Printable list of all endocrinology SAQs

College Answer

As with any drug/fluid there are problems associated with the use of normal saline as the sole fluid to  resuscitate the extracellular  fluid  deficit  of  DKA. Diabetic  ketoacidosis  is associated  with  a number of metabolic  disturbances, but most of the acute clinical  problems  are due to a lack of insulin (hyperglycaemia,  ketone  body  formation)  and  resultant  osmotic  diuresis  (severe  volume depletion [loss  of  water  and  sodium],  total  body electrolyte  depletion  [eg. K, Mg, PO.],  lactic acidosis. renal  insufficiency).  The  major  contributors  to  the  initial  metabolic  acidosis  are  the presence of ketone  bodies (increased anion gap), lactic acidosis (increased  anion gap), and hyperchloraemia  (normal   anion  gap).  The  first  two  of  these  will  be adequately   treated  by intravascular volume expansion and administration of exogenous insulin. Administration of isotonic saline (0.9% sodium  chloride)  may result in delayed correction of bicarbonate (ie. persistence of metabolic acidosis), now due predominantly to hyperchloraemia (normal anion gap).

Delayed correction of bicarbonate:
•   may  increase  the  time  that  the  patient  will  need  to  be  monitored  closely  (potentially confusing assessment patient response to treatment)
•  increases  the minute ventilation  (and work of breathing)  required to maintain steady state
(lower col for a given pH)
•  increases  the  temptation  to  administer  exogenous  bicarbonate  (with  associated  risks of hypokalaemia, hypophosphataemia, hypematraemia etc.)

Alternative crystalloid  solutions  are available  (eg. hartrnannslringers  lactate/plasmalyte/hypotonic saline) and should be considered  early  in the fluid resuscitation  of these patients. Choice of fluid should be based on the response of the patient to therapy (ie. ongoing, repeated assessment of Na [corrected for glucose], K, HC03 and Chloride).

Discussion

One cannot simply "comment briefly" on such a statement as this.

One must critically evaluate it.

Rationale for discussion

• DKA patients have a significant fluid deficit due to glucose and ketone diuresis
• Rehydration is a major part of therapy for DKA
• Isotonic saline is a standard rehydration fluid
• However, the large volumes which will be required may have undesirable consequences

Physiological basis for the statement

• Isotonic saline contains 150mmol/L of chloride
• The excess of chloride may contribute to the metabolic acidosis
• This contribution may delay recovery from ketoacidosis

Advantages

• Isotonic saline is a cheap widely available fluid
• Its high sodium content can promote the retention of fluid in the intravascular space
• It is safe to use in most settings
• Volume replacement will result in a more rapid resolution of ketoacidosis and lactic acidosis in DKA
• Normal anion gap acidosis due to the extra chloride may be mild and transient

Disadvantages

• Normal anion gap metabolic acidosis may develop
• Work of breathing may increase due to acidosis
• Existing (already near-depleted) buffer systems may be further depleted by this NAGMA.

Evidence and opinion in the literature

• Most guidelines for DKA resuscitation were written by endocrinologists rather than critical care specialists.
• Most of these guidelines still promote the use of normal saline, even though the acidosis-promoting effects of saline are well recognised.
• Normal saline has been treated as the default fluid of choice because the evidence for other fluids had been lacking.
• Most recent evidence comparing a "balanced" resuscitation crystalloid solution (Plasmalyte 148) with saline has suggested that though the metabolic acidosis resolves faster with Plasmalyte, the duration of ICU stay is not affected.
• Furthermore, there is some evidence that lactate-containing solutions (eg. Harmanns) may delay the resolution of ketoacidosis and achievement of normoglycaemia by contributing substrate (lactate) for hepatic gluconeogenesis, and thus by contributing additional glucose to the already hyperglycaemic patient.

In summary:

• This matter is far from settled. The choice of resuscitation fluid in DKA must rely on careful electrolyte and acid-base monitoring, and may need to be tailored to individual scenarios.
• Balanced fluid solutions may be beneficial in critically acidotic patients whose buffer systems are all but exhausted.
• Normal saline is likely a safe and inexpensive alternative in patients with mild DKA.

Dhatariya, Ketan K. "Diabetic ketoacidosis." BMJ: British Medical Journal334.7607 (2007): 1284.

LeRoith D, Taylor SI, Olefsky JM. Diabetes mellitus. A fundamental and clinical text. Philadelphia: Lippincott Williams and Wilkins, 2000

Skellett, S., et al. "Chasing the base deficit: hyperchloraemic acidosis following 0.9% saline fluid resuscitation." Archives of disease in childhood 83.6 (2000): 514-516.

Kitabchi, Abbas E., et al. "Hyperglycemic crises in adult patients with diabetes a consensus statement from the American Diabetes Association." Diabetes care 29.12 (2006): 2739-2748.

Chua, Horng-Ruey, et al. "Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis." Journal of critical care 27.2 (2012): 138-145.

Van Zyl, Danie G., Paul Rheeder, and E. Delport. "Fluid management in diabetic-acidosis—Ringer's lactate versus normal saline: a randomized controlled trial." Qjm 105.4 (2012): 337-343.

College Answer

Pathophysiology:  insulin  deficiency  (and/or  resistance)  impairs  peripheral  glucose  utilisation  in skeletal  muscle,  increases  fat  and  muscle  breakdown  and  promotes  hepatic  gluconeogenesis; glucagon excess also promotes hepatic gluconeogenesis.   Other stressors may precipitate (e.g. infection, myocardial infarction, and surgery), partially by increasing cortisol and catecholamine release;  omission  of  normal  treatment  may  also  be  responsible.    Osmotic  diuresis  results  in significant fluid depletion (e.g. 8 to 10 litres), with associated deficits of potassium and phosphate (despite variable plasma levels).

Complications:  CNS  depression/coma,  hypovolaemia,  hyperosmolality,  metabolic  acidosis, potassium and phosphate depletion, and thromboembolism.  Cerebral oedema if glucose lowering or fluid shifts too rapid.

Treatment:  of  underlying  precipitants  (sepsis,  myocardial  infarction),  replace  fluid  deficit  (± invasive monitoring) without rapidly dropping osmolality, insulin therapy (eg. infusion), careful monitoring and replacement of electrolytes (esp. potassium, phosphate), prevention of pulmonary thromboembolism.

Discussion

HONK is discussed in greater detail in a chapter dedicated to the wonders of HONK. It is the natural partner to the chapter on diabetic ketoacidosis.

In brief, one would have to say that HONK results from uncontrolled hyperglycaemia in a patient with some residual insulin secretion. Like the DKA patient, these people usually have some sort of precipinant, be it myocardial infarction, stroke, sepsis, or what have you- anything that causes a stress response and decreases peripheral insulin sensitivity. However, unlike the type 1 diabetic who would switch to ketone production and become acidotic, the HONK patient suffers few symptoms initially. Their decreased insulin sensitivity ensures that the hyperosomolar hyperglycaemic state is maintained, and the residual insulin secretion ensures that hepatic metabolism resists conversion into ketone production.

The resulting hyperglycaemia results in an osmotic diuresis, gradually dehydrating the patient and producing a hyperosmolar state.

The complications of HONK are also asked about in Question 18.1 from the second paper of 2008. In brief summary, they are as follows:

• HHS-specific physiological abnormalities
  • Hypotension and shock
  • Metabolic acidosis
  • Coma
• Complications arising from the HHS disease state:
  • Cardiac arrest
  • Cardiovascular collapse
  • Myocardial infarction
  • Stroke
  • Cerebral oedema and brain injury
  • Venous thrombosis
  • Aspiration
• Complications of therapy for HHS:
  • Dysnatraemia
  • Hyperchloremia from saline administration.
  • Phosphate depletion
  • Hypokalemia
  • Osmotic demyelination (Hegazi et al, 2013)

The stereotypical approach to management is listed below:

1. Assess airway patency. Intubate to protect the airway if comatose.
2. Ventilate with mandatory mode initially; aim for normocapnea if the metabolic acidosis is not particularly severe.
3. Insert arterial line for frequent sampling and haemodynamic monitoring.
   Insert central line to manage electrolyte and fluid infusions.
   Expect a 200ml/kg total water deficit
   Commence fluid resuscitation:
   1. 15-20ml/kg in the first hour
   2. 4-14ml/kg in the second hour (of 0.45% NaCl)
   3. 4-14ml/kg again in the third hour (use 0.9% NaCl if the sodium is low)
   4. When glucose is under 15mmol/L, start 5% dextrose 100-250ml/hr
4. May require benzodiazepines or anticonvulsants if the presentation history included seizures.
   May require a head CT venogram to rule out dural sinus thrombosis / venous infarction
5. Watch for a precipitous drop in serum osmolality.
   A safe drop is 3–8 mOsm/kg/h
   Correct electrolyte deficit:
   1. Sodium deficit: 5-13mmol/kg
   2. Potassium deficit: 5-15mmol/kg
   3. Chloride deficit: 3-7mmol/kg
   4. Phosphate deficit: 1-2mmol/kg
   5. Magneisum deficit: 1-1.5mmol/Kg
   6. Calcium deficit: 1-2mmol/Kg 
6. Monitor renal function and consider dialysis
7. Insulin therapy may not be required, and may even be dangerous.
   BSL may decrease at a satisfactory rate with fluid resuscitation alone.
8. May require anticoagulation for dural sinus thrombosis.
9. May require antibiotics, given that infection is a common precipitant.
   A septic screen should be sent.

Key issues of "specific therapy:

• Fluid resuscitation
• Electrolyte replacement
• Careful slow reduction of serum osmolality
• Investigation for complications:
  • Myocardial infarction
  • Stroke
  • Cerebral oedema and brain injury
  • Venous thrombosis
• Management of other possible precipitating causes:
  • Infection, systemic inflammatory response
  • Intracranial haemorrhage
  • Hepatic encephalopathy
  • Drugs, including illicit substances, steroids, phenytoin, diuretics, TPN, lithium

Hyperglycemic Comas by P. VERNON VAN HEERDEN from Vincent, Jean-Louis, et al. Textbook of Critical Care: Expert Consult Premium. Elsevier Health Sciences, 2011.

Oh's Intensive Care manual: Chapter 58  (pp. 629) Diabetic  emergencies  by Richard  Keays

Umpierrez, Guillermo E., Mary Beth Murphy, and Abbas E. Kitabchi. "Diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome." Diabetes Spectrum15.1 (2002): 28-36.

ARIEFF, ALLEN I., and HUGH J. CARROLL. "Nonketotic hyperosmolar coma with hyperglycemia: clinical features, pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and the effects of theraphy in 37 cases." Medicine 51.2 (1972): 73-94.

Gerich, John E., Malcolm M. Martin, and Lillian Recant. "Clinical and metabolic characteristics of hyperosmolar nonketotic coma." Diabetes 20.4 (1971): 228-238.

Kitabchi, Abbas E., et al. "Hyperglycemic crises in adult patients with diabetes." Diabetes care 32.7 (2009): 1335-1343.

Kitabchi, Abbas E., et al. "Hyperglycemic crises in adult patients with diabetes a consensus statement from the American Diabetes Association." Diabetes care 29.12 (2006): 2739-2748.

Ellis, E. N. "Concepts of fluid therapy in diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic coma." Pediatric clinics of North America 37.2 (1990): 313-321.

Pinies, J. A., et al. "Course and prognosis of 132 patients with diabetic non ketotic hyperosmolar state." Diabete & metabolisme 20.1 (1993): 43-48.

Hegazi, Mohamed Osama, and Anant Mashankar. "Central pontine myelinolysis in the hyperosmolar hyperglycaemic state." Medical Principles and Practice 22.1 (2013): 96-99.

College Answer

Causes:  consider  diabetes  mellitus  (previously  known  or not known,  type I or II, on diet, oral agents, insulin or combination), secondary causes of diabetes (e.g. pancreatitis, haemochromatosis, Cushing’s syndrome, acromegaly), insulin resistance (e.g. sepsis, systemic inflammatory response/stress response [including multiple trauma], beta-agonists [endogenous or exogenous], exogenous corticosteroids), carbohydrate load (e.g. feeding enteral/parenteral, peritoneal dialysis).

Management:  consider  control  of  factors  worsening  response  to  insulin  (sepsis,  drugs,  stress response), control glucose within acceptable range (minimise metabolic and immune effects), recommence oral agents or use insulin (dependent on severity).  Principle of glucose control in diabetics include always some insulin, administer some glucose, measure glucose frequently, expect sudden  changes,  and avoid  hypoglycaemia.    Recent  studies  suggest  tight glucose  control  using insulin  infusions  if necessary  may dramatically  reduce  mortality  after myocardial  infarction  (in diabetic patients: DIGAMI), and in the surgical intensive care (Van den Berghe et al).

Discussion

This question is identical to Question 24 from the first paper of 2006

College Answer

•    Hypothyroidism is very common in the ageing population, many unrecognised. Many clinical manifestations are specifically related to either generalised metabolic slowing (fatigue, delayed relation of deep tendon reflexes, bradycardia, depressed nervous system, and hypothermia) or accumulation of matrix glycosaminoglycans (coarse hair and skin, enlarged tongue, non-pitting oedema [myxoedema]). Other manifestations include pericardial effusion, hypertension, hypercholesterolaemia, respiratory muscle weakness, impaired gut motility, and normochromic normocytic anaemia. In some situations (usually
obvious), hypothyroidism occurs as a result of treatment for hyperthyroidism or after thyroid surgery.

•    Investigations should confirm diagnosis and detect complications (eg. hyponatraemia and lipid abnormalities). Confirmatory tests reveal high serum TSH and a low free T4. Uncommonly secondary or tertiary hypothyroidism (inappropriately low level of TSH for T4). Study of other pituitary or hypothalamic function may be required ± imaging.

•    Specific treatment involves replacement of thyroid hormone (usually as T4 50 – 200 mcg/day). Elderly, especially with heart disease require a more gradual introduction (eg. 25 mcg). Intravenous T3 (5-20mcg initially) may also be used in the treatment of myxoedema coma. Other treatment involves supportive care (ventilation, fluid and electrolyte management, temperature control) and corticosteroids (eg. hydrocortisone 100 mg tds) in severe cases until adrenal insufficiency excluded.

Discussion

Hypothyroidism in critical illness receives proper treatment in another chapter.

In order to render the process of revision simpler, I reproduce the table of clinical manifestations here:

The diagnosis of hypothyroidism rests on the measurement of TSH, T3 and T4 which can lead one to differentiate between the causes of hypothyroidism (eg. is it the pitutary, or is it the thyroid gland itself?). One may wish to test for rT3 - the "reverse" form of T3 - which is increased in "sick euthyroid" syndrome.

Lastly, the management is not clever, and consists of thyroxine replacement. The college insists we mentione corticosteroid replacement. One may wish to also mention the following features, unique to the intensive care setting:

• need for intubation in the context of a decreased level of consciousness
• delay in weaning from ventilation due to untreated hypothyroidism
• increased sensitivity to sedating agents
• decreased sensitivity to inotropes and vasopressors

Rosenstein, Nancy E., et al. "Meningococcal disease." New England Journal of Medicine 344.18 (2001): 1378-1388.

Mautner, L. S., and W. Prokopec. "Waterhouse-Friderichsen Syndrome."Canadian Medical Association journal 69.2 (1953): 156.

Kumar, Ajay, et al. "Plasma exchange and haemodiafiltration in fulminant meningococcal sepsis." Nephrology Dialysis Transplantation 13.2 (1998): 484-487.

College Answer

Causes of adrenal insufficiency in the critically ill can be categorised as primary (ie. diseases of the adrenal gland), secondary (interference with pituitary secretion of ACTH) and tertiary (interference with hypothalamic excretion of CRF).

Primary causes include autoimmune (may have vitiligo), haemorrhage (eg. with sepsis and/or anticoagulant therapy), emboli, sepsis and adrenal vein thrombosis.

Secondary causes include destruction of pituitary by tumour/cellular inflammation, infection, head trauma, and infarction.

Tertiary causes include abrupt cessation of high-dose corticosteroids, and any process that interferes with the hypothalamus (tumours, infiltration, irradiation). The stress of critical illness can unmask adrenal insufficiency in patients at risk

Consequences include shock (which may be refractory), abdominal tenderness, myalgias & arthralgias, nausea and vomiting, volume depletion, fever, and confusion. Electrolyte disturbances include hyperkalemia, and hyponatremia and hypoglycemia.

Management needs to commence before diagnosis is confirmed. Administration of corticosteroids (eg. hydrocortisone 100 mg or dexamethasone [4mg]; dexamethasone interferes least with cortisol assays associated with low or high dose short synacthen tests), fluid resuscitation (reversal of hypovolaemia and electrolyte abnormalities), and treatment for underlying causative and/or co-existing diseases (including sepsis) The diagnosis and treatment of stress induced impairment of the hypothalamic-pituitary–adrenal axis (functional adrenal insufficiency) remains controversial.

Discussion

Adrenal insufficiency in critical illness is discussed elsewhere.

For the purposes of answering this question, I produce the following tables from the above-linked chapter:

Management would have to be approached according tot he well-practiced answer algorithm:

• Attention to the ABCs;
  • Airway assessment and control (in context of a decreased level of consciousness)
  • Ventilation support (in context of metabolic acidosis)
  • Circulatory support with vasopressors (in context of fluid-refractory shock)
• Routine investigations, partiuclarly EUCs CMPs and BSL (looking for hypoglycaemia hyponatremia and hyperkalemia)
• Specific investigations, such as a random cortisol level, and a short synacthen test
• Specific management, featuring corticosteroid supplementation with hydrocortisone

Oh's Intensive Care manual: Chapter   61   (pp. 660) Adrenocortical  insufficiency  in  critical  illness by Balasubramanian  Venkatesh  and  Jeremy  Cohen

Oelkers, Wolfgang. "Adrenal insufficiency." New England Journal of Medicine335.16 (1996): 1206-1212.

Marik, Paul E. "Mechanisms and clinical consequences of critical illness associated adrenal insufficiency." Current opinion in critical care 13.4 (2007): 363-369.

Cooper, Mark Stuart, and Paul Michael Stewart. "Adrenal insufficiency in critical illness." Journal of intensive care medicine 22.6 (2007): 348-362.

College Answer

Routine ICU management includes the control of glucose to avoid the potential complications of hypoglycemia (arrhythmias, cardiac events, neurological deficits) and hyperglycemia (especially infections, eg.   documented using restrospective controls). Traditional goals have varied, but have in general been fairly broad (eg. glucose < 10-15 mmol/L).  Prospective randomised trails to guide therapy have been lacking until the last decade.

The potential role for tight glucose control in critically ill patients has been suggested in two main patient groups: acute myocardial infarction in diabetics, and the surgical ICU.

The DIGAMI study demonstrated that an insulin-glucose infusion followed by a multidose insulin regimen improved one year mortality in diabetic patients with acute myocardial infarction (Malmberg JACC 1995).

Much more interest, and significant debate, was generated by the study by Van den Berghe (NEJM 2001).   It demonstrated in a surgical intensive care population (enrolling 1548 patients) that tight glucose control using intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment (10 – 11.1 mmol/L) to 4.6 percent(4.5 - 6.5mmol/L)  (NNT = 29; P<0.04, with adjustment for sequential analyses) and “also reduced overall in-hospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure requiring dialysis or hemofiltration by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness polyneuropathy by 44 percent, and patients receiving intensive therapy were less likely to require prolonged mechanical ventilation and intensive care”.  This was apparently due to glucose control and not insulin dose, but the study could not properly blind the treating physicians, and there are problems in extrapolating this to the general Intensive care population, and further studies are underway.

Discussion

This question closely resembles Question 24 from the second paper of 2006. Essentially, it asks one to discuss the various studies which had (recently for 2006) been published to guide the management of sugars in the ICU. During this dark age, there was the belief that strict control over BSL had some sort of positive influence on the survival of ICU patients. The current strategies for BSL control in critical illness are discussed elsewhere.

College Answer

a) The most likely diagnosis is Myxoedema coma /severe hypothyroid coma. The normal CT brain excludes a significant organic brain pathology, and normal ammonia + normal hepatic enzymes make hepatic encephalopathy less likely. The clinical picture in concert with the features of a low Na, low glucose, high cholesterol, a pericardial effusion and the history of thyroxine supplementation is highly suggestive of hypothyroidism. Marks were also allocated if a reasonable alternative diagnosis was given, provided that this was accompanied by a rational justification.

b) Many precipitating factors could be present, but consider: sepsis, drugs (eg. betablockers, amiodarone), stroke, and a patient non-compliant with therapy.

Sixteen out of twenty-six candidates passed this question.

Discussion

The history is characteristic of myxoedema coma, which is discussed in greater detail elsewhere

In addition to the background of hypothyroidism, the patient has the trifecta of features:

• cardiovascular collapse
• hypothermia
• decreased level of consciousness

The associated features of pericardial effusion and hyponatremia complete the classical picture.

The college have not given you the puffy face and non-pitting oedema, but they are hardly necessary.

Also, the history of cirrhosis is given, and the patient does have a "flap", but it is probably not a flap of hepatic encephalopathy, but of hypercapnea, which is associated with myxoedema coma. The ammonium level is 41, which (though not related to the severity of encephalopathy) is not sufficiently abnormal to cause concern.

As for the precipitating factors... Surely, the osteomyelitis itself might cause the myxoedematous decompensation, but the clever college examiners have probably thrown this in because they know that osteomyelitis of this sort tends to be treated with rifampicin, and rifampicin tends to increase the rate of hepatic clearance of thyroxine.

Summers, V. K. "Myxoedema coma." British medical journal 2.4832 (1953): 366.

Wartofsky, Leonard. "Myxedema coma." Endocrinology and metabolism clinics of North America 35.4 (2006): 687-698.

Mathew, Vivek, et al. "Myxedema coma: a new look into an old crisis." Journal of thyroid research 2011 (2011).

Lezama, Maybelline V., Nnenna E. Oluigbo, and Jason R. Ouellette. "Myxedema Coma and Thyroid Storm: Diagnosis and Management." Internal Medicine 14.Part 2 (2011): 1.

Chu, Michael, and Terry F. Seltzer. "Myxedema coma induced by ingestion of raw bok choy." New England Journal of Medicine 362.20 (2010): 1945-1946.

Wall, Cristen Rhodes. "Myxedema coma: diagnosis and treatment." American family physician 62.11 (2000).

Bondugulapati, Laxmi, Mohamed Adlan, and Lakdasa Premawardhana. "Thyroid Emergencies." Sri Lanka Journal of Critical Care 2.1 (2011): 1-12.

College Answer

A list of potential  causes should include: diabetes mellitus (previously known or not known, type I
or II, on diet, oral agents, insulin or combination), secondary causes of diabetes (e.g. pancreatitis, haemochromatosis, Cushing’s syndrome, acromegaly), insulin resistance (e.g. sepsis, systemic inflammatory response/stress response [including multiple trauma], beta-agonists [endogenous or exogenous], exogenous corticosteroids), carbohydrate load (e.g. feeding enteral/parenteral, peritoneal dialysis).

The outline  of management should include: control of factors worsening response to insulin (sepsis, drugs, stress response), control glucose within acceptable range (minimise metabolic and immune effects), recommence oral agents or use insulin (dependent on severity).   Principles of glucose control in diabetics include always administering some insulin, administer some glucose, measure glucose frequently, expect sudden  changes, and  avoid hypoglycaemia. Tight  glucose control is still controversial in the critically ill patients. Recent studies suggest tight glucose control using insulin infusions if necessary may dramatically reduce mortality after myocardial infarction (in diabetic patients: DIGAMI. BMJ. 1997 May 24;314(7093):1512-5), and in the surgical intensive care (N Engl J Med 2001;345:1359-67) but a more recent study by same group in medical ICU patients provides less striking results (N Engl J Med 2006;354:449-61), and the risk of hypoglycemia appears significant (Am J Respir Crit Care Med 2006;173:367-9).

Discussion

The below-linked table of causes can be found in the chapter on stress-induced hyperglycaemia

As for the glucose control strategy: this is better discussed in the chapter on glucose control among the critically ill, but here is the basic breakdown of the current strategies, and the trials that spawned them. The college answer given here is written prior to 2009, and therefore shares the delusional attachment to tight glycaemic control which characterises the tumultuous first decade for the 21st century.

These days, with the benefit of the 2009 NICE-SUGAR trial and its 2012 post-hoc analysis, we know that keeping BSL under 10mmol/L is the ideal strategy, as it protects the patients from the evils of hyperglycaemia, while preventing the increase in mortality which is associated with unbearably tight glycaemic controls.

In summary,

• Keep the BSL between 5 and 8mmol/L, and definitely keep it under 10mmol/L

Finfer, Simon, et al. "Hypoglycemia and risk of death in critically ill patients."The New England journal of medicine 367.12 (2012): 1108-1118.

Finfer, Simon, et al. "Intensive versus conventional glucose control in critically ill patients." N Engl J Med 360.13 (2009): 1283-1297.

Griesdale, Donald EG, et al. "Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data."Canadian Medical Association Journal 180.8 (2009): 821-827.

College Answer

a. What is the likely diagnosis and cause to account for all these blood results?
•    Hypothyroidism
•    Amiodarone

b. List 4 measures essential for the specific management of this patient.

•    Commence thyroxine, probably low dose (50-100ug/day and slowly increase) or administer T3 orally or intravenously
•    Commence on glucocorticoids (Hydrocortisone 50mg 6 hourly)
•    Correct the hypoglycaemia with intravenous glucose
•    Correct  the  hyponatraemia  very  slowly  with  hypertonic  saline  to  a  sodium 130mmol/L (no more than 2 mmol/L per hour)

Discussion

This is no mere hypothyroidism, college - its myxoedema coma. The condition is characterised by shock, hypothermia and obtundation; and its triggered by amiodarone therapy, among other things.The chapter on myxoedema coma treats these complications with a deserving degree of detail.

Management of this condition consists of the following steps:

• Replace thyroid hormone - preferably IV
  • loading dose is 300-400μcg
  • a rising body temperature and normalising cardiovascular parameters alert you to the success of your management strategy
• Replace corticosteroids - there is usually a concomitant adrenal insufficiency. One would use a "stress dose".
• Good solid supportive management:
  • Establish an airway if this is needed
  • Maintain normoxia and normocapnea with the ventilator
  • Maintain normotension to support organ system perfusion, with a catecholamine infusion
  • Correct the Na⁺ deficit slowly- I am not sure why the college have specified such a vigorous replacement rate; most people would replace at a rate of rise of no more than 0.5mmol/L/hr, and one might even consider using water restriction alone.
  • Correct hypoglycaemia
  • Correct hypothermia with warming blanket

Summers, V. K. "Myxoedema coma." British medical journal 2.4832 (1953): 366.

Mathew, Vivek, et al. "Myxedema coma: a new look into an old crisis." Journal of thyroid research 2011 (2011).

College Answer

a. What diagnosis is likely?
•    Phaeochromocytoma

b. List 5 treatment measures for the management of the haemodynamic instability associated with this condition.
•    Admit to the intensive care unit for invasive monitoring
•    SNP/GTN for HT crisis
•    Alpha Blockade followed by beta blockade,
•    Intravenous magnesium has been shown to have an effective role in this situation
•    Hypotension with fluids / Adrenaline/noradrenaline

Discussion

This question on phaeochromocytoma closely resembles Question 22 from the second paper of 2010. The details of management are discussed there, as well as in the brief summary on phaeochromocytoma in the section on endocrine disorders in the ICU.

College Answer

a. List 4 likely causes of hypoglycaemia in this patient.
•    Accidental or non accidental overdose of long acting insulin
•    Sepsis
•    Glucocorticoid deficiency
•    Hypothyroidism
•    Insulin secreting tumour
•    Less likely: severe liver disease

Discussion

The causes of hypoglycaemia are protean. Here are just a few:

Pragmatically speaking, it is very rarely anything quite as exciting as an insulinoma.

Pragmatically speaking, it is very rarely anything quite as exciting as an insulinoma. A study of patients admitted with hypoglycaemia has identified several common causes, listed below and ordered from most to least common:

• Inadequate intake of carbohydrate (28%)
• Ingestion of alcohol (19%)
• Deliberate overdose of insulin (13%)
• Accidental overdose of insulin (6%)
• Strenuous exercise (7%)

UpToDate has a nice article on this for the paying customer.

Cryer, Philip E., Stephen N. Davis, and Harry Shamoon. "Hypoglycemia in diabetes." Diabetes care 26.6 (2003): 1902-1912.

Hart, S. P., and B. M. Frier. "Causes, management and morbidity of acute hypoglycaemia in adults requiring hospital admission." Qjm 91.7 (1998): 505-510.

College Answer

a. Which clinical condition  is most consistent  with the above data? - Justify your answer from the results provided.

Answer: Non ketotic hyper osmolar state

•    Marked hyperglycaemia (higher than usually observed DKA) plasma glucose may be >55mmol/L.
•    Hyperosmolarity (by definition osmolarity should be >320)
•    Relatively normal pH/HCO3 suggesting non ketotic state. A small anion gap acidosis may be present secondary to lactate.

b. List 3 complications of this condition.

•    Cerebral oedema:
•    Vascular thrombosis:
•    Electrolyte derangements in particular hypokalemia, dysnatraemia.
Hyperchloremia from saline administration.
•    Intercurrent events such as sepsis, aspiration,  myocardial infarction, iatrogenic (
eg vascular access related complication)
•    Hypotension and shock due to intravascular volume depletion or inadequate resuscitation.

Discussion

To analyase this gas, let us turn to the well-rehearsed bedside rules for blood gas compensation.

So, this appears to be a metabolic acidosis.

The respiratory compensation for a HCO₃^- of 20 should be (1.5 x 20)+8, or 38 mmHg; thus, there is also a mild respiratory alkalosis.

The anion gap is raised (18.9); the delta ratio is 1.7 suggesting that the metabolic alkalosis is almost entirely due to the unmeasured anions.

The lactate is raised (4.8) and this accounts for much of the rise in the anion gap. The rest can be blamed on the non-volatile acids retained in renal failure. There is probably little ketosis, as the pH is essentially normal (whereas in ketoacidosis one would expect a profound acidosis).

In summary, after reading the question again, one might come to the conclusion that this woman has the following combination of problems:

• Hyperosmolar hyperglycaemic state
• Metformin-induced lactic acidosis, due to decreased renal clearance of metformin, and probably also due to hypovolemic shock

The college did not give us a serum osmolarity, but we are expected to infer from the BSL that it is high.

Complications of HONK are discussed in greater detail elsewhere.

In brief summary, they are as follows:

• Cardiac arrest
• Cardiovascular collapse and shock
• Myocardial infarction
• Stroke
• Cerebral oedema and brain injury
• Venous thrombosis (particularly hideous is the possibility of dural sinus thrombosis)

Hyperglycemic Comas by P. VERNON VAN HEERDEN from Vincent, Jean-Louis, et al. Textbook of Critical Care: Expert Consult Premium. Elsevier Health Sciences, 2011.

Oh's Intensive Care manual: Chapter 58  (pp. 629) Diabetic  emergencies  by Richard  Keays

Umpierrez, Guillermo E., Mary Beth Murphy, and Abbas E. Kitabchi. "Diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome." Diabetes Spectrum15.1 (2002): 28-36.

ARIEFF, ALLEN I., and HUGH J. CARROLL. "Nonketotic hyperosmolar coma with hyperglycemia: clinical features, pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and the effects of theraphy in 37 cases." Medicine 51.2 (1972): 73-94.

College Answer

• Causes
  • Phaeochromocytoma
  • Physical stress - critical illness, hypoxia, hypercapnia, hypoglycemia
  • Use of catecholamines, amphetamine use
  • Prior h/o tricyclic use

Discussion

Proudly, I can report that there is an article out there (free full text) which responds to the question, "what non-phaeochromocytoma aetiology could be causing raised plasma catecholamine levels?" Thank you for answering, David S. Goldstein.

Goldstein, David S., Graeme Eisenhofer, and Irwin J. Kopin. "Sources and significance of plasma levels of catechols and their metabolites in humans."Journal of Pharmacology and Experimental Therapeutics 305.3 (2003): 800-811.

College Answer

This young lady most probably has diabetic ketoacidosis and is critically unwell. She requires:-

1. Resuscitation:
May need supplemental oxygen
Peripheral iv access
Commence iv fluids (hartmanns, plasmalyte, n/saline or colloid)

500ml to 1 litre stat then reassess BP/HR/RR/
blood test and ABG should be available to adjust fluid therapy
 Maintenance IV fluids with N.Saline, 0.45% saline
 Start 5% dextrose when BSL <15mmol/L

Monitoring:

ECG, pulse oximetry, NIBP
Early Art line and CVC
Bloods for    EUC (Na+, Creat, Urea),Mg++, Phos-, Ca++, FBC, LFTs, BSL 
Urine dipstick
IDC
 
Confirmation of diagnosis: Blood gases, a raised AG metabolic acidosis, ketones in urine/blood

2. Insulin therapy:

Insulin infusion - short acting insulin (actrapid)
Infusion Dose (candidate should provide a dosing regimen and rationale)
- 0.01 to 0.1units/kg/hr (max)
- Daily dose /24 as units per hour

Titrate to decrease in BSL 1-2 mmol/L/hr
Continue until metabolic disturbance is corrected (acidaemia and ketosis) rather than correction of BSL. May need dextrose infusion if BSL drops below normal range

3. Electrolyte replacement:

Potassium:- Start replacement when plasma K+ <5mmol/L as insulin therapy and correction of acidaemia may lead to precipitous fall and arrhythmias
Sodium:- May need to correct Na+ for BSL. Need to take care to avoid large shifts in Na as it may predispose to cerebral oedema
Bicarbonate:- almost no indication for bicarbonate therapy. Phosphate and Mg++ likely to need replacement
**Need very regular (Q2-4h) ABG and EUC for 1st 24 hours to avoid large electrolyte and BSL changes. Need regular urine dipstick q4-6h for ketones.

4. Identify and treat precipitant:

Common precipitants to consider include;
Non compliance and psycho-social issues
Infection:- gastroenteritis, UTI, respiratory tract, cholecystitis, meningitis, cellulitis

Ischaemia:- AMI, stroke, peripheral vascular disease, mesenteric `  ischaemia

Pregnancy

5. Prevention of expected complications:

Hypoglycaemia (q1h BSL, decrease insulin infusion, dextrose infusion) Hyponatraemia (regular electrolyte monitoring)
Hypokalaemia (regular electrolyte monitoring)
Hypomagnasaemia and hypophosphataemia (regular electrolyte monitoring) Venous thromboembolism (sci heparin/LMWH)
Hyperchloraemic acidosis (avoid N/saline when able)

Complications of critical illness (upper GIT bleeding, ARDS..)

Discussion

Like all the management questions, this one can be dissected into manageable pieces:

• Attention to the ABCS, with management of life-threatening problems simultanous with a rapid focused examination and a brief history.
• Airway
  • Assess the need for intubation - will rarely be required, unless cardiorespiratory arrest occurs
• Breathing/ventilation
  • Assess the need for supplemental oxygen- this will rarely be required, as oxygenation is rarely an issue
  • If intubated, maintain a high MV to prevent an exacerbation of acidosis
• Circulatory support
  • IV fluids and vasopressors may be required if the initial presentation is in a shocked state
• Supportive management
  • Ensure adequate thiamine supplementation
  • Protect gut mucosa with PPIs
  • DVT prophylaxis (s/c heparin)
• Monitoring
  • Frequent (hourly) ABGs
  • Frequent (4-6hourly) electrolyte levels
    • watch for hypokalemia and hypophosphataemia
• Specific management
  • Initial resuscitation with choride-poor fluids (eg. Plasmalyte)
  • Insulin infusion - 0.01 to 0.1units/kg/hr (to reduce the rate of ketogenesis)
  • Add 5% glucose when BSL is under 15mmol/L
  • Correct electrolytes aggressively
  • Search for and address the precipitating cause.

Out there, every man and his dog has a protocol for the management of diabetic ketoacidosis. One Google Scholar search for "management of diabetic ketoacidosis" has yielded several pages of articles, monotonously titled "Management of diabetic ketoacidosis".

As my primary reference, I have chosen a representative statement - the "Joint British Diabetes Societies guideline. Among the various issues raised by the guideline, a few stand out as mildly interesting:

• You may safely use VBGs instead of ABGs
• You should use crystalloid IVF (though there was never any controversy)
• You should use your judgement and give fluids at a careful rate, because there is no evidence regarding any befit from rapid fluid resuscitation
• The Brits recommend you use saline as your crystalloid of choice, which is heretical. The reasons given were "unfamiliar and not routinely kept on medical wards". My response would be "train your staff and stock better fluids".

Savage, M. W., et al. "Joint British Diabetes Societies guideline for the management of diabetic ketoacidosis." Diabetic Medicine 28.5 (2011): 508-515.

College Answer

a) Define S.I.H
Transient hyperglycaemia during acute illness –usually restricted to patients without prior evidence of diabetes with reversion to normal after discharge.

b) Outline the mechanisms thought important in the pathogenesis of S.I.H.

•    S.I.H is thought to develop due to complex interplay between counter regulatory hormones such as catecholamines, GH, cortisol and cytokines.
•    The   underlying   illness   and   treatments   (TPN,   enteral   feed,   steroids,   and vasopressors) might affect the scale of these derangements.
•    The   key   contributor   would   appear   to   be   high   hepatic   glucose   output   via gluconeogenesis  driven by glucagon,  adrenaline  and cortisol.  Cytokines  such as TNFα interact to enhance this response.
•    Insulin resistance plays a role.
•    Underlying abnormalities in glucose regulation may be present.

c) Outline clinical implications and treatment of S.I.H.

•    Recent  data  suggests  that  S.I.H  and  diabetic  hyperglycaemia  are  two  different phenomena with differing clinical outcomes.
•    Patients with S.I.H have been shown in several studies to have increased risk of mortality, adverse events, and greater organ failure scores compared to those with diabetes.
•    Whether S.I.H per se causes harm or instead is a marker of severity of counter regulatory response and degree of illness is unknown.
•    Management  of S.I.H cannot be distinguished  from hyperglycaemia  due to other causes.  In  most  cases  it  is  not  generally  predictable  or  preventable.   Early recognition and interception might prevent persistence and exacerbation. Recommendations include insulin therapy with more conservative glucose targets.
•    Candidates mentioning recent data from RCTs were given credit.

Discussion

Stress-induced hyperglycaemia is discussed elsewhere. In brief, one would define it as hyperglycaemis which occurs in the presence of severe illness and in the absence of pre-existing diabetes. Marik & Bellomo have a nice review of this from 2013.

One could summarise the mechanisms as follows:

• Increased glucose synthesis is due to the following mechanisms:
  • Increased lipolysis due to catecholamine activity
  • Increased gluconeogenesis due to catecholamine activity
  • Increased glycogenolysis due to catecholamine activity
• Increased insulin resistance is due to the decreased sensitivity of skeletal muscle to insulin, via the effects of the following hormones:
  • Catecholamines
  • Growth hormone
  • Cortisol
  • TNF-α
• Additional effects are the direct inhibition of insulin release by adrenaline, and the activation of hepatic glycolysis by glucagon.

Clinical implications of stress-induced hyperglycaemia and its treatment are detailed in the chapter on glycaemic conrol in critical illness.

The key points can be summarised as a list:

• Increased mortality
• Pro-inflammatory effects
• Increased susceptibility to infection

The college points out that association with mortality is not evidence of causation. Glucose may just be another acute phase reactant.

And as for management? In short, keep the BSL between 5 and 8. Finfer et al have demonstrated (NICE-SUGAR) that tight glycaemic control hurts more people than it helps.

McCowen, Karen C., Atul Malhotra, and Bruce R. Bistrian. "Stress-induced hyperglycemia." Critical care clinics 17.1 (2001): 107-124.

Falciglia, Mercedes, et al. "Hyperglycemia-related mortality in critically ill patients varies with admission diagnosis." Critical care medicine 37.12 (2009): 3001.

Finfer, Simon, et al. "Intensive versus conventional glucose control in critically ill patients." N Engl J Med 360.13 (2009): 1283-1297.

Marik, Paul E., and Rinaldo Bellomo. "Stress hyperglycemia: an essential survival response!." Critical Care 17.2 (2013): 305.

College Answer

a.   What is the likely diagnosis?

Phaeochromocytoma

b.  What investigations will help you confirm the diagnosis?

Investigations

•          Plasma free metanephrine
•          24 hour urine collection for creatinine, total catecholamines, vanillylmandelic acid and metanephrines
•           Imaging

-       MRI – most sensitive 
-       CT scan – less accurate for lesions <1cm 
-       MIBG  scan  – biochemical  confirmation  but  no tumour  seen  on CT scan or MRI 
-       PET scan

c. Outline your immediate management of this patient.

•    Admission to ICU or HDU for close monitoring
•    Increase inspired oxygen concentration
•    Start alpha blockade with IV phentolamine to control BP acutely and start phenoxybenzamine  orally.  Rate control of AF with calcium channel blocker
•    Once alpha blockade established, beta blockade can be added
•    IV fluid replacement as vasodilation occurs to normalise blood volume
•    Some authorities recommend magnesium sulphate infusion
•    Screen for myocardial damage with serial troponins, ECG and echo. Echo may show takutsubo type abnormality

d. List four complications of this condition.

•Malignancy 
•Death 
•Myocardial infarction 
•Arrhythmias 
•Seizures 
•Stroke

Discussion

The red herring of medulary thyroid cancer is thrown in, but the question is about a catecholamine-secreting adenoma. Of course, the examiners are taking advantage of the well-known associationbetween thyroid cardinoma and phaeochromocytoma - investigators in 1961 concluded that "the incidence of carcinoma of the thyroid gland is increased far beyond expectation based on chance concurrence". The features of the history which make one think of phaeochromocytoma in this instance is the onset of symptoms after the administration of a non-selective beta blocker. Propanolol, one ought to remember, is a potent agent used to control thyrotoxic crises- so it should not have been associated with the sudden onset of worsening symptoms.

The physiology here is likely to involve the selective blockade of beta-receptors, which has resulted in an unopposed alpha-agonist effect. The massive afterload increase resulting from this has caused the left ventricle to decompensate; LV falure in turn caused the LA dilatation (and AF), as well as the pulmonary oedema.

Investigations for phaeochromocytoma should include the following:

• Tests for catecholamines and their metabolites
  • Urinary catecholamines
  • Plasma catecholamines
  • Urinary fractionated metanephrines
  • Plasma free metanephrines (these appear to be the best single investigation)
  • Urinary vanillylmandelic acid
• Clonidine suppression test
  • In patients with phaeochromocytoma, serum catecholamine levels will not decrease in responswe to clonidine.
• Imaging: MRI and/or PET scan

The management of phaeochromocytoma is discussed in an excellent article from the Royal Adelaide hospital. The key is to block the alpha receptors first. Phenoxybenzamine is an exciting exotic substance used exclusively for this purpose, as it is a non-competitive alpha-antagonist. It binds irreversibly to alpha receptors, inactivating them, and no concentration of catecholamines will ever displace it. This is good, because competitive inhibition of alpha-receptors in this context will face strong opposition from the thousand-times-increased concentration of serum catecholamines.

The Adelaide paper does meantion that their practice has been to use atenolol before giving phenoxybenzamine, so as to ablate the reflexive tachycardia which will result from its use. This is probably because the population reported on in the paper were stable pre-operative outpatients. In the context of an acute crisis, one is obliged to control the vasoconstriction first, using something like phentolamine or sodium nitroprusside. In any case, the patient in this scenario has already taken a beta-blocker.

Thus, in brief, the list of management options should resemble this:

• Attention to the airway, oxygenation and ventilation
• Control of hypertension
  • Rapidly acting alpha-1 antagonist: phentolamine
  • Slowly acting non-competitive alpha-1 antagonist: phenoxybenzamine
  • Beta-antagonist
• Maintenance of circulating volume in the face of vasodilation:
  • IV fluid replacement
• Control of AF
  • Verapimil, diltiazem, or amiodarone
• Assessment of myocardial damage
  • ECG
  • TTE
  • CK and troponin

The college answer mentions a TTE. The typical findings are actually catecholamine-induced cardiomyopathy, but a Takotsubo pattern can also emerge. Such things are generally known from case reports, so it is difficult to broadly generalise.

Sardesai, Suhrud H., et al. "Phaeochromocytoma and catecholamine induced cardiomyopathy presenting as heart failure." British heart journal 63.4 (1990): 234-237.

Lenders, Jacques WM, et al. "Biochemical diagnosis of pheochromocytoma: which test is best?." Jama 287.11 (2002): 1427-1434.

Russell, Walter John, et al. "The preoperative management of phaeochromocytoma." Anaesthesia and intensive care 26.2 (1998): 196-200.

Eschen, Ole, et al. "Pheochromocytoma, a rare cause of acute cardiogenic shock." Clinical research in cardiology 96.4 (2007): 232-235.

Li, Ling, et al. "Transthoracic Echocardiographic Features of Cardiac Pheochromocytoma: A Single‐Institution Experience." Echocardiography 29.2 (2012): 153-157.

Leissner, Kay B., et al. "Catecholamine-induced cardiomyopathy and Pheochromocytoma." Anesthesia & Analgesia 107.2 (2008): 410-412.

Sanchez-Recalde, Angel, et al. "Pheochromocytoma-related cardiomyopathy inverted Takotsubo contractile pattern." Circulation 113.17 (2006): e738-e739.

Sipple, John H. "The association of pheochromocytoma with carcinoma of the thyroid gland." The American Journal of Medicine 31.1 (1961): 163-166.

College Answer

Critically   evaluate   the   use   of   sodium   bicarbonate   therapy   in   Diabetic
Ketoacidosis

•    Definition of DKA and it pathophysiological consequences
•    The possible rationale for the use of sodium bicarbonate
o   Severe acidaemia (generally pH < 7.10 although no hard data)
o   Severe hyperkalemia
o   Bicarbonate loss from Renal or GI tract
•    The possible problems of giving sodium bicarbonate
o   Worsening of intracellular acidaemia
o   Hypokalaemia & Hypernatraemia
o   Large bolus of hypertonic solution
•    No  evidence   for  the  use  of  HCO3-    to  treat  acidaemia,   or  improve   cardiac contractility. In fact many different texts have different values for the cut off pH which
requires treatment, suggesting no real consensus.
•    The   correction   of   the   acidaemia   is   achieved   by   correcting   the   underlying pathophysiology with fluids and insulin
•    Some evidence for the use of HCO3-  in hyperkalaemia,  as a temporising measure, assuming underlying renal function is maintained
•    Theoretical potential for giving HCO3-  with renal wasting of HCO3-  or GI loss if delta ratio is <1 (usual for DKA)
•    Evidence suggesting that HCO3- is associated with worse outcome, however this in paediatrics, in patients who presented sicker (lower PaCO2 and higher urea on presentation).  However this does not assume causality and paediatric patients can compensate for longer.
•    Despite the lack of evidence it would appear that most intensivists have a personal cut-off pH at which they consider giving HCO3-

Discussion

The "critically evaluate" questions should be approached in a structured manner.

Introduction

• DKA is a systemic illness associated with impaired glucose metabolism due to a lack of insulin (in IDDM) or due to insulin resistance (NIDDM). The decreased oxidative phosphorylation of glucose leads to a switch in metabolism, favouring lipolysis and the use of fatty acids for the purpose of ketone body synthesis. The ketone bodies dissociate into a conjugate base and hydrogen ion, acting as acids and thereby inducing acidosis.

Rationale for this practice

• Sodium bicarbonate is an alkaline compound used to correct metabolic acidosis; it acts as an exogenous source of bicarbonate buffer, and titrates the pH of the body fluids.
• The administration of bicarbonate in metabolic acidosis is expected to reverse the physiological disadvantages of acidosis, including cardiovascular instability
• Ketones in DKA are lost in the urine and therefore cannot be metabolised (which would absorb the H⁺ ion ) - the urinary loss of ketones therefore represents the urinary loss of bicarbonate, and exogenous bicarbonate needs to be given to replace this.

Advantages

• Return of pH to normality = restoration of normal cellular enzyme function
• Normalisation of pH also restores normal catecholamine receptor-ligand affinity relationships, resulting in the improvement of haemodynamic performance.
• Administration of Na⁺ cations results in an increase of the strong ion difference, which maintains the improvement in pH.
• In the event of severe hyperkalemia, sodium bicarbonate administration causes a intracellular shift of potassium, which may be useful in the context of DKA.

Disadvantages

• Return of pH to normality may be unnecessary, as many intracellular mechanisms of compensation for acidosis function optimally in the presence of acidosis. For instance, ketone body and lactate metabolism are delayed by bicarbonate administration.
• The administration of hyperosmolar solution may result in fluid shifts of significant magnitude, particularly dangerous in those patients who have significant cardiac comorbidities.
• The administration of a large volume of sodium bicarbonate to an already hypokalemic patient may result in worsening hypokalemia and cardiac arrest
• Sodium bicarbonate may be converted to CO₂ and internalised into cells, where it may counterproductively cause an intracellular acidosis.
• Sodium bicarbonate may be rapidly turned into CO₂ by the act of buffering, and thus may increase PaCO₂ contributing to respiratory acidosis.
• Oveshoot may occur, resulting in metabolic alkalosis
• The alkalinisation of body fluid will result in a decrease in the ionised fraction of Ca⁺⁺ leading to tetany and muscle spasm
• Rapid correction of acidosis with bicarbonate may impair oxygen delivery to tissues resulting in tissue hypoxia (by counteracting the rightward shift of the oxyhemoglobin dissociation curve, which is the result of acidosis).

Evidence against the use of bicarbonate in DKA

• It impairs the metabolism of lactate and ketones
• It may increase the hepatic synthesis of ketones
• It does not decrease the time to resolution of acidosis
• Chua, Schneider and Bellome incorporated all these studies (44 of them) into a systematic review in 2011 and their conclusion was "The evidence to date does not justify the administration of bicarbonate for the emergent treatment of DKA, especially in the pediatric population, in view of possible clinical harm and lack of sustained benefits".

Own practice

• The only situations in which I personally would give bicarbonate for DKA:
  • Haemodynamic instability with escalating vasopressor requirements, coupled with a blood gas pH of less than 7.00
  • A serum bicarbonate level which is approaching 0, suggesting that the endogenous buffer systems are all but depleted.

This LITFL article offers a balanced and concise overview of this topic.

Chua, Horng Ruey, Antoine Schneider, and Rinaldo Bellomo. "Bicarbonate in diabetic ketoacidosis-a systematic review." Annals of intensive care 1.1 (2011): 1-12.

Hale, P. J., J. Crase, and M. Nattrass. "Metabolic effects of bicarbonate in the treatment of diabetic ketoacidosis." British medical journal (Clinical research ed.) 289.6451 (1984): 1035.

Soler, N. G., et al. "Potassium balance during treatment of diabetic ketoacidosis with special reference to the use of bicarbonate." The Lancet300.7779 (1972): 665-667.

Duhon, Bryson, et al. "Intravenous sodium bicarbonate therapy in severely acidotic diabetic ketoacidosis." Annals of Pharmacotherapy 47.7-8 (2013): 970-975.

Okuda, Y. U. K. I. C. H. I., et al. "Counterproductive effects of sodium bicarbonate in diabetic ketoacidosis." The Journal of Clinical Endocrinology & Metabolism 81.1 (1996): 314-320.

College Answer

a)

i. Diagnosis: Carcinoid syndrome with cardiac involvement

ii. Investigation: 24 hour urinary HIAA (5-hydroxyindoleacetic acid) OR Serum chromogranin-A

Discussion

Carcinoid syndrome is freakishly rare. One ought to feel no remorse at knowing little about it, because in the course of one's medical practice one might never bump into one of these.

However, the facial flushing is a dead giveaway.

First described as a "unique syndrome" of facial flushing and elevated serotonin, carcinoid syndrome has become grouped together with all the other sorts of syndromes of malignant origin, particularly of neuroendocrine tumours. Carcinoid tumours are slowly growing neuroendocrine tumours of upper GI origin; indeed the term "carcinoid" refers to the fact that they are only carcinoma-like.

Additionally, the presence of facial flushing AND right heart valve damage is pathognomonic.

Its just a pattern one learns to recognise.

The damage is typically to the valve structures, and is typically a sclerosis, resulting in right heart failure. The mechanism is thought to be an effect of the vasoactive substances secreted by the tumour on the myocardium, resulting in fibrotic changes.

As for the diagnosis...

Twenty-four-hour measurement of urinary 5-hydroxyindole-3-acetic acid (5-HIAA), which is the degradation product of serotonin, is apparently 88% specific for serotonin-producing carcinoid tumours.

The MJA article cautions that tryptophan/serotonin-rich foods (bananas, avocados, plums, eggplants, tomatoes, plantains, pineapples and walnuts) can produce a falsely elevated 5-HIAA level.

Serum chromogranin-A is a much better test, because it is more reliable, does not require 24 hours of urine collection, and can be later used to monitor treatment.

Oates, John A., and Albert Sjoerdsma. "A unique syndrome associated with secretion of 5-hydroxytryptophan by metastatic gastric carcinoids." The American journal of medicine 32.3 (1962): 333-342.1 

Lundin, L., et al. "Carcinoid heart disease: relationship of circulating vasoactive substances to ultrasound-detectable cardiac abnormalities." Circulation 77.2 (1988): 264-269.

Modlin, Irvin M., et al. "Gastrointestinal neuroendocrine (carcinoid) tumours: current diagnosis and management." Med J Aust 193.1 (2010): 46-52.

Stridsberg, Mats, et al. "Measurements of chromogranin A, chromogranin B (secretogranin I), chromogranin C (secretogranin II) and pancreastatin in plasma and urine from patients with carcinoid tumours and endocrine pancreatic tumours." Journal of Endocrinology 144.1 (1995): 49-59.

College Answer

a)

• Low serum total T3 is most commonly observed-mean values are 40% of normal.
• Free T3 is also reduced but less so.
• Reverse T3 (rT3) is increased. Low T3 is caused by a reduced peripheral conversion of T4 to T3 secondary to inhibition of type 1 5’-deiodinase.
• Serum T4 and TSH may transiently rise then return to normal.
• On recovery T3 and rT3 return to normal.

b)

i. Amiodarone 
Inhibition of peripheral conversion T4 to T3

ii. Propranolol 
Inhibition of peripheral conversion T4 to T3

iii. Glucocorticoids

Inhibition of peripheral conversion T4 to T3

Suppression of TSH secretion

iv. Opiates 
Suppression of TSH secretion

c)

A sequential, multidrug approach is vital and the order of therapy is important. Three pathways need consideration-halting synthesis, preventing release of stored hormone and blockade of peripheral effects including blocking conversion of T4 toT3 as well as control of adrenergic symptoms.

Halting synthesis:

First line therapy with Thionamides- thiouracils (Propylthiouracil or PTU) and or imidazoles (methimazole and carbimazole) may be used. Both block thyroperoxidase coupling of idotyrosine residues in formation of T4 and T3.PTU (not imidazoles) will also block peripheral conversion of T4 to T3. 
Both given gastrically/PO/retention enema.

Halting release:

Thionamides block synthesis only but not secretion of preformed glandular stores of hormone. Separate treatment is needed to inhibit proteolysis of colloid and continuing release of T3 and 4. Inorganic iodine therapy either with orally administered Lugol solution or potassium iodide should be used. Iodine should only be used 30 -60 minutes

AFTER administration of Thionamides since hormone synthesis may be stimulated. 
Alternatives include Li Carbonate and some of the older radiographic contrast agents.

Blocking peripheral action: 
B blockade is essential to control peripheral actions of thyroid hormone.

Propranolol is commonly used either gastrically or IV. A drop in T3 levels may be seen with its use (decreases T3-T4 conversion). Glucocorticoids have a role in that they also block conversion of T4 to T3 and may treat any relative adrenal or vasomotor insufficiency that occurs.

Discussion

The sick euthyroid syndrome is discussed in greater detail elsewhere.

In brief, the TFT abnormalities are:

• T3: low
• rT3: high
• T3/rT3 ratio: low
• T4: high ...or normal
• TSH: high ...or normal

The drugs which affect thyroid metabolism are also discussed in another chapter("The influence of drugs on thyroid function")

In short:

• Amiodarone decreases the peripheral conversion of T4 to T3. It can either inhibit thyroid gland synthetic function, or it can stimulate them (particularly when it causes a thyroiditis). It can also decrease the clearance of T4.
• Propanolol merely inhibits the peripheral conversion of T4 to T3
• Corticosteroids decrease the secretion of TSH, and inhibit the peripheral conversion of T4 to T3
• Opiates merely inhibit the secretion of TSH.

In not so short:

The management of thyrotoxic crisis is well summarised by the college answer, but could be whittled down to point-form to improve the cerebral dwell-time among time-poor exam candidates:

• Prevent synthesis of T3 and T4:
  • Thiouracils: propylthiouracil - blocks synthesis of T3 and T4 as well as peripheral T4-T3 conversion
  • Imidazoles: carbimazole - block synthesis of T3 and T4
• Prevent T3 and T4 release:
  • Inorganic iodine therapy, eg. potassium iodide (given after synthesis is blocked)
• Block peripheral T3 and T4 activity:
  • β-blockade: propanolol (which also decreases T4-T3 conversion)
  • Corticosteroids: also decrease T4-T3 conversion

For those uncomfortable with the austere minimalism of point-form, an extensive rambling digression is also available.

UpToDate has an excellent entry on this topic, for the paying customer.

Alternatively, one can attempt to piece things together from free-full-text articles, and from this Life In The Fast Lane summary.

Zargar, A. H., et al. "Prevalence and pattern of sick euthyroid syndrome in acute and chronic non-thyroidal illness-its relationship with severity and outcome of the disorder." JOURNAL-ASSOCIATION OF PHYSICIANS OF INDIA 52 (2004): 27-32.

Peeters, Robin P., et al. "Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients." Journal of Clinical Endocrinology & Metabolism 88.7 (2003): 3202-3211.

Baruah, M. P., and R. J. Singh. "Effects of drugs on thyroid function." Thyroid Research and Practice 9.1 (2012): 3.

College Answer

a)
Hypothyroidism secondary to amiodarone toxicity.

b)
 Commence thyroxine, probably low dose (50 – 100ug/day and slowly increase) or consider T3 orally or intravenously (give cautiously).
 Commence on glucocorticoids (Hydrocortisone 50 mg 6 hourly).
 Correct the hypoglycaemia with intravenous glucose.
 Correct the hyponatraemia very slowly with hypertonic saline to sodium 130 mmol/L (no more than 2 mmol/L per hour).

Discussion

The generic approach to myxoedema coma is offered here.  Clearly, that is what is happening here: the patient is bradycardic, hypotensive and hypothermic, with hyponatremia, a raised CK and high cholesterol.

Management of this condition consists of the following steps:

• Replace thyroid hormone - preferably IV
  • loading dose is 300-400μcg
  • a rising body temperature and normalising cardiovascular parameters alert you to the success of your management strategy
• Replace corticosteroids - there is usually a concomitant adrenal insufficiency. One would use a "stress dose".
• Correct the sodium: this is usually a hypervolemic hyponatremia which resembles that of CCF (in fact, it is because of exactly the same mechanism: poor cardiovascular performance leads to ADH and aldosterone driven retention of water and sodium, with a resulting hypervolemic hyponatremia. Because the patient is usually obtunded, one is obliged to correct a particularly low sodium with hypertonic saline, being careful not to demyelinate the CNS.
• Good solid supportive management:
  • Establish an airway if this is needed
  • Maintain normoxia and normocapnea with the ventilator
  • Maintain normotension to support organ system perfusion, with a catecholamine infusion
  • Correct the Na⁺ deficit - consider using water restriction alone.
  • Correct hypoglycaemia
  • Correct hypothermia with warming blanket

For interest and reference, the generic manifestations of myxoedema coma are tabulated below:

College Answer

a)
1. History
i. Known type 1 DM; discontinuation of insulin therapy
ii. Presentation: DKA evolves rapidly (24 hours); HHS typically days-weeks with polydipsia, polyuria and weight loss.
2. Clinical features
i. Neurological symptoms more common in HHS.
ii. Abdominal pain and hyperventilation more common in DKA.
3. Laboratory features
i. Degree of hyperglycaemia (HHS typical higher, exceeding 56 mmol/l; DKA usually < 44 mmol/L)
ii. Degree of acidosis: severe in DKA, mild in HHS
iii. Anion gap acidosis present in DKA; absent (or mild in case of concomitant lactic acidosis) in HHS
iv. Ketones: HHS small ketonuria, absent to low ketonaemia [there is sufficient basal insulin secretion to prevent ketogenesis]; both high in DKA
v. Hyperosmolality more severe in HHS, typically > 320 mosm/L
4. NOTE: Significant overlap can occur in 30% of patients – represent part of a spectrum
b)
1. Fluid replacement
i. Expect fluid replacement of up to 10 litres, but GO SLOW (replace over 48 hours)
ii. Start with isotonic crystalloids (boluses if in shock, infusion rate up to 1L/hour). Need justification for choice of fluid, while recognising there is substantial controversy in this area.
iii. Continue isotonic if serum Na+ low; change to 0.45% NaCl if serum Na+ is normal or elevated.
iv. Change to 5% dextrose with 0.45% NaCl when serum glucose reaches 15 mmol/L or below
v. Individual tailoring based on heart rate, blood pressure, peripheral perfusion, urine output
2. Insulin infusion 0.05 U/kg/hr. initially following adequate fluid resuscitation aiming for steady but slow reduction in blood sugar levels (e.g. 5 mmol/hr)
3. Electrolyte replacement
i. Expect potassium deficit even if level appears normal
ii. Give 20 - 30 mmol K+ in each Litre of fluid or use separate infusion; aim for serum K+ 4 – 5 mmol/L
iii. Phosphate depletion only requires treatment if levels are very low (e.g. < 0.3 mmol/L) or symptomatic (Ref: BMJ best practice)
4. Treat possible precipitating cause (infection? need for broad spectrum antibiotics? Think about underlying precipitant in this case – there is a long list of possible causes (e.g. pancreatitis). What about drugs [both β blockers and HMGCo-A reductase inhibitors have been associated with HHS. Other common precipitating drugs e.g. antipsychotics, steroids…] Does she even have diabetes? [Check HbA1C].
5. Thromboprophylaxis mandatory – consider risks and benefits of heparin infusion.

6. Monitor
i. Haemodynamic situation
ii. Mental state
iii. Urine output
iv. Levels of glucose and electrolytes every 1 – 4 hours
v. Levels of ketones in DKA
7. Consider CT brain scan (possibility of ischaemic stroke).

Discussion

a)

In summary:

• DKA presents with acidosis as the major feature
• HONK presents with hyperglycaemia as the major feature

b)

A stereotypical approach to management is offered below:

1. Assess airway patency. Intubate to protect the airway if comatose.
2. Ventilate with mandatory mode initially; aim for normocapnea if the metabolic acidosis is not particularly severe.
3. Insert arterial line for frequent sampling and haemodynamic monitoring.
   Insert central line to manage electrolyte and fluid infusions.
   Check ECG/serial enzymes  for MI (common complication)
   Expect a 200ml/kg total water deficit
   Commence fluid resuscitation:
   1. 15-20ml/kg in the first hour
   2. 4-14ml/kg in the second hour (of 0.45% NaCl)
   3. 4-14ml/kg again in the third hour (use 0.9% NaCl if the sodium is low)
   4. When glucose is under 15mmol/L, start 5% dextrose 100-250ml/hr
4. May require benzodiazepines or anticonvulsants if the presentation history included seizures.
   May require a head CT venogram to rule out dural sinus thrombosis / venous infarction
5. Watch for a precipitous drop in serum osmolality.
   A safe drop is 3–8 mOsm/kg/h
   Correct electrolyte deficit:
   1. Sodium deficit: 5-13mmol/kg
   2. Potassium deficit: 5-15mmol/kg
   3. Chloride deficit: 3-7mmol/kg
   4. Phosphate deficit: 1-2mmol/kg
   5. Magneisum deficit: 1-1.5mmol/Kg
   6. Calcium deficit: 1-2mmol/Kg 
6. Monitor renal function and consider dialysis
7. Insulin therapy may not be required, and may even be dangerous.
   BSL may decrease at a satisfactory rate with fluid resuscitation alone.
8. May require anticoagulation for dural sinus thrombosis.
9. May require antibiotics, given that infection is a common precipitant.
   A septic screen should be sent.

Key issues of "specific therapy:

• Fluid resuscitation
• Electrolyte replacement
• Careful slow reduction of serum osmolality
• Investigation for complications:
  • Myocardial infarction
  • Stroke
  • Cerebral oedema and brain injury
  • Venous thrombosis
• Management of other possible precipitating causes:
  • Infection, systemic inflammatory response
  • Intracranial haemorrhage
  • Hepatic encephalopathy
  • Drugs, including illicit substances, steroids, phenytoin, diuretics, TPN, lithium

UpToDate has a nice summary of this topic for the paying customer.

Oh's Intensive Care manual: Chapter 58  (pp. 629) Diabetic  emergencies  by Richard  Keays

Umpierrez, Guillermo E., Mary Beth Murphy, and Abbas E. Kitabchi. "Diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome." Diabetes Spectrum15.1 (2002): 28-36.

ARIEFF, ALLEN I., and HUGH J. CARROLL. "Nonketotic hyperosmolar coma with hyperglycemia: clinical features, pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and the effects of theraphy in 37 cases." Medicine 51.2 (1972): 73-94.

Alberti, K. G. M. M., et al. "Role of glucagon and other hormones in development of diabetic ketoacidosis." The Lancet 305.7920 (1975): 1307-1311.

Kitabchi, Abbas E., et al. "Management of hyperglycemic crises in patients with diabetes." Diabetes care 24.1 (2001): 131-153.

Foster, Jennifer Ruth, Gavin Morrison, and Douglas D. Fraser. "Diabetic ketoacidosis-associated stroke in children and youth." Stroke research and treatment 2011 (2011).

Edge, J. A., et al. "The risk and outcome of cerebral oedema developing during diabetic ketoacidosis." Archives of disease in childhood 85.1 (2001): 16-22.

Woodrow, G., A. M. Brownjohn, and J. H. Turney. "Acute renal failure in patients with type 1 diabetes mellitus." Postgraduate medical journal 70.821 (1994): 192-194.

Bonfanti, R., et al. "Disseminated intravascular coagulation and severe peripheral neuropathy complicating ketoacidosis in a newly diagnosed diabetic child." Acta diabetologica 31.3 (1994): 173-174.

Chua, Horng-Ruey, et al. "Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis." Journal of critical care 27.2 (2012): 138-145.

Stowe, Michele L. "Plasma-Lyte vs. Normal Saline: Preventing Hyperchloremic Acidosis in Fluid Resuscitation for Diabetic Ketoacidosis." (2012).

Jivan, Daksha. "A comparison of the use of normal saline versus Ringers lactate in the fluid resuscitation of diabetic ketoacidosis." (2013).

Basnet, Sangita, et al. "Effect of Normal Saline and Half Normal Saline on Serum Electrolytes During Recovery Phase of Diabetic Ketoacidosis." Journal of intensive care medicine 29.1 (2014): 38-42.

Hillman, K. "Fluid resuscitation in diabetic emergencies—a reappraisal."Intensive care medicine 13.1 (1987): 4-8.

Wagner, Arnd, et al. "Therapy of severe diabetic ketoacidosis. Zero-mortality under very-low-dose insulin application." Diabetes care 22.5 (1999): 674-677.

Chiasson, Jean-Louis, et al. "Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state." Canadian Medical Association Journal 168.7 (2003): 859-866.

Kitabchi, Abbas E., et al. "Hyperglycemic crises in adult patients with diabetes a consensus statement from the American Diabetes Association." Diabetes care 29.12 (2006): 2739-2748.

College answer

a) 

1. History
   1. Known type 1 DM; discontinuation of or inadequate insulin therapy in DKA
   2. HHS – history of type 2 DM +/- non-compliance
   3. Age – DKA usually younger, HHS usually older
   4. Presentation: DKA evolves rapidly (24 hours); HHS typically days-weeks with polydipsia, polyuria and weight loss.
   5. Abdominal pain may be a presenting symptom in DKA
2. Clinical features
   1. Neurological symptoms more common in HHS. ii. Abdominal pain more common in DKA.
   3. Kussmaul respiration / hyperventilation in DKA
   4. Ketotic breath
3. Laboratory features
   1. Degree of hyperglycemia (HHS typical higher, exceeding 56 mmol/l; DHA usually< 44 mmol/l)
   2. i. Degree of acidosis: severe in DKA, mild in HHS
   3. Anion gap acidosis present in DKA; absent (or mild in case of concomitant lactic acidosis) in HHS
   4. Ketones: HHS small ketonuria, absent to low ketonaemia [there is sufficient basal insulin secretion to prevent ketogenesis]; both high in DKA
   5. Hyperosmolality more severe in HHS, typically > 320 mosm/l
4. NOTE: Significant overlap can occur in 30% of patients

 b) 

1. Hypoglycaemia
2. Hypokalaemia
3. Hypophosphataemia
4. Hypo or Hypernatremia
5. Cerebral oedema (more common in DKA, has been reported in HHS), may result in decreased LOC, seizures, bradycardia and respiratory arrest
6. Pulmonary oedema
7. Deep venous thrombosis and pulmonary embolism
8. Hyperchloraemic acidosis (usually not clinically significant)

Additional Examiners‟ Comments:

There was a lack of reference to clinical features. Surprisingly few candidates mentioned the presence of ketones and ketoacidosis as a distinguishing feature.

Discussion

Most intelligent people would view the presence of ketones and acidosis in ketoacidosis to be so obvious that it does not merit a mention in a serious discussion. However, it appears to have been one of the tickboxes for the marking examiners. Let that be a lesson to all us candidates. Next time in an exam answer regarding lactic acidosis, be sure to strongly stress the fact that lactate and acidaemia are cardinal features.

a)

This question closely resembles the first part of Question 17 from the first paper of 2014.

In summary:

• DKA presents with acidosis as the major feature
• HONK presents with hyperglycaemia as the major feature

b)

The following list of complications of HHS is a combination of several sources, including local resources as well as the college answers to Question 18.1 from the second paper of 2008 and Question 13 from the first paper of 2002.

• HHS-specific physiological abnormalities
  • Hypotension and shock
  • Metabolic acidosis
  • Coma
• Complications arising from the HHS disease state:
  • Cardiac arrest
  • Cardiovascular collapse
  • Myocardial infarction
  • Pulmonray oedema
  • Stroke
  • Cerebral oedema and brain injury
  • Venous thrombosis (DVT, PE)
  • Aspiration
• Complications of therapy for HHS:
  • Dysnatraemia
  • Hyperchloremia from saline administration
  • Phosphate depletion
  • Hypokalemia
  • Hypoglycaemia
  • Osmotic demyelination (Hegazi et al, 2013)

College answer

1. Wernickes encephalopathy                                                                                                
2. Thiamine IV
2. Red blood cell transketolase activity (reduced)                                                                                                  

Discussion

This question closely resembles Question 13.3 from the second paper of 2013 and Question 9.2  from the first paper of 2008. Each time, the college accepts "Wernicke's encephalopathy" and "100mg thiamine" as sufficient two-word responses.

The college also asks for a laboratory test. Of course, Wernicke's encephalopathy is a clinical diagnosis.  However, thiamine deficiency is readily diagnosed by the levels of red cell transketolase.   One may test the levels before and after thiamine supplementation. A low transketolase level along with a >25% rise in level following thiamine supplementation is diagnostic of thiamine deficiency.

Of note is the dose of thiamine. Historuically, the college has accepted 100mg IV daily. However, locally we give 300mg IV tds, UpToDate recommends 500mg IV tds, and Cook et al (1998) recommended 1g daily. Obviously there is disagreement about the ideal dose. A Cochrane review (Day et al, 2013) was not able to reac hany sensible conclusions about the dosage, siting methodological problems in the one and only trial which met the inclusion criteria (Ambrose et al, 2001).

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.

College answer

a) Assessments of nutritional status: 
 
This is notoriously unreliable as there are many conditions that can alter the non-specific markers of nutritional status.  
 
A good history should include the circumstances of poor intake (duration, cause, etc.), a background of previous eating behaviours, and GIT symptoms (nausea, vomiting diarrhoea, weight loss)  
 
a.    Specifics in the examination, beyond the general examination and vital signs are: Anthropometric 
              Weight, height and BMI calculation 
              Arm circumference 
              Triceps skin fold thickness 
 
b.    Clinical: 
          Hair: Hair loss or abnormal distribution (lanugo), 
          Skin: Conjunctival pallor and skin pallor, xerosis (dry skin, A), spooning of nails (Iron),            ecchymoses or petechiae (C or K), pressure ulcers, poor wound healing 
          Mouth: Glossitis (Niacin, Folate, B12, B2, B6), bleeding or sores on the gums and oral mucosa (C), angular cheilosis or stomatitis (B2, B6), leucoplakia, poor dentition 
              Neck: Thyromegaly 
          Extremities: loss of muscle mass (arm circumference, bitemporal wasting), loss of subcutaneous fat (triceps skin thickness), bone tenderness (Vit D) 

Investigations to assess protein status for protein calorie malnutrition, must all be taken in context of other evidence of acute and chronic illness and will alter as part of acute phase response. 

Serum albumin (longest half-life at 18 – 20d) 

Serum transferrin (half-life of 8 – 9d), but also reflects iron status, and low transferrin should be considered an indicator of protein status only in the setting of normal serum iron. 

Serum pre albumin (half-life at 2 – 3d) - responds quickly to the onset of malnutrition and rises rapidly with adequate protein intake, but altered in the acute phase response due to acute or chronic inflammation. 
 
Other investigations: 
o    Anaemia with Fe levels, or B12 / Folate if macrocytic.

o Vitamin and trace elements 

o    Ca, PO4, Mg, Glucose, UEC are all non-specific

o Retinol binding protein 

b) Pathophysiology of Re-feeding Syndrome 

Reintroduction of glucose into diet after a considerable period of fasting with a low BMI 
     Insulin in response to glucose load moves the glucose into cells (with K and Mg) 
     The first step of glycolysis is the phosphorylation of glucose.  This holds the glucose in cells.        This leads to sudden and precipitous fall in phosphate that is the hallmark of refeeding      syndrome 
     Severely reduced phosphate is available for ATP, cAMP 
     Failure of tissues with high energy requirement - heart, kidney, muscle (rhabdomyolysis),      brain, respiratory (diaphragm) 
     Untreated leads to death 
 
Additional Examiners' Comments: 
Poorly answered, with no specific details about the relative importance of measures of nutritional status. Candidates were expected to comment that nutritional assessment in the critically ill is difficult with many of the objective measures confounded by the consequences of the acute illness. A simple list of anthropometry, clinical signs and investigations was not sufficient as it missed the point that a careful history is crucial. 
 

Discussion

a)

An approach to the assessment of nutritional status:

History:

• Premorbid weight and the pattern of its change
• Premorbid nutritional routine
• Diseases affecting gastrointestinal function (eg. coeliac disease)
• Disease affecting satiety control (eg. Prader-Willi syndrome)
• Factors influencing metabolic substrate utilisation (eg. thyroid dysfunction, hypoadrenalism, Cushings disease or corticosteroid therapy)

Examination:

• Observed quality of nails and hair (an indicator of chronic protein intake)
• Subcutaneous fat measurements (triceps)
• Muscle bulk and muscle tone of quadriceps and deltoids
• Presence of oedema and ascites
• Evidence of any specific micronutrient deficiency

Anthropometry

• BMI
• Ideal body weight
• Lean body mass

Biochemistry and physiology:

• Cholesterol and triglycerides
• Random BSL
• HbA1C
• Serum cortisol
• TFTs
• FBC for lymphocyte count
• Albumin and prealbumin
• Transferrin
• Calculation of nitrogen balance
• Micronutrient levels:
  • Fat-soluble vitamins A, D and E
  • Thiamine
  • Zinc
  • Selenium
  • Vitamin B12
  • Folate
• Delayed hypersensitivity skin-testing

b)

Though the pathophysiology of refeeding syndrome can expressed as a stupidly complex flowchart,  the non-insane candidate may wish to make use of a logical point-form description:

• With starvation, less carbohydrate becomes available
• As the result of this, there is a switch to fatty acid and ketone based metabolism
• This switch is in part mediated by a decrease in the insulin levels
• Low oral intake also means decreased phosphate intake
• However, there is a daily requirement for phosphate (for ATP synthesis)
• This phosphate is not replenished by the poor oral intake
• As a result, intracellular phosphate is depleted
• Homeostatic mechanisms maintain a normal serum phosphate in spite of this
• As carbohydrate is reintroduced, the secretion of insulin results in a large-scale uptake of phosphate into the tissues
• As the intracellular phosphate is depeleted, there is nowhere to mobilise more phosphate from, and hypophosphataemia results.

Or, the diagram.

College answer

a) Thyroid storm

b) Propranolol 60-80mg 4-6 hourly (or other beta blocker) to control BP and HR Propylthiouracil (200mg 4hrly) or Carbimazole 20-30 mg every 4-6 hours Hydrocortisone 100mg 6hrly

Discussion

The patient clearly demonstrates many classic features of hyperthyroidism:

• Tachycardia
• Hypertension
• Hyperthermia
• Hypereflexia

The intuitive candidate will leap immediately to the conclusion that this is a TSH release mediated thyroid storm, as seen in one case report every ten years or so. How being able to identify this zebra diagnosis discriminates good intensivists from bad, one can only guess. 

Pharmacological management of thyroid storm consists of the following steps:

• Prevent synthesis of T3 and T4:
  • Thiouracils: propylthiouracil - blocks synthesis of T3 and T4 as well as peripheral T4-T3 conversion
  • Imidazoles: carbimazole - block synthesis of T3 and T4
• Prevent T3 and T4 release:
  • Inorganic iodine therapy, eg. potassium iodide (given after synthesis is blocked)
• Block peripheral T3 and T4 activity:
  • β-blockade: propanolol (which also decreases T4-T3 conversion)
  • Corticosteroids: also decrease T4-T3 conversion
• Other potentially useful agents include lithium and cholestyramine.
• Severe refractory disease may call for extracorporal clearance of thyroid hormone by plasma exchange or charcoal haemoperfusion.

College answer

a)

• The first priority is to prevent intubation. Induction will reduce minute ventilation and  worsen acidosis with a probably fatal result. Many ED ventilators would struggle to provide 40 Lpm ventilation and the PPV in a severely hypovolaemic patient may cause  haemodynamic collapse. Avoid sedation. Acidosis should resolve rapidly with fluid resuscitation and insulin.
• IV line and fluids – preferably HCO3- containing to minimise hyperchloraemic acidosis (note CVC is optional) e.g. CSL. Water deficit around 4L for 70 kg man
• IV insulin infusion (suggest 2-5 U/hr) with hourly glucose monitoring. Institute IV glucose once BGL < 12, and continue insulin until ketones cleared and beyond
• Hourly K+ and early replacement – watch for massive drop as pH rises
• Replace other electrolytes as needed (Mg, PO4)
• Check for precipitants esp. intoxication and infection
• Investigate cause of anaemia
• Disposition to appropriate high-care area (HDU/ICU/other)

b)

• Younger age (especially under 5’s)
• Newly diagnosed diabetes
• Severity of acidosis & hyperglycaemia
• Severity of dehydration
• Change in corrected [Na]
• Speed of rehydration & correction of hyperglycaemia
• Administration of bicarbonate

Additional Examiner Comments:
Many candidates stated they would intubate the patient; this would likely have precipitated a cardiac arrest due to acute rise in CO2 and worsening acidosis.

Discussion

a)

The ED registrar is unimpressed with the agitated patient's behaviour, and would prefer to intubate them to improve their manners. The college wisely cautions against this, as it might precipitate cardiac arrest from acidosis. This is likely correct. A CO₂ of 9 likely represents the physiological limits of hyperventilation. An important early goal would be to correct this acidosis, bringing the patient closer to the possibility of safe airway control. The story of "found collapsed" is going to score a head CT, and judging by the way the situation is evolving this guy will not hold still for it, so an intubation is still on the cards at some stage.

The college suggested insulin. This is rarely required in pure HHS; fluid resuscitation alone is often enough because the hyperosmolar state is frequently associated with an abnormally elevated insulin level in a Type 2 diabetic. However, in this scenario the patient is a Type 1 diabetic, and is probably more DKA than HHS (he clearly has high ketones; the anion gap is around 26.6, and only 4.0 mmol/L of this is explaied by lactate). So some insulin would be required (but probably not the 0.1u/kg/hr recommended by the usual DKA protocols, as you do not want to drop the BSL too quickly)

Thus, a standard approach to DKA is described below.

1. Assess airway patency. Intubate to protect the airway if comatose.
2. Ventilate with mandatory mode initially; aim for normocapnea if the metabolic acidosis is not particularly severe. 
3. Insert arterial line for frequent sampling and haemodynamic monitoring.
   Insert central line to manage electrolyte and fluid infusions.
   Expect a 200ml/kg total water deficit
   Commence fluid resuscitation:
   1. 15-20ml/kg in the first hour (and use colloid if they are shocked)
   2. 4-14ml/kg in the second hour (of 0.45% NaCl)
   3. 4-14ml/kg again in the third hour (use 0.9% NaCl if the sodium is low)
   4. When glucose is under 15mmol/L, Oh's Manual recommends to start 5% dextrose 100-250ml/hr, as well as some other sort of sodium-containing fluid to prevent hyponatremia 
4. May require benzodiazepines or anticonvulsants if the presentation history included seizures.
   May require a head CT venogram to rule out dural sinus thrombosis / venous infarction
5. Watch for a precipitous drop in serum osmolality.
   A safe drop is 3–8 mOsm/kg/h
   Correct electrolyte deficit:
   1. Sodium deficit: 5-13mmol/kg
   2. Potassium deficit: 5-15mmol/kg
   3. Chloride deficit: 3-7mmol/kg
   4. Phosphate deficit: 1-2mmol/kg
   5. Magneisum deficit: 1-1.5mmol/Kg
   6. Calcium deficit: 1-2mmol/Kg
6. Monitor renal function and consider dialysis
7. May require anticoagulation for dural sinus thrombosis.
8. May require antibiotics, given that infection is a common precipitant.
   A septic screen should be sent.

Key issues of "specific therapy:

• Fluid resuscitation
• Electrolyte replacement
• Careful slow reduction of serum osmolality
• Careful introduction of insulin
• Investigation for complications:
  • Myocardial infarction
  • Stroke
  • Cerebral oedema and brain injury
  • Venous thrombosis
• Management of other possible precipitating causes:
  • Infection, systemic inflammatory response
  • Intracranial haemorrhage
  • Hepatic encephalopathy
  • Drugs, including illicit substances, steroids, phenytoin, diuretics, TPN, lithium

b) This list of risk factors from the college seems to come from multiple references (see the list from the HHS chapter) and may be mainly paediatric in origin, as it appears this complication is much less common among adult patients  (Matz, 1999).

A complete list of risk factors from around the literature would look like this:

College answer

a) 
Primary metabolic acidosis  
Associated respiratory acidosis, or inadequate compensation 
Increased anion gap. (22) 
Delta ratio 1.2 –pure high anion gap acidosis 
 
ECG: low voltage  
Relative bradycardia 
Prolonged QT 
 
b) 
Myxoedema coma. 
Sepsis 
 

Discussion

Acid base status, in detail:

1. There is acidaemia
2. The CO₂ is within normal range, which is inappropriate (it should be low)
3. There is metabolic acidosis, as the SBE is -10
4. There is also a respiratory acidosis: the expected CO₂ is 30 (or 32 by the Boston rules)
5. The anion gap is 25.1, or 22 sans potassium. Either way, the lactate of 3.1 does not fully explain it. 
6. The delta ratio is either 1.6 or 1.25, but either way it points to a pure HAGMA.

ECG abnormalities 

• Bradycardia
• Long PR interval
• Long QT interval
• Borderline widened QRS
• Low voltage QRS in the limb leads

Overall, the ECG is consistent with hypothermia. Which the patient has. And with ... one other thing.

So... those two most likely differentials? 

Well. One of them HAS to be myxoedema coma. 

How can one be so confident? It's easy, when the college lifted their ECG directly from the LITFL page on ECG changes in hypothyroidism. Which is excellent: as that work is covered by the Creative Commons license, this offers the author a rare opportunity to reproduce the original college image without fear of the CICM intellectual property stormtroopers. 

The other differential could easily be sepsis, MI, acute kidney injury due to prolonged lie and rhabodomyolysis, and so on. 

College answer

1. List important clinical features of thyroid storm.                                            3 marks

1. 1. Hyperpyrexia – temperature 40 - 41º C
   2. CVS – sinus tachycardia usually exceeding 140, atrial fibrillation, decompensated CCF, hypotension/shock and in extreme cases cardiac arrest.
   3. CNS – agitation, anxiety, delirium, stupor and coma.         
   4. GI symptoms – diarrhoea, abdominal pain, jaundice
   5. Physical exam may reveal Goiter, opthalmopathy, lid lag, tremors, warm moist skin.

2. Outline the principles of management of myxoedema coma.                            7 marks

1. 1. Establish IV access including CVC and collect blood for Investigations including thyroid function tests, BSL, electrolytes etc.
   2. Establish monitoring – arterial BP, ECG, temp, pulse oximetry etc.
   3. Airway – Intubation to protect airway and Mechanical ventilation to normal gas exchange
   4. Fluid + vasopressors as appropriate to a MAP 65-70 mmHg.
   5. Passive rewarming while close monitoring of haemodynamics and temperature.
   6. slow replacement is key. IV T3 and T4 – T3 has greater biologic activity and quicker onset of action. Daily monitoring of T3 and T4 levels to avoid toxicity.
   7. IV hydrocortisone to treat possible coexisting adrenal insufficiency. viii.     IV dextrose to maintain BSL, NG feeding if possible.

1. 9. Consider IV antibiotic if clinical evidence of infection after collecting appropriate cultures.
   10. Monitor and treat cardiac arrhythmias, coronary ischaemia

Discussion

Clinical features of thyroid storm:

1. Goitre: possible airway compromise)
2. Tachypnoea due to increased CO2 production;
   Increased O₂ER (increased metabolic fuel use)
3. Tachycardia,
   Atrial fibrillation and ventricular arrhythmias
   Heart failure
   Hypertension (early), hypotension (late)
4. Tremor;
   Agitation, progressing to encephalopathy, coma and seizures.
   There is the phenomenon of "apathetic thyrotoxicosis" which presents with weakness
5. Low potassium and magnesium (particularly in "apathetic thyrotoxicosis")
   Serum cortisol should be elevated. If it is not, one might consider a relative adrenal insufficiency, and supplement some hydrocortisone.
6. Rhabdomyolysis may be present; CK may be elevated. This is "thyrotoxic myopathy"
7. Diarrhoea, nausea and vomiting
   Increased metabolic rate; increased demand for metabolic substrate.
   Nutritional requirements are increased
   Hyperglycaemia may be apparent in the non-diabetic patient
   Jaundice may develop
8. Leukocytosis; a left shift
9. Fever: in fact, may go up to 41°C. This is apparently the most characteristic feature.

Management of myxoedema coma

The model answer offered for this section is somewhat surprising, as some of its components - on first assessment - could not possibly score any marks in a question which asks for the principles of management of myxoedema coma. Statements such as "mechanical ventilation to normal gas exchange" and "consider IV antibiotic if clinical evidence of infection after collecting appropriate cultures" not only violate the rules of grammar but do nothing to support one's impression that the writer was an expert on extreme hypothyroidism. But, as these generic supportive strategies are offered by the college in their model answer template, one must assume that they expected them to also appear in the candidate's written responses, and so they are offered as a post-script in the management strategy here.

Thus:

• Replace thyroid hormone - preferably IV
  • loading dose is 300-400μcg
  • a rising body temperature and normalising cardiovascular parameters alert you to the success of your management strategy
• Replace corticosteroids - there is usually a concomitant adrenal insufficiency. One would use a "stress dose".
• Correct the sodium: this is usually a hypervolemic hyponatremia which resembles that of CCF (in fact, it is because of exactly the same mechanism: poor cardiovascular performance leads to ADH and aldosterone driven retention of water and sodium, with a resulting hypervolemic hyponatremia. Because the patient is usually obtunded, one is obliged to correct a particularly low sodium with hypertonic saline, being careful not to demyelinate the CNS.
• Good solid supportive management:
  • Establish an airway if this is needed
  • Maintain normoxia and normocapnea with the ventilator
  • Maintain normotension to support organ system perfusion, with a catecholamine infusion
  • Correct the Na⁺ deficit - consider using water restriction alone.
  • Correct hypoglycaemia
  • Correct hypothermia with warming blanket

College answer

Kudva, Yogish C., et al. "Adrenal incidentaloma: an important component of the clinical presentation spectrum of benign sporadic adrenal pheochromocytoma." The endocrinologist9.2 (1999): 77-80.

Goldstein, David S., Graeme Eisenhofer, and Irwin J. Kopin. "Sources and significance of plasma levels of catechols and their metabolites in humans."Journal of Pharmacology and Experimental Therapeutics 305.3 (2003): 800-811.

Sardesai, Suhrud H., et al. "Phaeochromocytoma and catecholamine induced cardiomyopathy presenting as heart failure." British heart journal 63.4 (1990): 234-237.

Lenders, Jacques WM, et al. "Biochemical diagnosis of pheochromocytoma: which test is best?." Jama 287.11 (2002): 1427-1434.

Russell, Walter John, et al. "The preoperative management of phaeochromocytoma." Anaesthesia and intensive care 26.2 (1998): 196-200.

Eschen, Ole, et al. "Pheochromocytoma, a rare cause of acute cardiogenic shock." Clinical research in cardiology 96.4 (2007): 232-235.

Li, Ling, et al. "Transthoracic Echocardiographic Features of Cardiac Pheochromocytoma: A Single‐Institution Experience." Echocardiography 29.2 (2012): 153-157.

Leissner, Kay B., et al. "Catecholamine-induced cardiomyopathy and Pheochromocytoma." Anesthesia & Analgesia 107.2 (2008): 410-412.

Sanchez-Recalde, Angel, et al. "Pheochromocytoma-related cardiomyopathy inverted Takotsubo contractile pattern." Circulation 113.17 (2006): e738-e739.

Sipple, John H. "The association of pheochromocytoma with carcinoma of the thyroid gland." The American Journal of Medicine 31.1 (1961): 163-166.

Pacak, Karel, et al. "Pheochromocytoma: recommendations for clinical practice from the First International Symposium." Nature clinical practice Endocrinology & metabolism 3.2 (2007): 92-102.

Reisch, Nicole, et al. "Pheochromocytoma: presentation, diagnosis and treatment." Journal of hypertension 24.12 (2006): 2331-2339.

Cohen, C. D., and D. M. Dent. "Phaeochromocytoma and acute cardiovascular death (with special reference to myocardial infarction)." Postgraduate medical journal 60.700 (1984): 111-115.

Liao, Wei-Ber, et al. "Cardiovascular manifestations of pheochromocytoma."The American journal of emergency medicine 18.5 (2000): 622-625.

Jiang, Lei, et al. "123I-labeled metaiodobenzylguanidine for diagnosis of neuroendocrine tumors." Reports in Medical Imaging 2 (2009): 79-89.

College answer

Goldstein, David S., Graeme Eisenhofer, and Irwin J. Kopin. "Sources and significance of plasma levels of catechols and their metabolites in humans."Journal of Pharmacology and Experimental Therapeutics 305.3 (2003): 800-811.

Sardesai, Suhrud H., et al. "Phaeochromocytoma and catecholamine induced cardiomyopathy presenting as heart failure." British heart journal 63.4 (1990): 234-237.

Lenders, Jacques WM, et al. "Biochemical diagnosis of pheochromocytoma: which test is best?." Jama 287.11 (2002): 1427-1434.

College answer

Not available.

Discussion

It's difficult not to introduce false subtext into the exam stems, as this is a high-stakes piece of text, and people will surely scrutinise each letter as carefully as Biblical scholars, inflating the meaning of seemingly random choices of wording and grammar. For example, "list the likely clinical and laboratory findings" leaves the reader to wonder how many findings such a list ought to contain.  These should be findings "that are seen in a patient with severe hypothyroidism, that requires ICU management", presumably implying that one should not list findings seen in relatively healthy community-based outpatients with hypothyroidism (and the comma in the middle is suspicious). And then, we are invited to "outline your approach to managing this patient in a)", but..... there is no specific patient case mentioned in a), only "a patient with severe hypothyroidism, that requires ICU management". What mysterious grade items lurk in the difference between this wording, and simply asking the candidates to "otline your approach to managing a patient with severe hypothyroidism in the ICU"?

Pushing down the paralysing fear that one completely misinterpreted the question, the following potential answer can be offered:

a) Clinical and laboratory findings in severe hypothyroidism: left without instructions regarding how many of these were required, the author has listed all of them; though one might make the argument that postural dizziness  amenorrhoea and decreased libido are unlikely to be important in a patient that requires ICU management, and could have been omitted.

• Symptoms
  • Lethargy
  • Depression
  • Psychosis
  • Decreased level of consciousness
  • Cold intolerance
  • Dry skin
  • Hoarse voice
  • Neck swelling (goitre)
  • Postural dizzyness
  • Gastro-oesophageal reflux
  • Constipation
  • Myalgia
  • Amenorrhoea
  • Decreased libido

• Signs

  • Hair loss
  • Loss of the lateral eyebrows (Queen Anne sign)
  • Dry thickened skin
  • Oedema (usually, non-pitting)
  • Proximal muscle weakness
  • Periorbital oedema
  • Enlarged tongue
  • Bradycardia
  • Pericardial effusion
  • Hypothermia
  • Delayed reflexes

• Laboratory features

  • Decreased T4 and T3
  • Increased TSH
  • Hyperlipidaemia
  • Hyponatremia
  • Normochromic normocytic anaemia

b) An approach to the management of the severely hypothyroid patient: for 40% of the total mark, this should have been a relatively thick paragraph or point-form list. What follows is a management plan for a patient with a very severe ICU-level hypothyroidism, bordering on myxoedema coma:

• Specific management:
  • Replace thyroxine.   
    • Initially, IV triiodothyronine 10mcg 8-hourly
    • Also large loading dose (300-500 mcg per day) of enteral thyroxine
    • Decrease to 200mcg/day as the symptoms improve
    • Monitor TSH and clinical response
  • Add corticosteroids (stress dose of hydrocortisone, 50mg 8-hourly)
• Supportive management:
  • Intubate and ventilate if unconscious 
  • Vasopressors and inotropes (expecting catecholamine resistance)
  • Gentle sedation (expecting increased sensitivity to anaesthetics)
  • Correct hyponatremia
  • Correct hypoglycaemia
  • Watch for bleeding (increased rate of fibrinolysis)

c) Features of sick euthyroid: 

• T3: low
• rT3: high
• T3/rT3 ratio: low
• T4: high ...or normal
• TSH: high ...or normal

The sick euthyroid syndrome is a biochemical pattern of decreased circulating T3 levels, without a strong compensatory TSH response. The raised levels of rT3 result in a disproportionate degree of thyroid dysfunction, as rT3 is an inactive form, and therefore a competitive antagonist of "real" T3.

d) Management of sick euthyroid syndrome, in 90 seconds, 

• There is no benefit in routinely supplementing T3 or T4
• Focus on the management of the underlying critical illness
• Correct malnutrition (euthyroid sick syndrome is strongly associated with malnutrition and hypercatabolic states)
• Use IV triiodothyronine to support patients who have euthyroid sick syndrome and some degree of heart failure or cardiogenic shock

College answer

Not available.

Discussion

a)

The biochemical abnormalities, important and unimportant, are:

• Hypoxia (assuming this is a gas on 21% FiO₂)
• Either polycythaemia or - more likely, looking at the rest of the results - haemoconcentration (a raised haemoglobin, a haematocrit of 0.54)
• Mild hypokalemia
• Hyperglycaemia: BSl 47 mmol/L
• Hypernatremia: the sodium, corrected by a conventional formula, is 148 mmol/L, which is probably what they meant when they said "showing your calculations".  

Sodium (corrected) = Sodium (measured) + glucose / 4 

= 136 + (47/4)

= 136+ 11.75

= 148, or so

• Lactate is elevated, contributing to the impression that the patient is dehydrated
• The creatinine and urea are raised, in a ration which also supports water loss

b)

This is HHS, an obvious spot diagnosis which was rewarded with the absolute minimum of marks.

c)

To pick three complications would be hard, as this condition has a million possible complications:

• HHS-specific physiological abnormalities
  • Hypotension and shock
  • Metabolic acidosis
  • Coma
• Complications arising from the HHS disease state:
  • Cardiac arrest
  • Cardiovascular collapse
  • Myocardial infarction
  • Pulmonary oedema
  • Stroke
  • Cerebral oedema and brain injury
  • Venous thrombosis (DVT, PE)
  • Aspiration
  • Osmotic demyelination (Hegazi et al, 2013)
• Complications of therapy for HHS:
  • Dysnatraemia
  • Hyperchloremia from saline administration.
  • Phosphate depletion
  • Hypokalemia
  • Hypoglycaemia
  • Cerebral oedema

College answer

Answers in part a) were commonly around causes of Addison's disease rather than causes or precipitants of an adrenal crisis. Some candidates listed more than the number asked in part a), and this is a reminder to trainees that if the question asks for five answers, and candidates list more than five, only the first five answers will be considered.

Discussion

a) Of these six causes, at least five should be correct:

• Insufficient supplementation
  • Poor medication compliance for chronic steroid replacement
  • Abrupt weaning of long term steroids
  • Decreased oral steroid absorption (eg. bowel obstruction)
• Increased demand
  • Acute infection
  • Surgery or trauma
  • Pregnancy

b) Laboratory abnormalities:

• Hyponatremia
• Hyperkalemia
• Metabolic acidosis (NAGMA)
• Raised urea (due to volume depletion)
• Hypoglycaemia
• Hypercalcemia

c) Management priorities:

• Immediate priorities:
  • Steroid replacement: hydrocortisone 100mg IV immediately, followed by 50mg four times a day
    • In patients with suspected adrenal insufficiency who do not yet have a diagnosis, giving emergency dexamethasone may be an option, because it will not interfere with cortisol measurements (or, one may simply send a cortisol level and then immediately start hydrocortisone)
  • Volume replacement: isotonic saline, titrated to clinical response
  • Glucose replacement: dextrose, to aim for normal BSL
• Supportive management:
  • Correct hypotension with vasopressors (noradrenaline) 
  • Correct hyperkalemia with standard measures (cation exchange resin, insulin, salbutamol, etc)
    • Add fludcorotisone if using dexamethasone instead of hydrocortisone
  • Cease any medications that may be precipitating the crisis, eg. any CYP 3A4 inducers, azoles, etomidate, rifampicin, carbamazepine

College Answer

Syllabus topic/section:

2.1.9    Endocrine Intensive Care – L1.
2.1.21 Applied Pharmacology in Intensive Care.

Aim:

To demonstrate a detailed understanding of the practical management of diabetic ketoacidosis and to demonstrate knowledge of the pathogenesis of the most important complications of these drugs.

Discussion:

Part (A) – This question tests recall of how to manage DKA and explores the application of these management principles to the clinical scenario given. Candidates scored well if: They detailed a standard approach to DKA specifically addressing 24hrs management of fluids, electrolytes, and insulin for the patient scenario provided with clearly mentioned endpoints. Candidates scored poorly if they did not mention management of these domains and failed to write clear endpoints or inaccurate doses of insulin and inadequate fluids were administered.
Strategies to improve: Address the question asked by reading and understanding the question, do not waste time in writing things not asked e.g. resuscitation issues other than those of volume status. Mentioning management plan/goals with reference to standard guidelines are rewarded.

Part (B) – Candidates scored if well if they mentioned: as the SGLT2 inhibitors block the sodium-glucose co- transporter 2, the resulting glucosuria leads to decreased plasma glucose levels and decreased insulin release. Carbohydrate deficit, insulinopenia, and increased glucagon release lead to upregulation of lipolysis and ketogenesis resulting in ketoacidosis. Candidates scored poorly if they were unable to demonstrate the pathophysiology of euglycaemic ketogenesis.
 

Discussion

a)  

These management strategies are derived from the 2022 JBDSIC guidelines 

• Fluid replacement
  • 20ml/kg of IV fluid (saline or balanced crystalloid) in the first hour
  • 4-14 ml/kg/hr in the next two hours
  • Aim for total replacement of up to 100ml/kg (total water deficit in DKA)
  • Endpoints:
    • Restoration of circulating volume: haemodynamic goals, eg. SBP 90 mmHg, as well as clinical features such as urine output and peripheral perfusion
• Electrolyte replacement
  • Replace potassium (ideally as potassium acetate)
  • Replace phosphate (as potassium dihydrogen phosphate)
  • Ideally via central line, to allow concentrated electrolyte infusion
  • Expect to replace about 3-5 mmol/kg of potassium and 1 mmol/kg of phosphate, in total
  • Endpoints:
    • maintain normal potassium concentration (4.0-5.0 mmol/L)
    • maintain normal phosphate and magnesium concentration
• Insulin therapy
  • Insulin infusion at 0.1u/kg/hr
  • Hourly monitoring of BSLK and ketones
  • Endpoints:
    • Increase the HCO₃^- by 3mmol/L every hour
    • Decrease the BSL by 3mmol/L every hour
    • Decrease the blood ketone concentration by 0.5mmol/L every hour
  • Continued until BSL is reduced to below 14mmol/L
  • Then, continued together with IV dextrose (5% or 10%) until ketone levels <1.5

b)  Pathophysiology of euglycaemic ketoacidosis, for 2 marks, would literally have to be something in about forty words. Thus:

• Reduced glucose availability due to glycosuria produced by the SGLT2 inhibitor
• Thus, reduced insulin secretion and increased glucagon secretion
• Thus, lipolysis and ketogenesis
• Plus, glycosuria produced by the SGLT2 inhibitor adds to the problem by producing volume depletion

College answer

Syllabus topic/section:

2.1.9 Endocrine Intensive care / Acute Thyroid crises: L1
2.1.9 Endocrine Intensive care / Other thyroid disorders: L2

Discussion:  

This was a simple didactic question. In general, the management section was dealt with well. Many candidates could have been more successful in demonstrating the standard required if detailed and structured answers for the questions on clinical presentation and investigations were given.
For example, a structured answer for part A detailing neurological, respiratory, GIT and cardiovascular signs and symptoms, was required. For Part B, the laboratory investigations required detailing the findings on thyroid function tests with the corresponding laboratory profile (normocytic anaemia, elevated CK, hyponatraemia's, hypoglycaemia, hypercapnia and respiratory acidosis).
The better answers in part C included management of precipitating factors and rationale for use of T3 versus T4.
The rubric is included to aid the candidate's future study.

Discussion

"Outline the clinical presentation" has not been asked for this condition before. That the vocabulary term "list" was not used suggests that some additional structure was expected:

a)

Airway features

• Macroglossia
•  Oedema (myxoedema) of the nasopharynx and larynx
• Goitre displacing the airway

Respiratory features

• A "puffy" face, propensity to sleep apnoea
• Reduced hypoxic respiratory drive
• Decreased ventilatory response to hypercapnia

Cardiovascular features

• Bradycardia
• Pericardial effusion
• Cardiogenic shock
• Prolonged PR interval
• Decreased QRS voltages, especially in the limb leads
• Prolonged QT
• Deep T-wave inversions

Neurological features

• Decreased level of consciousness
• Seizures (in up to 25%)
• Psychosis or depression ("myxoedema madness")

Renal consequences

• Bladder atony and urinary retention

Gastrointestinal features

• Anorexia, nausea, abdominal pain
• Constipation,  ileus, all the way to megacolon

Immunological features

• Hypothermia, which masks fever

Other associated examination findings:

• Hypothermia
• Periorbital oedema
• Coarse, sparse hair
• Non-pitting oedema

b) Laboratory investigations and expected results:

• EUC: hyponatremia
• Serum osmolality: hyposmolarity
• BSL: Hypoglycaemia
• CSF biochemistry: normal, except for elevated protein levels
• Serum lipids: high serum cholesterol
• CK: Raised CK (increased muscle permeability)
• ABG: hypoxia and hypercapnia

• FBC: normocytic normochromic anaemia from decreased erythropoiesis 

• TFTs: hypothyroidism, duh. Surely that would not have scored any marks?

c) "Key principles" of management:

• Replace thyroid hormone - preferably IV T3
  • loading dose is 300-400μcg
  • Continue until body temperature and haemodynamics renormalise
  • IV T3 is preferred mostly because of the atonic bowel, where absorption is likely to be erratic. IV T4 has been used as well, but apparently it is less effective because it has lower intrinsic activity. Plus if there is some concurrent illness (an there always is) the T4  is not converted to T3 because of reduced 5′-deiodinase activity. 
• Replace corticosteroids - there is usually a concomitant adrenal insufficiency. One would use a "stress dose".
• Fluid restriction to correct the sodium: this is usually a hypervolemic hyponatremia
• Good solid supportive management:  this appears as an essential element in the rubric and also seemed necessary in the CICM answer to Question 13 from the second paper of 2018, even though it is in no way specific to the management of myxoedema coma. Judging by the allocation of the marks in the rubric, mentioning that the comatose person needs to be intubated would have upgraded your answer 
  • Establish an airway if this is needed
  • Maintain normoxia and normocapnea with the ventilator
  • Maintain normotension to support organ system perfusion, with a catecholamine infusion
  • Correct the Na⁺ deficit - consider using water restriction alone.
  • Correct hypoglycaemia
  • Correct hypothermia with warming blanket
• Underlying cause:  often something like sepsis is in the background.

College answer

Syllabus topic/section:

2.1.9 Endocrine Intensive Care / Diabetes Mellitus: L1

Discussion:  

In general candidates were familiar with the calculations, were able to recognise HHS/ DKA and describe management. It is helpful to show formulae that are being used (so if the calculations are incorrect, marks can be allocated for the principles), provide specifics in answers to management questions, and provide lists relevant to the scenario and explaining why. For instance, specifics of fluid resuscitation, the role and dosage of insulin use, resuscitation and metabolic targets to achieve were outlined in the more successful answers.

Discussion

a)

To go through these results systematically:

• There is acidaemia.
• The CO2 is appropriately depressed;  for a HCO3 of 4, it should be something like (1.5 × 4) + 8 = 14. 
• The anion gap is (145 - 108 - 4) =  33
• Assuming the albumin is normal, the delta ratio is (33-12)/(24-4) = 1.05; i.e. a pure HAGMA.
• The lactate is raised, but only by 7 mmol/L, which means it does not account for all of the anion gap. 

So:

• this is HHS
• the pH is depressed by the combined lactic acidosis and ketoacidosis
• There is a good earnest attempt at compensation
• The renal failure is due to dehydration (as revealed by the urea:creatinine ratio, which, using an online calculator to cheat,  is 13.1  - i.e. there is no intrinsic renal damage, and this is all pre-renal).

b) 

The corrected sodium and the osmolar gap:

• The corrected sodium, using the classical equation, is (55/5.6) × 1.6 + [measured Na], which ends up being 160.6.
• The calculated osmolality, (145 × 2) + 55 + 46, = 391. 
• This leaves us with an osmolar gap of 406-391 = 15, which is slightly abnormal (it is supposed to be no greater than 10)

c) "List the likely etiologies" sounds a lot like "explain the abnormalities", but okey:

• Again, this is HHS
• The hyperglycaemia acted as an osmotic diuretic, producing the volume loss, renal failure, urea accumulation, and lactic acidosis. The vom,citing surely did not help.
• The insulin resistance has resulted in the ketoacidosis

d)  For every decrease of 10 g/L i albumin, the anion gap will decrease by 2.5; i.e. the expected normal anion gap of a hypalbuminaemic patient is smaller.

e) The "management of blood glucose and osmolality" here sounds like a hint that the examiners wanted to see a slow deliberate strategy that prevents cerebral oedema. Thus:

• Start fluid resuscitation:
  • 15-20ml/kg in the first hour
  • 4-14ml/kg in the second hour (of 0.45% NaCl)
  • 4-14ml/kg again in the third hour (use 0.9% NaCl if the sodium is low)
  • Then, when glucose is under 15mmol/L, can add some 5% dextrose
• Insulin may be required to address the ketosis, and would be used at a constant rate of 0.1 U/kg/hr 
• Aim for a decrease in osmolality by about 3–8 mOsm/kg/h, as a safe rate (Diabetes UK Position Statement - Scott et al, 2015) - this can often be achieved with fluid resuscitation alone
• Remember to replace electrolytes such as phosphate and potassium

College answer

Syllabus topic/section:

2.1.9 Endocrine Intensive Care: Acute thyroid crises: L1

Discussion: 

Good answers to part a) included a well organised list of clinical features including the presence of a high fever with neurological, cardiac and abdominal symptoms discussed in some detail. Good answers also noted the possibility of longer standing hyperthyroidism and it's features with possible triggers of storm.

Candidates mostly did well in part b) and were able to mention the expected T3, T4 and TSH result (of note thyroid storm is almost never due to secondary hyperthyroidism). Good answers also included some of the other likely laboratory abnormalities and that these are not specific. Some candidates wrote about non- laboratory-based tests such as ECHO and CT which did not score marks as the question specifically asked for laboratory ones.
Part c) of the question was less well answered by candidates. Candidates who did well were able to discuss the resuscitative and supportive measures as well as outlining the specific treatments and their rationale (the glossary headings for management). Supportive treatments needed to be targeted to the condition and good candidates linked the clinical presentation features from part a to their management plan.
Good answers discussed the timing of specific treatments (e.g. iodide after PTU and the rationale), included looking for a precipitant, and mentioned rescue therapies (PLEX, thyroidectomy). Excellent answers demonstrated superior subject grasp by discussion of areas of uncertainty or controversy - e.g. using beta blockers in patients at risk of decompensating shock or the use of amiodarone.

Discussion

Clinical features and laboratory findings of thyroid storm (there is no possible way you would write this much in 5 minutes, but the ABCDE structure is probably reasonable, just to prevent you from forgetting a key feature like fever which might be missed in a systems-based approach)

1. Goitre: possible airway compromise)
2. Tachypnoea due to increased CO2 production;
   Increased O₂ER (increased metabolic fuel use)
3. Tachycardia,
   Atrial fibrillation and ventricular arrhythmias
   Heart failure
   Hypertension (early), hypotension (late)
4. Tremor;
   Agitation, progressing to encephalopathy, coma and seizures.
   There is the phenomenon of "apathetic thyrotoxicosis" which presents with weakness
5. Low potassium and magnesium (particularly in "apathetic thyrotoxicosis")
   Serum cortisol should be elevated. If it is not, one might consider a relative adrenal insufficiency, and supplement some hydrocortisone.
   Also, obviously, TFTs:
   • Raised T3 and T4
   • Low TSH
   • Deranged LFTs
6. Rhabdomyolysis may be present; CK may be elevated. This is "thyrotoxic myopathy"
7. Diarrhoea, nausea and vomiting
   Increased metabolic rate; increased demand for metabolic substrate.
   Nutritional requirements are increased
   Hyperglycaemia may be apparent in the non-diabetic patient
   Jaundice may develop
8. Leukocytosis; a left shift
9. Fever: in fact, may go up to 41°C. This is apparently the most characteristic feature.

Management

• Look for a precipitant (eg. autoimmune thyroiditis, 
• Main goals are:
• Prevent synthesis of T3 and T4:
  • Thiouracils: propylthiouracil - blocks synthesis of T3 and T4 as well as peripheral T4-T3 conversion
  • Imidazoles: carbimazole - block synthesis of T3 and T4
• Prevent T3 and T4 release:
  • Inorganic iodine therapy, eg. potassium iodide (given after synthesis is blocked)
  • Lithium is an alternative
• Block peripheral T3 and T4 activity:
  • β-blockade: propanolol (which also decreases T4-T3 conversion)
  • Corticosteroids: also decrease T4-T3 conversion
• Add corticosteroids: there is always some relative adrenal insufficiency.
• Add cholestyramine to block reabsorption of thyroid hormone which is excreted with the bile
• Severe refractory disease may call for extracorporal clearance of thyroid hormone by plasma exchange or charcoal haemoperfusion.
• Thyroidectomy is a last resort