normal renal function may make ischaemic liver damage less likely. The high AST may reflect AMI as a precipitating factor for the arrest. 
 

Discussion

"Rationale for the results observed" appears to be a request for an unordered list of abnormalities, judging by the college answer. Thus, they are presented here in the format of abnormality(rationale)

  • Trivial hyponatremia (liver disease, or fluids, or diuretics)
  • Trivial hypokalemia (fluids or diuretics)
  • Mild NAGMA -anion gap is 4.7 (saline resuscitation)
  • Low albumin (liver disease or malnutrition)
  • Raised bilirubin (liver disease)
  • Trivially deranged LFTs (liver disease)
  • Low phosphate (malnutrition)

It is unclear how this tests anything.

References

Question 16 - 2019, Paper 1

Outline the mechanism of action and list the indications, contraindications and complications of the TIPSS procedure (Transjugular intrahepatic portosystemic shunt).

College answer

Mechanism of action:

Percutaneous formation of a tract between hepatic vein and intrahepatic segment of portal vein. Blood is shunted away from portal circulation to systemic circulation, thereby reducing portal pressure.

Indications:              (20% Marks)

  • Uncontrolled variceal bleeding
  • Refractory ascites
  • Hepatic pleural effusion
  • Also consider in: bridge to transplant
  • Budd Chiari (may need a DIPS- shunt from IVC to portal vein)
  • HRS
  • Hepatic veno occlusive disease
  • Hepatic hydrothorax

Contraindications      (1 mark/point to max 4 points)            (30% marks)

  • Severe progressive liver failure with imminent death
  • Severe encephalopathy
  • Severe Right or congestive heart failure ( increases preload)
  • Polycystic liver disease
  • Caution in: portal vein thrombosis
  • Pulmonary hypertension/tricuspid regurg
  • Hepatopulmonary syndrome
  • Active infection
  • Tumor in shunt pathway

Complications:         (50% marks)

Peri-insertion:

  • Technical failure
  • Trauma to heart/liver
  • Bleeding haemoperitoneum
  • Bile leak
  • Stent Migration

Post insertion:

  • Encephalopathy
  • Stenosis/obstruction of shunt (uncommon with modern stents)
  • Portal or hepatic vein thrombosis
  • Acute liver ischamia
  • Infection: peritonitis, endotipsitis
  • Heart failure
  • Deterioration in hepatic function

Examiners Comments:

Candidates responses lacked specific details.

Discussion

In short, the rationale for a TIPS can be summarised as follows:

  • Portal hypertension causes the majority of the morbidity from chronic liver disease
  • This is due to raised portal pressure
  • TIPS decompresses the portal circulation by allowing it to empty into the comparatively lower central venous circulation
  • Ergo, TIPs should relieve the majority of the morbidity from chronic liver disease

Indications for TIPS include:

Contraindications (from Boyer and Haskal, 2009) include

  • Absolute contraindications:
    • Moderate to severe pulmonary hypertension
    • Congestive heart failure
    • Multiple hepatic cysts
    • Uncontrolled sepsis
    • Uncontrolled biliary obstruction
    • Total portal vein thrombosis (in the absence of any patent intrahepatic branches)
  • Relative contraindications:
    • A MELD score above 18
    • Central hepatocellular carcinoma
    • Portal vein thrombosis (in the absence of an experienced operator)
    • Hepatic vein thrombosis
    • Severe coagulopathy or thrombocytopenia

Technical complications of TIPS procedure:

  • Vascular access complications
  • Hepatic damage (through-and-through puncture): risk of intraperitoneal haemorrhage is 1-2%
  • Haemobilia (damage to the biliary tree)
  • Shunt stenosis or thrombosis (it happens in up to 70%)
  • Shunt migration
  • Hepatic vein stenosis (this can sabotage a future transplant)

Complications from portal venous shunt:

  • Worsening hepatic encephalopathy
  • Shunt thrombosis or portal vein thrombosis (7-10%). If there is already a portal vein thrombosis, this risk appears to increase somewhat (Perarnau et al, 2010) - which probably reflects the overall prothrombotic diathesis.
  • Bilirubin rise: the diseased liver doesn't even get a chance to metabolise it
  • Ischaemic hepatitis: the liver gets much of its oxygen from the portal vein, and even in spite of the hepatic arterial buffer response there is a risk of ischaemic hepatitis.
  • Haemolysis (due to the direct shearing effect of being in contact with the shunt)
  • "Unmasked" cardiomyopathy: the TIPS returns splanchnic blood to the heart and acts as a volume challenge, and if there was pre-existing cardiomyopathy, it may be dramatically revealed in this manner.
  • Tricuspid endocarditis (organisms may now travel directly from the leaky gut into the systemic circulation)
  • Shunt infection may occur, where the shunt may become the source of infection. The term "edotipsitis" is supposed to reflect the fact that persistent bacteraemia resembles bacterial endocarditis. 

References

Ochs, Andreas, et al.New England Journal of Medicine 332.18 (1995): 1192-1197."The transjugular intrahepatic portosystemic stent–shunt procedure for refractory ascites." 

Guevara, Mónica, et al. "Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and vasoactive systems."Hepatology 28.2 (1998): 416-422.

Papatheodoridis, George V., et al. "Transjugular intrahepatic portosystemic shunt compared with endoscopic treatment for prevention of variceal rebleeding: A meta‐analysis." Hepatology 30.3 (1999): 612-622.

Azoulay, D., et al. "Transjugular intrahepatic portosystemic shunt (TIPS) for severe veno-occlusive disease of the liver following bone marrow transplantation." Bone marrow transplantation 25.9 (2000).

Ganger, Daniel R., et al. "Transjugular intrahepatic portosystemic shunt (TIPS) for Budd-Chiari syndrome or portal vein thrombosis." The American journal of gastroenterology 94.3 (1999): 603-608.

Freedman, A. M., et al. "Complications of transjugular intrahepatic portosystemic shunt: a comprehensive review." Radiographics 13.6 (1993): 1185-1210.

Rösch, J., et al. "Transjugular intrahepatic portacaval shunt an experimental work." The American Journal of Surgery 121.5 (1971): 588-592.

Rössle, Martin. "TIPS: 25years later." Journal of hepatology 59.5 (2013): 1081-1093.

Colapinto, R. F., et al. "Creation of an intrahepatic portosystemic shunt with a Grüntzig balloon catheter." Canadian Medical Association Journal 126.3 (1982): 267.

Conn, Harold O. "Transjugular Intrahepatic Portal‐systemic Shunts: The State of the Art." Hepatology 17.1 (1993): 148-158.

Gülberg, Veit, et al. "Hepatic arterial buffer response in patients with advanced cirrhosis." Hepatology 35.3 (2002): 630-634.

Boyer, Thomas D., and Ziv J. Haskal. "The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension: update 2009." Hepatology 51.1 (2010): 306-306.

Perarnau, Jean-Marc, et al. "Feasibility and long-term evolution of TIPS in cirrhotic patients with portal thrombosis." European journal of gastroenterology & hepatology 22.9 (2010): 1093-1098.

Orloff, Marshall J. "Emergency treatment of bleeding esophageal varices in cirrhosis." Current problems in surgery3.7 (1966): 13-28.

Unger, Lukas W., et al. "The role of TIPS in the management of liver transplant candidates." United European gastroenterology journal 5.8 (2017): 1100-1107.

DeSimone, J. A., et al. "Sustained bacteremia associated with transjugular intrahepatic portosystemic shunt (TIPS)." Clinical infectious diseases 30.2 (2000): 384-386.

Bouza, Emilio, et al. "Endotipsitis: an emerging prosthetic-related infection in patients with portal hypertension." Diagnostic microbiology and infectious disease 49.2 (2004): 77-82.

Sanyal, Arun J., and K. Rajender Reddy. "Vegetative infection of transjugular intrahepatic portosystemic shunts." Gastroenterology 115.1 (1998): 110-115.

Question 13 - 2019, Paper 2

You are asked to review a 25-year-old patient with severe diarrhoea. He is two weeks post-allogeneic hematopoietic stem cell transplant.

  1. List four likely causes. (20% marks)
  1. Outline your assessment and management. (80% marks)

College answer

Causes

Drugs: promotility agents, antibiotics
Infection – multiple possible organisms
Radiation
Neutropenic enterocolitis
VHD

Outline your assessment and management

ABC

History:

Details of the indication for and type of transplant – esp. HLA matching etc.
Details of pre-transplant chemo/radiation etc.

Course and complications post-transplant
Whether engraftment has occurred
Medication history – esp. antibiotics

Details related to diarrhoea – associated with pain, blood etc,

Examination:

General physical with specific attention to Volume status

Abdominal examination – signs of peritonitis Signs of GVHD: rash, liver tenderness

Investigations:

Standard blood tests -FBC, Electrolytes, LFT’s, Cultures Stool culture including C difficile PCR

Plain AXR CT abdomen

Sigmoidoscopy +- biopsy

Discussion

Management

Fluid resuscitation – volume loss replaced by saline or balanced salt solution
Electrolyte replacement – as required but particularly potassium and magnesium

Nutrition – general enteral nutrition is satisfactory but TPN may be required where whole bowel rest is required

Antidiarrheal – loperamide can be used once infectious cause has been excluded
Anti-secretory – octreotide – particularly in early GvHD

Infection control, contact proportions

Treatment of underlying cause e.g. GVHD, C Diff.

Discussion

This question is functionally quite similar to Question 11 from the first paper of 2014, except in 20144 this patient was a 65-year-old male, 18 days following BMT for multiple myeloma, and who clearly has some serious abdominal pathology.

The causes of diarrrhoea in a bone marrow transplant recipient are so vastly numerous that they require a table to manage them:

Causes of Diarrhoea in the Bone Marrow Transplant Recipient

Infectious

Non-Infectious

Viruses

  • Rotavirus
  • Norovirus
  • Adenovirus
  • Cytomegalovirus

Bacteria:

  • Clostridium difficile
  • Shigella
  • Salmonella
  • Campylobacter
  • E.coli
  • Aeromonas

Parasites

  • Giardia
  • Cryptosporidium
  • Microsporidium

Fungi

  • Candida

Immunosuppressant therapy

  • Cytotoxic drugs
  • Tacrolimus
  • Whole-body irradiation

Consequences of BMT

  • Neutropenic enterocolitis
  • Graft vs host disease

ICU therapy

  • Pro-motility agents
  • High caloric feeds
  • Lactulose
  • Opioid withdrawal
  • Broad spectrum antibiotics

Assessment:

  • Supportive assessment:
    • A) - assessment of the urgent need for intubation
    • B) - Support of ventilation:
           - may be tachypnoeic if compensating for a metabolic acidosis
    • C) - Haemodynamic assessment: fluid resuscitation +/- vasopressors
    • E) - investigation of electrolyte abnormalities: EUC, CMP, ABG
    • F)- Monitoring of urine output and renal function; CRRT support as indicated
    • G)- assessment of the need for surgical consultation (is there peritonitis?)
      Also, assessment of the patient's nutritional state
  • Specific investigations:
    • Blood cultures
    • Stool sample for
      • Culture
      • Ova/cyst/parasite microscopy
      • C.difficile toxin PCR
    • CT abdomen (looking for evidence of colitis): it will reveal such nasties as neutropenic enterocolitis (in the BMT recipient) as well as the pneumatosis of C.difficile infection and gut ischaemia. A plain abdominal xray is almost never useful. Hamdeh et al (2016) report a false negative rate of 48%.
    • CMV quantitative titer (perhaps this is CMV colitis?)
    • Colonoscopy and biopsy

Management:

  • Supportive management
    • Fluid resuscitation, electrolyte replacement and haemodynamic control with vasopressors as needed
    • TPN if enteral nutrition is clearly inadequate
  • Specific management:
    • Antibiotics empirically
    • Loperamide if the diarrhoea is not infectious
    • Octreotide if it is definitely secretory
  • Targeted therapy for cause of diarrhoea:
    • Metronidazole for C.difficile, etc
    • High dose steroids for GVHD
    • Albendazole or ivermectin for parasitic infections

References

UpToDate have a good article on acute diarrhoea for the paying customer.

Kelly, T. W. J., M. R. Patrick, and K. M. Hillman. "Study of diarrhea in critically ill patients." Critical care medicine 11.1 (1983): 7-9.

Wiesen, Patricia, Andre Van Gossum, and Jean-Charles Preiser. "Diarrhoea in the critically ill." Current opinion in critical care 12.2 (2006): 149-154.

Ferrie, Suzie, and Vivienne East. "Managing diarrhoea in intensive care."Australian Critical Care 20.1 (2007): 7-13.

Pawlowski, Sean W., Cirle Alcantara Warren, and Richard Guerrant. "Diagnosis and treatment of acute or persistent diarrhea." Gastroenterology 136.6 (2009): 1874-1886.

Schiller, Lawrence R. "Diarrhea." Medical Clinics of North America 84.5 (2000): 1259-1274.

Timothy A. Woods. "Diarrhea." Chapter 88 in: Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990.

Guerrant, Richard L., et al. "Practice guidelines for the management of infectious diarrhea." Clinical infectious diseases 32.3 (2001): 331-351.

Cox, George J., et al. "Etiology and outcome of diarrhea after marrow transplantation: a prospective study." Gastroenterology 107.5 (1994): 1398-1407.

Hamdeh, Shadi, et al. "Clinical approach to diarrheal disorders in allogeneic hematopoietic stem cell transplant recipients." World Journal of Hematology 5.1 (2016): 23-30.

Question 5.3 - 2020, Paper 1

A 55-year-old patient is admitted with an exacerbation of chronic liver disease. Results of an ascitic tap and serum results are listed below:

ASCITIC FLUID

Parameter

Patient Value

Appearance

Clear Yellow

pH

micro-clots present, no value obtained

Red Cell Count

0 erythrocytes/µL

White Cell Count

378 leukocytes/µL

Ascitic Fluid Protein

25 g/L

Ascitic Fluid Albumin

18 g/L

Ascitic Fluid Lactic Acid Dehydrogenase (LOH)

480 U/L

Gram Stain

no organisms seen

SERUM

Parameter

Patient Value

Adult Normal Range

Serum

Protein

32 g/L*

60-80

Serum

Albumin

23 g/L*

35-50

Serum Lactic Acid Dehydrogenase (LOH)

320 U/L*

120- 250

a)    List four possible underlying diagnoses.    (20% marks)

College answer

Spontaneous bacterial peritonitis

Perforated viscus

Cirrhosis

Malignancy

TB

Discussion

Carrying on with theme for Question 5, this is another middle-aged gentleman with liver disease.  This time, the question really is, "what does this ascitic tap mean". The history offered with the results ("exacerbation of liver disease"?) is so uninformative it may as well not exist. 

So: using the 2009 article by Koulaouzidis and Such & Runyon (1998) as the main sources, one can concoct an unordered list which describes the reported findings, and their possible meaning.

  • Clear ascitic fluid: probably meaningless. About a third of such people could still have SBP (Aminiahidashti et al, 2014)
  • pH not available: that's a pity, because it could have been helpful - a pH < 7.3 seems to be strongly associated with SBP (Gitlin et al, 1982)
  • RBC of 0 cells per µL: a good sign, as haemorrhagic ascites (RBC count > 10,000) is prognostically terrible ( Urrunaga et al, 2013). The presence of micro-clots in the fluid suggests that the RBCs were there, but then clotted.
  •  WCC in excess of 250 leukocytes/µL without any organisms potentially puts this in the territory of "culture-negative neutrocytic ascites". It meets the cell count criteria for SBP.
  • A high ascitic fluid protein and albumin suggest infection or malignancy. An albumin of 18 is too high for "plain" ascites of portal hypetension, as the SAAG (serum-ascites albumin gradient) is expected to be no higher than 11 g/L. So, the albumin should be no higher than 12 in this sample. 
  • Ascitic LDH is elevated, also suggesting malignancy or infection. The LDH should be under 400 U/L, and the ascites:serum LDH ratio should be no higher than 0.6. In this scenario the ratio is (480/320) = 1.5.

So, in summary, what could this be?

  • Malignancy: there are lots of features
  • Bacterial SBP infection with a non-Gram-staining organism, eg. tuberculosis
  • Sarcoid-associated ascites
  • Pancreatitis-associated ascites
  • Abdominal fluid in the presence of bowel obstruction
  • It's not ascites! Could this have been urine

References

Ward, Patrick CJ. "Interpretation of ascitic fluid data." Postgraduate medicine 71.2 (1982): 171-178.

Tarn, A. C., and R. Lapworth. "Biochemical analysis of ascitic (peritoneal) fluid: what should we measure?." Annals of Clinical Biochemistry 47.5 (2010): 397-407.

Bar-Meir, Simon, Emanuel Lerner, and Harold O. Conn. "Analysis of ascitic fluid in cirrhosis." Digestive diseases and sciences 24.2 (1979): 136-144.

Boyer, Thomas D., Arthur M. Kahn, and Telfer B. Reynolds. "Diagnostic value of ascitic fluid lactic dehydrogenase, protein, and WBC levels." Archives of internal medicine 138.7 (1978): 1103-1105.

Runyon, Bruce A., John C. Hoefs, and Timothy R. Morgan. "Ascitic fluid analysis in malignancy‐related ascites." Hepatology 8.5 (1988): 1104-1109.

Al-Mandeel, Hazem, and Abeer Qassem. "Urinary ascites secondary to delayed diagnosis of laparoscopic bladder injury." Journal of minimal access surgery 6.2 (2010): 50.

Develing, L., J. F. Hamming, and B. Speelberg. "[Chylous ascites following surgical repair of a ruptured abdominal aortic aneurysm]." Nederlands tijdschrift voor geneeskunde 147.31 (2003): 1513-1516.

Frank, Denis J., et al. "Traumatic rupture of the gallbladder with massive biliary ascites." JAMA 240.3 (1978): 252-253.

Cameron, JOHN L., et al. "Internal pancreatic fistulas: pancreatic ascites and pleural effusions." Annals of surgery 184.5 (1976): 587.

Berner, C., et al. "Diagnosis of ascites." British Medical Journal 282 (1981): 1499.

BERNER, CHARLES, et al. "Diagnostic probabilities in patients with conspicuous ascites." Archives of internal medicine 113.5 (1964): 687-690.

Aminiahidashti, Hamed, et al. "Diagnostic Accuracy of Ascites Fluid Gross Appearance in Detection of Spontaneous Bacterial Peritonitis." Emergency 2.3 (2014): 138.

Gitlin, Norman, John L. Stauffer, and Ronald C. Silvestri. "The pH of ascitic fluid in the diagnosis of spontaneous bacterial peritonitis in alcoholic cirrhosis." Hepatology 2.4 (1982): 408S-411S.

Urrunaga, Nathalie H., et al. "Hemorrhagic ascites. Clinical presentation and outcomes in patients with cirrhosis." Journal of hepatology 58.6 (2013): 1113-1118.

Pare, Pierre, Jean Talbot, and John C. Hoefs. "Serum-ascites albumin concentration gradient: a physiologic approach to the differential diagnosis of ascites." Gastroenterology 85.2 (1983): 240-244.

Boyer, Thomas D., Arthur M. Kahn, and Telfer B. Reynolds. "Diagnostic value of ascitic fluid lactic dehydrogenase, protein, and WBC levels." Archives of internal medicine 138.7 (1978): 1103-1105.

Banerjee, Mithu, et al. "Biomarkers of malignant ascites—a myth or reality." Medical Journal Armed Forces India 67.2 (2011): 108-112.

Ekpe, E. E. L., and A. J. Omotoso. "The Relevance of Ascitic Lactate Dehydrogenase (LDH) and Serum Ascites Albumin Gradient (SAAG) in the Differential Diagnosis of Ascites among Patients in a Nigerian Hospital." Journal of Advances in Medicine and Medical Research (2015): 211-219.

Pattinson, H. A., et al. "Clotting and fibrinolytic activities in peritoneal fluid." BJOG: An International Journal of Obstetrics & Gynaecology 88.2 (1981): 160-166.

Question 11 - 2020, Paper 1

Critically evaluate the role of proton pump inhibitors to prevent upper gastrointestinal bleeding in ICU patients.

College answer


Rationale
Upper GI bleeding can occur due to stress ulceration in critically ill patients; risk of clinically significant bleeding estimated at around 1.5% in ventilated patients taking stress ulcer prophylaxis, historically up to 15% in those without prophylaxis.

Major risk factors for GI bleeding appear to be duration of mechanical ventilation and presence of a coagulopathy, also use of steroids, past history of peptic ulcer disease [Cook NEJM 1994]
Enteral nutrition may be preventative [Marik Crit Care Med 2010]

Many studies have shown a reduction in GI bleeding with the use of prophylaxis
PPIs are very effective at treating stress ulcer-related bleeding and are the most potent medications available to prevent GI bleeding in ICU patients [Barkun AN et al Gastroenterol 2012 Apr; 107(4)] Cook et al 2013, Int Care Med 2018).

Disadvantages
Side effects of use of PPI may include increase risk of VAP, C. Difficile infection, acute interstitial nephritis, and cost (included unintended long-term use). They may have an immunosuppressive effect.

Evidence
SUP-ICU [NEJM 2018] demonstrated that PPI use compared to placebo resulted in a reduced rate of clinically important GI bleeding (2.5% vs 4.2%], NNT = 59. No difference in mortality.
PEPTIC (JAMA 2020) demonstrated that in ventilated ICU patients, PPIs were more effective at reducing GI bleeding than H2RBs. No effect on mortality, ICU LOS or C Difficile infection rate. The study had a high crossover rate.
In a subset of cardiac surgical patients, the GI bleeding rate was very low, and mortality was increased with allocation to PPI group.

REVISE trial currently underway will provide an update on the beneficial effect of PPI compared to placebo for stress ulcer prophylaxis in ICU patients.

Overall, there is a clear need to define high-risk critically ill patient sub-group that is likely to benefit from stress ulcer prophylaxis, accounting for those that receive enteral nutrition. In light of PEPTIC, it is unlikely that PPIs offer a mortality benefit over H2RBs.

Summary: (candidates should justify their own practice; there is not currently a clear “correct” answer for this and so this serves as an example only):
In my practice, I would only use stress ulcer prophylaxis in ICU patients who are at high risk of GI bleeding (mechanically ventilated >48 hours and either: coagulopathy; shock/MODS/high illness severity; or high dose corticosteroids)
I would use H2RB as my standard prophylaxis medication
 
I would use PPI as treatment for any patients with signs of GI bleeding
I would assess the ongoing need for prophylaxis daily and cease when patient is no longer high risk, including when enteral nutrition is commenced.
I would routinely cease stress ulcer prophylaxis prior to discharge to the wards

Good answers contained the following points:
The rationale for using them. Advantages (cheap, widely available) Potential disadvantages
A summary of the evidence. The key points would be that they do appear to lower the incidence of GI bleeding, but do not seem to reduce mortality (and some suggestion that mortality might be increased in particular populations). A grasp of what the evidence suggests was sufficient, although detailed knowledge of recent studies was awarded marks.
A summary statement.
 

Discussion

Rationale

  • Gastrointestinal bleeding in the critically ill patient may be due to a variety of causes; these include bleeding from stress ulceration, oesophageal varices, and colonic polyps.
  • Given that in the ICU GI bleeding is combined with a series of other major organ dysfunction syndromes, it tends to have a catastrophic mortality rate
  • It is therefore important to be able to protect at-risk patients from this complication.

Advantages

  • Decreased risk of gastrointestinal bleeding
  • Decreased exposure to blood products, and the attendant risks thereof

Disadvantages

  • Decreased gastric acidity, thus increased risk of non-sterile aspiration
  • Increased risk of gastrointestinal bacterial overgrowth and translocation
  • Increased risk of Clostridium difficile infections
  • Possibly an increase in the risk of VAP

Evidence for the routine use of ulcer prophylaxis

  • A recent meta-analysis suggests that the quality and quantity of the evidence is still poor, but on the weight of the available evidence there is neither a mortality improvement nor any increase in the risk of nosocomial pneumonia.
  • There appears to be no benefit for stress ulcer prophylaxis in patients who are tolerating enteral feeding, and in these patients stress ulcer prophylaxis is not needed.
  • There is insufficient evidence to recommend the mandatory use of stress ulcer prophylaxis in any specific patient group 
  • Obviously, correcting coagulopathy (and not triggering any new coagulopathy, nor disabling the platelets with NSAIDs) is a good way to prevent catastrophic bleeding in the ICU.
  • SUP-ICU (Krag et al, 2018) did not find any mortality benefit, but there was a reduction in clinically significant UGI bleeding events. Having said this, even in the control group, the risk of this bleeding was only 4.4%.

Evidence to support one drug class over another

  • Contemporary meta-analsysis suggests some benefit from the use of PPIs.  
  • Pro-PPI studies include a big 2016 meta-analysis by Alshamsi et al, which revealed them to be more effective at preventing clinically significant episodes of bleeding.
  • However, it must be pointed out that many of the studies which met inclusion criteria didn't even specify what they meant by "bleeding". When other meta-analysis authors selected studies limited to ones with a low risk of bias, the results they arrived at were not significant (Barletta et al, 2016).

Summary

PPIs are indicated in at-risk patient in ICU who are intolerant of enteral feeding, and who are otherwise at risk of gastrointestinal bleeding. Further research is required to discriminated between different classes of drugs in terms of efficacy, and to identify the at-risk population.

References

Oh's Intensive Care manual: Chapter 42  (pp. 487)  Acute  gastrointestinal  bleeding  by Joseph  JY  Sung

Cook, Deborah J., et al. "Risk factors for gastrointestinal bleeding in critically ill patients." New England Journal of Medicine 330.6 (1994): 377-381.

Marik, Paul E., et al. "Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis." Crit Care Med 38.11 (2010): 2222-2228.

Krag, Mette, et al. "Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients." Intensive care medicine 40.1 (2014): 11-22.

Madsen, Kristian Rørbæk, et al. "Guideline for Stress Ulcer Prophylaxis in the Intensive Care Unit." Danish medical journal 61.3 (2014): 1-4.

Plummer, Mark P., Annika Reintam Blaser, and Adam M. Deane. "Stress ulceration: prevalence, pathology and association with adverse outcomes."Critical Care 18.2 (2014): 213.

Yearsley, K. A., et al. "Proton pump inhibitor therapy is a risk factor for Clostridium difficile‐associated diarrhoea." Alimentary pharmacology & therapeutics 24.4 (2006): 613-619.

Steinberg, Kenneth P. "Stress-related mucosal disease in the critically ill patient: risk factors and strategies to prevent stress-related bleeding in the intensive care unit." Critical care medicine 30.6 (2002): S362-S364.

Buendgens, Lukas, Alexander Koch, and Frank Tacke. "Prevention of stress-related ulcer bleeding at the intensive care unit: Risks and benefits of stress ulcer prophylaxis." World journal of critical care medicine 5.1 (2016): 57.

Gonzalez, Edgar R., and Anthony R. Morkunas. "Prophylaxis of stress ulcers: Antacid titration vs. histamine2-receptor blockade." Drug intelligence & clinical pharmacy 19.11 (1985): 807-811.

Cook, Deborah, et al. "A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation." New England Journal of Medicine 338.12 (1998): 791-797.

Oh's Intensive Care manual: Chapter 42  (pp. 487)  Acute  gastrointestinal  bleeding  by Joseph  JY  Sung

Cook, Deborah J., et al. "Risk factors for gastrointestinal bleeding in critically ill patients." New England Journal of Medicine 330.6 (1994): 377-381.

Marik, Paul E., et al. "Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis." Crit Care Med 38.11 (2010): 2222-2228.

Krag, Mette, et al. "Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients." Intensive care medicine 40.1 (2014): 11-22.

Madsen, Kristian Rørbæk, et al. "Guideline for Stress Ulcer Prophylaxis in the Intensive Care Unit." Danish medical journal 61.3 (2014): 1-4.

Plummer, Mark P., Annika Reintam Blaser, and Adam M. Deane. "Stress ulceration: prevalence, pathology and association with adverse outcomes."Critical Care 18.2 (2014): 213.

Yearsley, K. A., et al. "Proton pump inhibitor therapy is a risk factor for Clostridium difficile‐associated diarrhoea." Alimentary pharmacology & therapeutics 24.4 (2006): 613-619.

Steinberg, Kenneth P. "Stress-related mucosal disease in the critically ill patient: risk factors and strategies to prevent stress-related bleeding in the intensive care unit." Critical care medicine 30.6 (2002): S362-S364.

Buendgens, Lukas, Alexander Koch, and Frank Tacke. "Prevention of stress-related ulcer bleeding at the intensive care unit: Risks and benefits of stress ulcer prophylaxis." World journal of critical care medicine 5.1 (2016): 57.

Gonzalez, Edgar R., and Anthony R. Morkunas. "Prophylaxis of stress ulcers: Antacid titration vs. histamine2-receptor blockade." Drug intelligence & clinical pharmacy 19.11 (1985): 807-811.

Cook, Deborah, et al. "A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation." New England Journal of Medicine 338.12 (1998): 791-797.

MacLaren, Robert, Catherine L. Jarvis, and Douglas N. Fish. "Use of enteral nutrition for stress ulcer prophylaxis." Annals of Pharmacotherapy 35.12 (2001): 1614-1623.

El-Kersh, Karim, et al. "Enteral nutrition as stress ulcer prophylaxis in critically ill patients: A randomized controlled exploratory study." Journal of critical care 43 (2018): 108-113.

Alhazzani, Waleed, et al. "Withholding pantoprazole for stress ulcer prophylaxis in critically ill patients: a pilot randomized clinical trial and meta-analysis." Critical care medicine 45.7 (2017): 1121-1129.

Lucas, Charles E., et al. "Natural history and surgical dilemma of stress gastric bleeding." Archives of surgery 102.4 (1971): 266-273.

Hastings, Paul R., et al. "Antacid titration in the prevention of acute gastrointestinal bleeding: A controlled, randomized trial in 100 critically ill patients." New England Journal of Medicine298.19 (1978): 1041-1045.

Krag, Mette, et al. "Stress ulcer prophylaxis with a proton pump inhibitor versus placebo in critically ill patients (SUP-ICU trial): study protocol for a randomised controlled trial." Trials17.1 (2016): 205.

Krag, Mette, et al. "Pantoprazole in patients at risk for gastrointestinal bleeding in the ICU." New England Journal of Medicine 379.23 (2018): 2199-2208.

Question 18 - 2020, Paper 1

Using the headings of history, examination, biochemical findings, haematological findings, imaging and biopsy, compare and contrast the clinical features and investigation findings of Acute Fulminant Hepatic Failure with Decompensated Chronic Liver Disease


 


 

College answer

Acute Fulminant

Decompensated Chronic

History

Acute, toxic ingestion (examples) Viral Infections, Ischaemia

Post-surgery

Chronic  Liver disease

Encephalopathy GI Bleeding

Examination

Jaundice

Jaundice

Coma

Coma

Intracranial hypertension common

Intracranial hypertension rare

No signs chronic liver disease

Signs chronic liver disease

No ascites

Ascites/oedema

No portal hypertension

Signs of Portal hypertension

Biochemistry

Hypoglycaemia common

Hypoglycaemia rare

Hyponatraemia rare

Hyponatraemia common

Severe acidosis

Mild acidosis

High Bilirubin

High Bilirubin

LFT’s severely deranged

LFT’s mildly deranged

Renal failure common

Renal failure less common

Haematology

Platelets usually normal

Platelets usually low

INR very high

INR mildly raised

Fibrinogen low

Fibrinogen normal

Imaging

Head

Cerebral oedema

No cerebral oedema

Abdomen

Normal – may show swollen liver or vascular cause of fulminant failure

Small fibrotic/cirrhotic liver, splenomegaly, varices.

Biopsy

Necrosis

Fibrosis

Discussion

This question is well-formed and gives an accurate impression of exactly what the college wanted to from this comparison of Inappropriately Capitalised Conditions. 

Differences between Acute and Chronic Liver Failure
Domain Acute fulminant hepatic failure Decompensated chronic liver disease
History
  • Abrupt onset
  • Clear antecedent cause, eg. toxin ingestion like paracetamol, or trauma, or ischaemia
  • Gradual onset
  • Associated virus (eg. Hep C)
  • Associated toxin exposure (eg. alcohol)
Examination
  • Acute lung injury
  • Systemic inflammatory response, vasodilated state
  • SvO2 is high because of hyperdynamic circulation
  • Decreased level of consciousness due to cerebral oedema
  • Euvolaemic and without ascites
  • Well-nourished
  • No evidence of portosystemic shunting (thus, no varices)
  • SvO2 is an unreliable marker of tissue perfusion, because of all the shunts.
  • Confusion and delirium due to hepatic encephalopathy
  • Fluid-overloaded, with ascites
  • Portal hypertension is present (thus, varices)
  • Malnourished
  • Spider naevi
Biochemistry
  • High ammonia level
  • Normal urea
  • Extremely high LFTs
  • Acute renal failure
  • Ammonia may be normal 
  • Low urea (unless bleeding)
  • Normal-ish LFTs
Haematology
  • Initially, normal coags
  • INR may be elevated
  • Chronically low levels of clotting factors
Imaging
  • US/CT: enlarged liver, hypodense, heterogenous echogenicity
  • US/CT: small liver, irregular contours, increased density, hyperechoic. Dilated portal vein, evidence of portal hypertension
Biopsy
  • "Acute necrosis" is what it usually says (i.e. it is often uninformative)
  • Discriminates between different causes
  • Diagnostic for cirrhosis
  • Useful for prognosis
CT brain
  • Cerebral oedema
  • No cerebral oedema

Credit was given to any additional correct answers under the relevant headings.

References

Oh's Manual: Chapter 44   (pp. 501) Liver  failure by Christopher  Willars  and  Julia  Wendon

Kim, Tae Yeob, and Dong Joon Kim. "Acute-on-chronic liver failure." Clinical and molecular hepatology 19.4 (2013): 349.

Bernal, William, et al. "Acute liver failure." The Lancet 376.9736 (2010): 190-201.

Question 21.4 - 2020, Paper 1

A 60-year-old patient with regular heavy alcohol intake is admitted to ICU in a stuporous state after a two­ week history of difficulty in walking and repeated falls. On examination, his Glasgow Coma Score is E2M4V3, with bilateral nystagmus and limited outward movement of both eyes on turning his head. There is no neck stiffness, asterixis or focal neurological deficit. A CT scan of the brain shows generalised cerebral atrophy.

 
a)    What is the diagnosis? (15% marks)

b)    What is the specific treatment for this condition? (10% marks)
 


 

College answer

1. Wernicke’s Encephalopathy

2. IV Thiamine in high doses (500mg thrice a day x 2 days; 250mg daily thereafter) followed by IV    Glucose

Discussion

Those trainees who are wondering what the scientific definition of "stuporous" is will be enouraged to learn that there isn't one. Merriam-Webster defines it as 

"a condition of greatly dulled or completely suspended sense or sensibility; specifically : a chiefly mental condition marked by absence of spontaneous movement, greatly diminished responsiveness to stimulation, and usually impaired consciousness".

One would think that this sounds very colloquial and 19th century (where a young lady might have been accused of having greatly dulled or completely suspended sense or sensibility for rejecting a wealthy suitor). A slightly more modern and medical-sounding definition can be found in the 2007 edition of Plum & Posner's Diagnosis of stupor and coma (p.7):

 "Stupor, from the Latin ‘‘to be stunned,’’ is a condition of deep sleep or similar behavioral unresponsiveness from which the subject can be aroused only with vigorous and continuous stimulation. Even when maximally aroused, the level of cognitive function may be impaired. Such patients can be differentiated from those with psychiatric impairment, such as catatonia or severe depression, because they can be aroused by vigorous stimulation to respond to simple stimuli."

Anyway. This is clearly Wernicke's encephalopathy. Recall its features, of which this patient has several:

  • Encephalopathy
    • Rarely, stupor and coma
    • Most often, confusion and impaired memory
  • Ataxia
    • Usually, there are no upper limb or speech cerebelar signs
    • This is because only the anterior and superior vermis are affected
    • The lower limb cereballar signs conspire with vestibular damage and thiamine-associated polyneuropathy(i.e. "I can't feel my legs").
  • Eye signs
  • Hypothermia
    • due to impairment of thermoregulation: the hypothalamus is damaged
  • Hypotension
    • due to heart failure, "wet Beri-Beri"

The specific treatment is  IV thiamine. There is a disagreement as to how much is actually enough (The college answer to Question 13.3 from the second paper of 2013 suggests 100mg IV daily is a big enough dose, whereas Cook et al (1998) recommended 1g daily).

References

Johnson, J. "Stupor: a review of 25 cases." Acta Psychiatrica Scandinavica 70.4 (1984): 370-377.

Flynn, Alexandra, et al. "Wernicke’s Encephalopathy: Increasing Clinician Awareness of This Serious, Enigmatic, Yet Treatable Disease." The primary care companion for CNS disorders 17.3 (2015).

Thomson, Allan D., and E. Jane Marshall. "The natural history and pathophysiology of Wernicke's encephalopathy and Korsakoff's psychosis." Alcohol and Alcoholism 41.2 (2006): 151-158.

Gussow, Leon. "Myths of toxicology: thiamine before dextrose." Emergency Medicine News 29.4 (2007): 3-11.

Isenberg-Grzeda, Elie, Haley E. Kutner, and Stephen E. Nicolson. "Wernicke-Korsakoff-syndrome: under-recognized and under-treated." Psychosomatics 53.6 (2012): 507-516.\

Watson, A. J. S., et al. "Acute Wernickes encephalopathy precipitated by glucose loading." Irish journal of medical science 150.1 (1981): 301-303.

Kissoon, Niranjan. "Thiamine before glucose to prevent Wernicke encephalopathy: examining the conventional wisdom." JAMA 279.8 (1998): 583.

Day, Ed, et al. "Thiamine for prevention and treatment of Wernicke‐Korsakoff Syndrome in people who abuse alcohol." The Cochrane Library (2013).

Ambrose, Margaret L., Stephen C. Bowden, and Greg Whelan. "Thiamin Treatment and Working Memory Function of Alcohol‐Dependent People: Preliminary Findings." Alcoholism: Clinical and Experimental Research 25.1 (2001): 112-116.

Cook, Christopher CH, Phillip M. Hallwood, and Allan D. Thomson. "B Vitamin deficiency and neuropsychiatric syndromes in alcohol misuse." Alcohol and Alcoholism 33.4 (1998): 317-336.

Question 24.2 - 2020, Paper 1

A 40-year-old patient with a background of alcohol abuse presents with a history of 8 days of diarrhoea and vomiting.


The following results are obtained: 

Parameter

Patient Value

Adult Normal Range

Sodium

129 mmol/L*

135 – 145

Potassium

5.1 mmol/L*

3.5 – 5.0

Chloride

105 mmol/L

95 – 105

Bicarbonate

14.0 mmol/L*

22.0 – 26.0

Urea

16.3 mmol/L*

3.0 – 8.0

Creatinine

659 µmol/L*

45 – 90

Glucose

7.0 mmol/L*

3.5 – 6.0

Magnesium

1.49 mmol/L*

0.75 – 0.95

Albumin

27 g/L*

35 – 50

Protein

45 g/L*

60 – 80

Total bilirubin

148 µmol/L*

< 26

Conjugated bilirubin

143 µmol/L

Aspartate transferase

2250 U/L*

< 35

Alanine transferase

1218 U/L*

< 35

Alkaline phosphatase

43 U/L

30 – 110

g-Glutamyl transferase

68 U/L*

< 40

Ionised calcium

0.97 mmol/L*

1.10 – 1.35

Calcium corrected

1.95 mmol/L*

2.12 – 2.62

Phosphate

1.11 mmol/L

0.80 – 1.50

Creatinine Kinase

500 U/L*

55 – 170

Iron Level

34 µmol/L

6 – 35

Ferritin

181,900 µg/L*

30 – 400

Transferrin

0.6 g/L*

2.0 – 3.6

Ammonia

78 µmol/L*

16 – 60

Parameter

Patient Value

Adult Normal Range

Haemoglobin

132 g/L

120 – 160

White Cell Count

5.2 x 109/L

4.0 – 11.0

Platelet count

24 x 109/L*

150 – 350

Parameter

Patient Value

Adult Normal Range

Prothrombin time

20.0 sec*

12.0 – 16.5

International normalised ratio (INR)

1.8*

0.9 – 1.3

Activated    partial    thromboplastin time (APTT)

77.0 sec*

27.0 – 38.5

Fibrinogen

0.7 g/L*

2.0 – 4.0

D-Dimer

66.0 mg/L*

< 0.5

a)    What is the acid-base disturbance in this patient? (20% marks)

b)    What are the likely causes in this context? (30% marks)
 

College answer

a)
Metabolic acidosis- Anion gap= 116-(67+14) = 35 Delta ratio= 23/10=2.3
HAGMA with metabolic alkalosis OR Increased SID

b)
Metabolic alkalosis – due to vomiting- Acid loss and contraction alkalosis. HAGMA-
Lactic acidosis from hypovolaemia or bowel obstruction/sepsis, Ketoacidosis from starvation/alcohol.
 

Discussion

In some sort of a structured fashion:

  • The bicarbonate is low, suggesting a metabolic acidosis
  • The anion gap is (116-67-15) = 34
  • The delta ratio is therefore (34-12)/(24-15) =  2.44; 
    in other words, this is a mixed HAGMA and metabolic alkalosis.
  • The calculated osmolality is (116 × 2) + 2.9 + 6.8 = 241.7, and so the osmolar gap is minimal (254-241.7 = 12.3)

Causes of HAGMA appropriate to this scenario include:

  • Toxic alcohol ingestion (classically, methanol) - though the low osmolar gap makes this less likely
  • Alcohol-induced or starvation-associated ketoacidosis (more likely)
  • Lactic acidosis due to the hypovolemic state, and the failure of the liver to metabolise it 

The metabolic alkalosis can be attributed to the vomiting and diarrhoea, and more directly to the aldosterone excess which develops in states of volume depletion.

References

Question 25 - 2020, Paper 1

With regards to open surgery for carcinoma of the head of the pancreas, list the anastomoses formed during a Whipples procedure. (30% marks)

List the complications of this procedure that are of relevance to its ICU management. (70% marks)

College answer

(A list of anastomoses was acceptable; the diagram is provided for clarity).

whipples.jpg

b)
List complications specific to this procedure of relevance to the Intensive Care management of patients who have had this procedure. (7 marks)

Specific early surgical complications (4 marks) Primary haemorrhage
Pancreatic fistula Pancreatitis
Bile leak
GI anastomotic failure Portal or SMA thrombosis Diabetes Mellitus
Gastric outlet obstruction Late complications
Anastomotic stricture Delayed gastric emptying Pancreatic fistula
Gastric fistula
Malabsorption and electrolyte abnormalities secondary to the above

Examiners Comments:

There was poor knowledge of the anatomy of a procedure that is commonly encountered in intensive care.
 

Discussion

The sites of anastomosis:

  • Bile duct anastomosed to jejunum
  • Stomach stump anastomosed to jejunim
  • Pancreatic duct anastomosed to jejunum

    Like so:

    Whipple procedure

This image is from thefreedictionary.com.

As one might imagine of a 6-8 hour procedure which ends with three anastomoses in the abdomen, "the complications of this procedure that are of relevance to its ICU management" are numerous, and making a coherent answer to this sort of question really relies on the candidate's abilities to categorise them quickly. 

Surgical complications

  • Specific to the Whipple procedure:
    • Anastomotic leak
    • Pancreatic fistula:  defined as drain output of amylase-rich fluid;  in 20%.
    • Hepaticojejunal fistula
  • Common to all major abdominal surgery
    • Abdominal wound infection (in 23.5%)
    • Wound dehiscence

Airway-related concerns

  • These patients may return from theatre intubated
  • The decision to extubate them is more delicate than usual, given their predisposition to pain-associated atelectasis
  • This is complicated further by the relative contraindication for any positive airway pressure (eg. high flow nasal prongs and NIV)

Respiratory complications

  • Atelectasis
  • Hospital-acquired pneumonia

Vascular complications

  • Intra-abdominal haemorrhage occurs in <2%, but accounts for 38% of the deaths following Whipples- mainly from the gastroduodenal artery.
  • Hepatic ischaemia (due to compression or inadvertant damage to the hepatic artery)

Pain

  • The transverse subcostal incision which is usually required is a significant source of pain
  • The operation takes place high enough that even a high thoracic epidural may not cover all of the involved structures

Electrolyte derangement

  • Normal anion gap metabolic acidosis can be produced by a high-volume pancreaticojejunal fistula

Fluid balance

  • High output pancreatic fistula can produce a lot of fluid loss
  • High volume NG drainage due to delayed gastric emptying can also cause you to become rapidly very volume-depleted

Nutritional problems

  • Delayed gastric emptying (20%)
  • Prolonged period of fasting post operatively
  • These people have pancreatic cancer, so they are not coming off a particularly high nutritional baseline

Intra-abdominal collections (12.2%)

  • Bilious collection ("biloma") in <2%
  • Hepatic abscess (due to the reflux of enteric contents up the bile duct)

Thromboembolic disease

  • Apart from the major surgery they've just had, these people are also prone to clots because of their underlying malignancy

References

Schnelldorfer, Thomas, and Michael G. Sarr. "Alessandro Codivilla and the first pancreatoduodenectomy." Archives of Surgery 144.12 (2009): 1179-1184.

Kausch, W. "Das Carcinom der Papilla duodeni und seine radikale Entfernung." Beitr Klin Chir. 78 (1912): 439-486.

Are, Chandrakanth, Mashaal Dhir, and Lavanya Ravipati. "History of pancreaticoduodenectomy: early misconceptions, initial milestones and the pioneers." Hpb 13.6 (2011): 377-384.

Whipple, A. O. "Observations on radical surgery for lesions of the pancreas." Surg Gynecol Obstet 82 (1946): 623-631.

Whipple, Allen O., William Barclay Parsons, and Clinton R. Mullins. "Treatment of carcinoma of the ampulla of Vater." Annals of surgery 102.4 (1935): 763.

Butturini, Giovanni, et al. "Complications after pancreaticoduodenectomy: the problem of current definitions." Journal of hepato-biliary-pancreatic surgery 13.3 (2006): 207-211.

Karim, Sherko Abdullah Molah, et al. "The outcomes and complications of pancreaticoduodenectomy (Whipple procedure): Cross sectional study." International Journal of Surgery 52 (2018): 383-387.

McEvoy, S. H., et al. "Pancreaticoduodenectomy: expected post-operative anatomy and complications." The British journal of radiology 87.1041 (2014): 20140050.

Keim, Volker, et al. "Postoperative care following pancreatic surgery: surveillance and treatment." Deutsches Ärzteblatt International 106.48 (2009): 789.