Question 4

A 42-year-old male is admitted to your intensive care day 4 post induction chemotherapy for acute promyelocytic leukemia (AML-M3). The patient was initially treated with idarubicin and all-trans retinoic acid (ATRA). He has progressively become more dyspnoeic in the ward. A chest X-Ray demonstrates a bilateral, diffuse pulmonary infiltrate.

Initial examination reveals:

  • RR 40 breaths/min, SpO2 88% on 10 L/min O2 by face mask
  • Glasgow Coma Scale 14 (E4 M6 V4)
  • Temperature 38.9 ºC
  • Heart rate 144 beats/min
  • Blood pressure 95/50 mmHg

Full blood count is as follows on admission:


Patient value

Normal Adult Range


88 g/L*

135 – 180

White Cell Count

26 x 109/L* ( no differential)

4.0 – 11.0


22 x 109/L*

150 – 400

Comment: Blasts visible

International normalised ratio (INR)


a)   Give your differential diagnosis for his respiratory failure.        (40% marks)
b)   What are the major issues in this patient and how would you manage them?    (60% marks)

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College Answer


Sepsis in a patient with immune compromise secondary to leukaemia. Nosocomial pneumonia

–   Bacterial –Gm negative –E.coli, Pseudomonas, Klebsiella
–   Gm positive: Strep, Staph epi
–   Fungal:  Aspergillus, Candida, Cryptococcus
–   Atypical:  Legionella, mycoplasma
–   Viral:  CMV, HSV, RSV, Influenza, H1N1, VZV
–   PCP:  Toxoplasmosis
–   TB (depending on background)

Non- infective
-    Idiopathic pneumonia syndrome
-    Cardiac failure (cardiotoxicity due to induction chemo)
-    Diffuse alveolar haemorrhage
-    Non cardiogenic capillary leak syndrome

-    Chemo induced ALI / pneumonitis
-    Retinoic Acid Syndrome

Major issues are:

1.    Hypoxic respiratory failure

Probable nosocomial pneumonia now requiring respiratory support and is likely to be progressive

Problem with invasive respiratory support carrying very high mortality and complications including barotrauma, further nosocomial infections

Management - Non-invasive respiratory support commencing with CPAP progressing to BiPAP using the lowest FiO2 to maintain PaO2 above 60 mmHg. Attempt to avoid invasive respiratory support if possible.

2.    Possible Sepsis

May rapidly progress to septic shock in this patient Possible unusual infective agent

Early commencement of Broad cover (Cefepime / Ceftazadime / Tazocin and Vancomycin + Voriconazole / caspofungin / liposomal amphotericin + acyclovir + Bactrim.) Discussion with ID and haematology specialists for prior antimicrobial therapy, CMV status, previous aspergillus infection etc

Removal of indwelling intravenous catheters that are in anyway suspicious for infection

Central access (with platelet cover), consideration of inotropes after transfusion of blood products and IV fluids preferentially using Albumin containing solutions.


3.    Prognosis from acute promyelocytic leukemia (AML-M3).

Management is to liaise early with treating haematologist to ascertain likely outcome from primary disease and also discuss with family and patient the significant risk of deterioration and mortality.

4.    Other

Treatment of coagulopathy- Vit K, Platelets, FFP
Difficulties in making definitive diagnosis

Possible atypical infection with low yield probable from cultures Significant other non-infective differential diagnosis.

Management includes having a high degree of suspicion for resistant or unusual organism and managing with broad cover.

Additional Examiners’ Comments:

Candidates were expected to give some indication of treatment strategies e.g. antibiotics, reversal of coagulopathy rather than just writing D/W ID, haematology etc.


A long list of differenials  for a diffuse pulmoanry infiltrate is given in the chapter on the causes of ARDS. After this question came out, the list was amended to include ATRA syndrome, which is a freakishly rare thng and unlikely to ever be seen by anyobne outside of a major bone marrow transplant centre. The list mainly comes from an excellent article from Silvia Blanco and Antoni Torres (

Differential Diagnosis for Diffuse Bilateral Pulmonary Infiltrates


  • Pulmonary haemorrhage
  • Cardiogenic pulonary oedema


  • Bacterial
  • Viral
  • Fungal
  • PJP


  • Lymphangitis
  • Infiltrative neoplasm


  • ARDS
  • Idiopathic pneumonia syndrome


  • Eosinophilic pneumonitis
  • BOOP
  • Alveolar haemorrhage
  • Methotrexate-induced


  • Goodpastures (haemorrhagic)
  • Rheumatoid pneumonitis
  • Graft vs host disease in BMT
  • Engraftment syndrome
  • ATRA syndrome


  • Bilateral atelectasis
  • Pulmonary contusions
  • Chemical pneumonitis

ATRA syndrome (or "retinoic acid syndrome", or "differentiation syndrome") listed in the differentials above is a complication of therapy with all-trans-retinoic acid. A good references for those interested is a 2008 paper by Patatanian and Thompson. The authors describe this complication of ATRA therapy as "unpredictable but frequent" and offer little in the way of aetiological information.

Idiopathic pneumonia syndrome (also mentioned in the college list of differentials) is a (probably autoimmune) complication of bone marrow transplant, which is well covered in this 2011 article by Panoskaltsis et al. Characteristic features consist of pneumonia-like infiltrates and a demonstrated absence of respiratory tract infection.


"What are the major issues in this patient and how would you manage them?" This part of the question requires a structured answer. There are many ways to structure an answer like this. The suggested answer below is organised by important systems.


  • Airway: The need to avoid intubation
  • Respiratory: Hypoxic respiratory failure
  • Circulatory: Haemodynamic instability: likely, septic shock (HR 144, BP 95/50)
  • Neuro: A decreased level of consciousness (GCS 14)
  • Haematological: anaemia, thrombocytopenia, likely neutropenia, and coagulopathy.
  • Infectious: High fever (38.9°C) and raised WCC (26)
  • Definitive diagnosis:  cause of respiratory failure is uncertain
  • Social: prognosis and family understanding of the situation, medical consensus


  • Airway plan:
    • Avoid intubation- unless it is clear that the patient is failing. See the non-invasive ventilation chapter for the rationale behind this. In short, recommendations to avoid intubation in immunosuppressed patients are based on early trials (eg. Scales et al, 2008) which do not reflect the recent improvements in critical care for such patients. The college answer to Question 11 from the second paper of 2018 reflects this fact; they actually say "Invasive ventilation is not routinely avoided given overall good prognosis". This is very interesting, as in this 2015 version of the question, the college model answer recommended to avoid intubation. To digress briefly on this important topic, in a more recent review Lueck et al (2018) found markedly improved outcomes (eg. 1-year survival up from 14% to 32%) in BMT patients admitted to ICU. 
    • Keep patient fasted (nil by mouth) in the event intubation is required
  • Respiratory support plan:
    • Commence CPAP NIV
    • Aim for SpO2 >90%, PaO2 > 60mmHg
    • Breaks every 2 hours for chest physiotherapy (on high flow nasal prongs)
    • Ensure humidified circuit
    • Ensure frequent cough; encourage expectoration of sputum
  • Circulatory support plan:
    • Assess for fluid responsiveness using dynamic parameters
    • If fluid responsive, resuscitate with 20% albumin
    • If fluid resuscitation is ineffective, maintain MAP >65 with noradrenaline
    • Consider stress dose steroids (unless steroids are already being given)
  • Neurological plan:
    • Avoid sedating analgesics
    • Change NIV mode to BiPAP if hypercapnea develops
  • Haematological:
    • Transfuse to Hb >70 (TRISS)
    • Correct platelets for CVC insertion
    • Administer Vitamin K and FFP for correction of the INR
    • Seek clarification re. WCC differential (All neutrophils? All blasts?)
  • Infectious:
    • Fungal cover with voriconazole or caspofungin
    • PJP cover with Bactrim
    • Viral cover with aciclovir
    • Atypical cover with azithromycin
    • Gram negative and anaerobe cover with meropenem
    • Gram-positive cover with vancomycin
  • Definitive diagnosis:
    • Blood and sputum cultures
    • Atypical pneumonia serology
    • Urinary legionella and pneumococcal antigens
    • Sputum culture
    • TTE to exclude the contribution of cardiac failure to shock and hypoxia
    • Discussion with haematology team regarding the use of high dose steroids for ATRA syndrome (10mg bd of dexamethasone for 3 days, or addition of cytarabine to the chemotherapy cocktail to suppress the bone marrow).
  • Social:
    • Schedule family discussion
    • Confer with haematology regarding prognosis



Panoskaltsis-Mortari, Angela, et al. "An official American Thoracic Society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia syndrome." American journal of respiratory and critical care medicine 183.9 (2011): 1262-1279.

Patatanian, E., and D. F. Thompson. "Retinoic acid syndrome: a review." Journal of clinical pharmacy and therapeutics 33.4 (2008): 331-338.

Lee, Hwa Young, Chin Kook Rhee, and Jong Wook Lee. "Feasibility of high-flow nasal cannula oxygen therapy for acute respiratory failure in patients with hematologic malignancies: A retrospective single-center study." Journal of critical care 30.4 (2015): 773-777.

Scales, Damon C., et al. "Intensive care outcomes in bone marrow transplant recipients: a population-based cohort analysis." Critical Care 12.3 (2008): R77.

Lueck, Catherina, et al. "Improved short-and long-term outcome of allogeneic stem cell recipients admitted to the intensive care unit: a retrospective longitudinal analysis of 942 patients." Intensive care medicine 44.9 (2018): 1483-1492.