Viva 3

A 28-year-old Australian aid worker, returns from the Philippines’ flood disaster and is subsequently admitted to your ICU via the Emergency Department. Twelve days following her return she developed fevers, headaches and severe myalgias. This continued for a week, and then improved. Despite feeling weak she remained well for 3 days before deteriorating again and presenting to ED.

On clinical examination the following is evident:
She appears unwell, respiratory rate 24 breaths/min, bibasal crackles on auscultation, Heart Rate 102 beats/min

Blood Pressure 92/45 mmHg, cool peripheries, conjunctival suffusion, and mild meningism.
She is confused but with no focal neurology.
She has no rash and moderate hepato-splenomegaly.

Provide a differential diagnosis.

The candidates should come up with leptospirosis as the dominant hypothesis. The 2003 WHO document on leptospirosis gives an exhaustingly long list of non-specific signs and symptoms, as well as a similarly long list of differential diagnoses.

"The following diseases should be considered in the differential diagnosis of leptospirosis:"

• influenza;
• dengue and dengue haemorrhagic fever;
• hantavirus infection, including hantavirus pulmonary syndrome or other respiratory distress syndromes;
• yellow fever and other viral haemorrhagic fevers;
• rickettsiosis;
• borreliosis;
• brucellosis;
• malaria;
• pyelonephritis;
• aseptic meningitis;
• chemical poisoning;
• food poisoning;
• typhoid fever and other enteric fevers;
• viral hepatitis;
• pyrexia of unknown origin (PUO)
  -this is not a high quality differential, IMO - A.Y.
• primary HIV seroconversion;

Which three possibilities do you feel are the most likely?

This is an optional question, in case they give you a thousand options.

The ED physician thinks this is severe malaria. Which clinical features would you expect from a classical presentation of severe malaria?

For the "severe malaria" section, the list of features is borrowed from the WHO severity definitions, abridged for easier recall.

• Coma
• Generalised weakness ("prostration")
• Seizures
• Acidosis and tachypnoea (mainly a lactic acidosis)
• Shock
• Haemolysis, haemoglobinuria and anaemia
• Hepatic failure
• DIC
• Pulmonary oedema or ARDS
• Acute renal failure

The original full-scale WHO list of criteria for severe malaria can be found in this 2012 review article from the Malaria Journal, as Table 1.

The ID physician has also examined the patient, and thinks this is leptospirosis. What clinical features would support this diagnosis?

Clinical features of Leptospirosis in general; particularly of Phase 1 (early disease)

• History of travel to a tropical flood-prone area
• Conjunctival suffusion
• Headache, particularly retroorbital
• Myalgia, particularly of the lower back and calf.

Clinical features of Weil's disease in particular (Phase 2)

• Jaundice
• Bleeding diathesis
• Hepatosplenomegaly and hepatic necrosis
• Renal failure
• Pulmonary haemorrhage
• Aseptic meningitis
• Uveitis
• Cholecystitis
• Pancreatitis
• Myocarditis
• Rhabodomyolysis

The specific references used to generate this answer were "Diagnosis of acute leptospirosis" by Toyokawa et al (2011) and  "Chapter 171. Leptospirosis" by Vinetz, in: Harrison's Principles of Internal Medicine, 18^th ed. The clinical features of leptospirosis are also presented in a good 2011 article, which asserts a certain order of importance over the protean manifestations of this disease.

What is meant by a "biphasic" course when referring to leptospirosis?

• Incubation period: 5-14 days.
• Leptospiraemia (Phase 1) - 1 week. Oh's Manual calls it the "Septicaemic phase"
  • Characterised by fevers, myalgia, conjunctival effusion, etc.
• A brief break in symptoms usually follows.
• Leptospiruria (Phase 2) - up to 1 month. Oh's Manual calls it the "Immune phase"
  • Weil's syndrome usually occurs at the beginning of this phase, and is characterised by some mixture of horrible inflammatory complications and organ system failures, including
    • Hepatic necrosis
    • Renal failure
    • Pulmonary haemorrhage
    • Aseptic meningitis
    • Uveitis
    • Cholecystitis
    • Pancreatitis
    • Myocarditis
    • Rhabodomyolysis

Once the spirochetes generate a vigorous antibody response, their numbers in the bloodstream dwindle (that usually takes about a week). Thereafter, they remain adherent to the renal tubular epithelium, and are shed into the urine.

 

While the ED staff perform basic resuscitative manoeuvres, which investigations would you and the ID physician need to organise?

Laboratory diagnosis of leptospirosis

• Gold standard: the microscopic agglutination test (MAT)- apparently, only available at the CDC.
• Isolation of the organism by slow laborious culture and microscopy (takes up to 2 weeks)
• PCR, which seems to be very accurate

Generic investigations:

• CXR
• ECG
• ABG
• LFTs
• FBC
• EUC / CMP
• Inflammatory markers
• Blood cultures

The PCR for leptospirosis comes back as positive. Which treatment is appropriate?

The Sanford Guide recommends benzylpenicillin.

... when they say "benzylpenicillin", you say...

The patient is allergic to penicillin. What alternatives are there?

Alternatives include ceftriaxone or doxycycline. A 2012 Cochrane review could not demonstrate any difference between antibiotic regimens, nor indeed any benefit from antibiotics in general. 

The college answer to  Question 7 from the second paper of 2014 suggested

• Penicillin (1.5 million units IV every 6 hours) OR
• Doxycycline (100 mg IV twice daily) OR
• Ceftriaxone (1 to 2 g IV once daily), OR
• Cefotaxime (1 g IV every 6 hours).

Also, "Use of intravenous corticosteroid therapy has been proposed given the vasculitic nature of severe leptospirosis, particularly in the setting of pulmonary involvement; however there is insufficient evidence for routine use of corticosteroids."

How long would you treat the patient?

The course is for 7 days.

The patient has a history of safely tolerating cephalosporins, and ceftriaxone is commenced. 
Shortly after arriving to the ICU, the patient becomes more agitated.
The vital signs and ABG are as you see below.
Evaluate these data and explain your findings.

Obs:

• BP     86/44
• HR    133, sinus rhythm
• RR     30 (manual count)
• Temp 39.5°C
• FiO₂ = 50% via HFNP at 60L/min

(albumin is 20)

In summary, 

The acid-base findings are:

• There is a widened A-a gradient (236, in case you are wondering; PF around 158)
• There is an acidaemia
• There is a metabolic acidosis (SBE  -11.2)
• There is inadequate respiratory compensation, (the expected CO₂ is ~ 28)
  i.e there is also respiratory acidosis
• The anion gap is 14.6, which - with an albumin of 20 - means it is elevated by about 7
• The lactate is elevated by 5.9, which incompletely accounts for the SBE o value in this metabolic acidosis
• The delta ratio is around 0.7, which makes this a mixed HAGMA/NAGMA

In short, this person is hypoxic with a mixed respiratory and metabolic acidosis, of which part is from a raised lcatate and part is from the saline ED gave her.

She is also a bit hypoglycaemic and is in acute renal failure.

What are the possible causes of this sudden deterioration?

This is a fairly mindless exercise in the differentials of shock.

Distributive shock (most likely)

• Worsening sepsis
• Anaphylaxis
• A non-allergic drug reaction, eg. the Jarisch-Herxheimer reaction, which is horrible inflammatory state featuring rigors, shock, a temperature up to 42°C, and possibly DIC.

Less likely:

• Blood loss
• Third space losses

Obstructive shock:

• Tension pneumothorax
• PE
• Cardiac tamponade due to infected effusion

Cardiogenic shock

• Acute coronary event
• Septic cardiomyopathy
• Myocarditis
• Sudden acute valve regurgitation

The patient's level of consciousness deteriorates further and she is intubated.

With fluid boluses of up to a total of 50ml/kg and noradrenaline at 0.20 mcg/kg/min,
the vital signs remain unstable. The monitor screen is as you see below.

Evaluate these data and explain your findings.

(FiO₂ is 100%)

The monitor shows:

• tachycardia with some ST depression
• A pulse pressure variation ("swing" in the art line)
• A very low CVP, for somebody on positive pressure ventilation
• An EtCO2 which is low, consistent with acidosis
• A level of hypoxia which is severe given the high FiO₂

A repeat set of bloods is sent. The result is called through as "critical".
Interpret this biochemistry profile in the context of this situation.

Creatinine	350*µmol/l		40– 100
Urea	17.0 mmol/l		3.1– 7.5
Bilirubin (total)	149*µmol/l		2–22
Protein (total)	40* g/l		65– 85
Albumin	12* g/l		38– 48
ALP	1153* IU/l		40– 100
GGT	3459* IU/l		0–50
ALT	2336* IU/l		0 - 45

WCC	*2.77	(3.5 – 11.00 x109/L)
Hb	*65	(115 –165 g/L)
Platelets	*14	(150-400 x109/L)
PT	*28.9	(12.0 – 15 Sec)
INR	*2.7	(0.8 – 1.1)
APTT	*122.5	(25.0 – 37.0 Sec)
Fibrinogen	*1.1	(2.20-4.30g/L)

The bloods come from Question 6.1 from the second paper of 2008. 

The college answer to the question "what is the most likely cause of the coagulation abnormalities?" was "DIC".

There is also acute renal failure and a severe LFT derangement which does not fit any specific pattern, and could represent severe hepatitis.

What could explain this sudden deterioration?

The candidate should be putting two an two together. The patient has moderate hepatosplenomegaly, and has suddenly dropped her Hb from 122 to 65 over a short time. She is likely bleeding. Potential sources of blood loss include the spleen, the gut, the retroperitoneal space and (less likely) the chest, particularly tracking down from the IJ insertion site.

The patient becomes anuric, and is commenced on CRRT. 
On the next morning, her oxygenation continues to deteriorate. Another ABG is and EUC/CMP are collected. 

Please analyse these data and offer your analysis of the situation, as well as a plan of management. 

Ventilator settings

• Pressure control mode
• PEEP = 5
• Pinsp = 20
• I:E ratio 1:1
• FiO₂ = 100% 
• VT = 300ml
• Rate 30

Urea	5.0 mmol/L	3.0 – 8.0
Creatinine	110*µmol/l	40-100
Total Calcium	2.4 mmol/L	2.15 – 2.6
Phosphate	1.3 mmol/L	0.7 – 1.4
Albumin	12 G/L*	33 – 47

In summary, 

• The patient has very poor lung compliance (15 cm/ml)
• There is a profound hypoxia (PF ratio is 73!)
• there is no acidaemia
• There is a metabolic acidosis
• The "respiratory compensation" (i.e. the ventilator MV) is excessive, i.e. there is an iatrogenic metabolic alkalosis - the expected CO₂ is around 26
• The anion gap is 24.8. The expected anion gap is 5
• The delta ratio is therefore 1.4. This is a pure HAGMA.
• The lactate does not account for all of the elevation in the anion gap.
• The ionised calcium is desperately low.

This is probably citrate toxicity.  Question 3.3 from the second paper of 2013 is where the bloods were stolen from. 

Disclaimer: the viva stem above may be an original CICM stem, acquired from their publicly available past papers. Or, perhaps it is a slightly altered version of the original CICM stem. Or, it is a completely original viva stem, concocted by the monstrously amoral author of Deranged Physiology for nothing more than his own personal amusement. In either case, because the college do not make the main viva text or marking criteria available, almost everything here has been confabulated. It might sound like a plausible viva and it could be used for the purpose of practice, but all should be aware that it does not represent the "true" canonical CICM viva station.