A 65-year-old male is admitted to your intensive care unit from the haematology ward with hypotension and diarrhoea (1.5L/day). He received an allogeneic stem cell transplant 18 days ago as part of his treatment for multiple myeloma.
 
On arrival to the ICU he is febrile, tachypnoeic, with a tachycardia and hypotension and a distended abdomen, which is diffusely mildly tender.

Blood results on ICU admission are as follows:
 

 

Parameter

Patient Value

Normal Adult Range

Sodium

137 mmol/L

135 – 145

Potassium

4.8 mmol/L

3.5 – 5.0

Chloride

99 mmol/L

95 – 105

Bicarbonate

16 mmol/L*

22 – 32

Urea

21 mmol/L*

3.0 – 8.5

Creatinine

146 micromol/L*

40 – 90

Albumin

19 G/L*

36 – 52

Bilirubin

33 micromol/L*

0 – 18

Alanine Aminotransferase (ALT)

49 IU/L*

0 – 30

Aspartate Aminotransferase (AST)

140 IU/L*

0 – 30

Alkaline Phosphatase (ALP)

120 IU/L*

30 – 100

Gamma Glutamyl Transferase (GGT)

225 IU/L*

0 – 35

Haemoglobin

84 G/L*

115 – 165

Platelets

12 x 109/L*

150 – 400

White Cell Count

0.1 x 109/L*

4 – 11

Neutrophils

0.0 x 109/L*

2.0 – 7.5

FiO2

0.4

pH

7.37

7.35 – 7.45

PCO2

28 mmHg*

35 – 45

PO2

108 mmHg

HCO3

16 mmol/L*

24 – 31

Base excess

-8 mmol/L*

-3 – +3

Lactate

8.1 mmol/L*

< 2.2

Glucose

6.2 mmol/L

3.0 – 7.8

Calcium

1.24 mmol/L

1.2 – 1.3

a) Outline your management priorities.

b) List the likely causes of diarrhoea in this patient.

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College Answer

NB: Important points in bold.

a)
This is a critically ill, immunocompromised patient with febrile neutropenia following a stem cell transplant. There is evidence of septic shock with evidence of organ dysfunction (lactic acidosis, renal, hepatic and bone marrow dysfunction)
Management priorities: resuscitation, determination of relevant history, appropriate investigations and definitive therapy.

i. Resuscitation
 Assessment of work of breathing & NIV, if required.
 Assessment of volume status/responsiveness & cardiac output, IV access and fluid resuscitation, invasive central venous and arterial lines with platelet cover, vasoconstrictor/inotrope therapy aiming for appropriate goals.
 Early antibiotic therapy.

ii. Relevant history
 Organ specific symptoms.
 Information about transplant, related chemotherapy, current medications.
 Prior infections/colonisations.
 Consideration of non-infectious causes - e.g. pancreatitis .

iii. Investigations
 Detailed clinical examination, source of sepsis.
 Blood cultures-peripheral and through existing central lines, urine, stool cultures, removal of existing lines if likelihood of infection and tip for culture.
 Investigation for diarrhoea- stool for ova, cysts, parasites, C diff toxin, P/R examination, proctosigmoidoscopy (caution due to thrombocytopenia).
 Erect AXR – rule out perforated viscous and surgical review, if indicated.
 Other relevant imaging based on history and examination- chest x-ray, abdominal ultrasound/CT.

iv. Therapy 
 Empiric antibiotic therapy within an hour- either based on existing cultures or colonisation, allergies, recent antibiotic use, local antibiograms. Otherwise established febrile neutropenia protocol - Antipseudomonal, anti-staphylococcal and antifungal therapy. Dose adjustment for organ function. 
 Source control where possible, removal of existing lines, catheters. 
 Management of diarrhoea- fluid and electrolyte correction, loperamide if cultures negative. 
 G-CSF (haematology guidance), platelet transfusion if < 20,000 or active bleeding/pre-procedure. 
 Management of symptoms- pain, nausea, mucositis. 
 Establishment of nutrition- Parenteral nutrition if severe mucositis or diarrhoea, trace element supplementation.

b) Possible causes of diarrhoea: 
 Infectious 
o Bacterial- Clostridium difficile, salmonella, shigella, E coli including ESBL. 
o Viral - CMV, rotavirus, adenovirus, norovirus. 
o Parasitic – cryptosporidium, microsporidia, giardia. 
o Fungal- candida.

 Non-Infectious 
o Acute Graft versus Host Disease. 
o Neutropenic enterocolitis (Typhilitis). 
o Drugs- antibiotic related, opioid withdrawal, promotility agents, tacrolimus (thrombotic microangiopathy), chemotherapy conditioning regime for stem cell transplant. 
o Severe hypoalbuminaemia .

Discussion

a)

This question is broadly about the resuscitation of sepsis, but the patient has specific issues which need to be addressed, and one would not do well if one simply applied an algorithmic approach.

The issues are:

  • Septic shock (likely from an abdominal source)
  • Multi-organ system failure
    • Acute renal failure
    • Hepatic insufficiency
    • Bone marrow failure
    • Respiratory failure
  • Lactic acidosis

A structured approach:

Immediate management:

A) - assessment of the urgent need for intubation

B) - Support of oxygenation with NIV or high flow nasal prongs

    • if the patient is mechanically ventilated, minute volume must take into account the need for compensation in this metabolic acidosis

C) - Hemodynamic control:

    • Vigorous fluid resuscitation with combination of balanced crystalloid and albumin, as directed by dynamic assessment of fluid responsiveness
    • Arterial blood pressure monitoring
    • Central venous access
    • Vasopressor support as indicated
    • Reassessment of resuscitation efficacy (lactate)

D) - Adequate analgesia

E) - Correction of electrolyte abnormalities

F) - Monitoring of urine output and renal function; CRRT support as indicated

G) - Nutritional support (ideally, enteral)

H) - Haematological interventions:

    • Maintenance of Hb over 70g/L
    • Consultation with haematology regarding the need for G-CSF
    • Replacement of clotting factors
    • Correction of thrombcytopenia as required by invasive procedures

I) - Early administration of broad-spectrum antibiotics

Investigations:

  • Blood, urine, sputum, stool cultures
  • C.difficile toxin stool test
  • CXR and AXR
  • CT of the abdomen (if permitted by patient stability)
  • Removal of old central venous catheters, or at least cultures from their lumens

b)

Causes of Diarrhoea
In the Bone Marrow Transplant Recipient

Infectious

Non-Infectious

Viruses

  • Rotavirus
  • Norovirus
  • Adenovirus
  • Cytomegalovirus

Bacteria:

  • Clostridium difficile
  • Shigella
  • Salmonella
  • Campylobacter
  • E.coli
  • Aeromonas

Parasites

  • Giardia
  • Cryptosporidium
  • Microsporidium

Fungi

  • Candida

     

Immunosuppressant therapy

  • Cytotoxic drugs
  • Tacrolimus
  • Whole-body irradiation

Consequences of BMT

  • Neutropenic enterocolitis
  • Graft vs host disease

ICU therapy

  • Pro-motility agents
  • High caloric feeds
  • Lactulose
  • Opioid withdrawal
  • Broad spectrum antibiotics

References

References

Timothy A. Woods. "Diarrhea." Chapter 88 in: Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990.

Cox, George J., et al. "Etiology and outcome of diarrhea after marrow transplantation: a prospective study." Gastroenterology 107.5 (1994): 1398-1407.