fever in critical illness: can the critically ill take the heat? -paul young

#HEATtrial

Dr Paul Young

Can the critically Ill take the HEAT?

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• Phase 2b RCT comparing IV paracetamol with placebo in ICU patients with fever and infection

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Kluger MJ, Ringler DH, Anver MR. Fever and survival. Science. 1975 Apr 11;188(4184):166-8. PubMed: 1114347

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Why doesn’t Campylobacter make

chickens sick?

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Click here to add titleClick here to add

text

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Neurosyphilis resolves after febrile illnessMalaria

causes a feverDoes Malaria cure

syphilis?Wagner-Jauregg J (1927) The treatment of dementia paralytica by malaria innoculation. Nobel Lectures: Physiology or Medicine 1922-1941. Elsevier, New York, pp. 159-169

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n=269,078

No infection Infection

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Schortgen F et al. Fever control using external cooling in septic shock: a randomized controlled trial. Am J Respir Crit Care Med. 2012 May 15;185(10):1088-95. Pubmed ID: 22366046.

Sepsiscool study

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External cooling of patients with septic

shock requiring sedation and

ventilation may delay death

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Mourvillier B, et al. Induced Hypothermia in Severe Bacterial Meningitis: A Randomized Clinical Trial. JAMA. 2013 Oct 8. PubMed ID: 24105303.

Comatose patients with bacterial meningitis

48 hours of physical cooling

to 32-34°Cstandard care

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98 patients enrolled DSMB said...

51% mortality in external

cooling group

31% mortality in the control

groupvs.

Relative Risk =1.99; 95% CI, 1.05-3.77; P=0.04

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Early stopping

High risk of bias

=

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Janz DR, Bastarache JA, Rice TW, et al. Randomized, Placebo-Controlled Trial of Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis: The Acetaminophen for the Reduction of Oxidative injury in Severe Sepsis Trial. Crit Care Med. 2014 Dec 3. [Epub ahead of print]

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Plasma cell-free Hb

Oxidative damage

acetaminophen

Lipid membranes

F2 isoprostanes

Janz DR, Bastarache JA, Rice TW, et al. Randomized, Placebo-Controlled Trial of Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis: The Acetaminophen for the Reduction of Oxidative injury in Severe Sepsis Trial. Crit Care Med. 2014 Dec 3. [Epub ahead of print]

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Janz DR, Bastarache JA, Rice TW, et al. Randomized, Placebo-Controlled Trial of Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis: The Acetaminophen for the Reduction of Oxidative injury in Severe Sepsis Trial. Crit Care Med. 2014 Dec 3. [Epub ahead of print]

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Janz DR, Bastarache JA, Rice TW, et al. Randomized, Placebo-Controlled Trial of Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis: The Acetaminophen for the Reduction of Oxidative injury in Severe Sepsis Trial. Crit Care Med. 2014 Dec 3. [Epub ahead of print]

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effect on renal

function

effect on survival

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antipyretics physical cooling

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Hammond NE, Saxena MK, Taylor C, Young P, Seppelt I, Glass P, Myburgh J; George Institute for Global Health; Australian and New Zealand Intensive Care Society Clinical Trials Group. Temperature management of non-elective intensive care patients without neurological abnormalities: a point prevalence study of practice in Australia and New Zealand. Crit Care Resusc. 2013 Sep;15(3):228-33.

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N Adjusted HR (95%CI)

P value

All patients 15818 0.51 (0.46-0.56) <0.0001

Surgical patients

9994 0.51 (0.42-0.61) <0.0001

Febrile patients 4397 0.57 (0.49-0.66) <0.0001

Medical, fever, & infection

681 0.47 (0.33-0.65) <0.0001

Suzuki et al. Paracetamol Therapy and Outcome of Critically Ill Patients: a Multicenter Retrospective Observational Study, Crit Care, 2015 (in press)

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• It is unclear whether administration of paracetamol to treat fever is beneficial OR harmful

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• Phase 2b RCT comparing IV paracetamol with placebo in ICU patients with fever and infection

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Inclusion Criteria1. ≥16 years

2. ≥38.0°C

3. Suspected infection

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Some Exclusion Criteria

1.Contraindications

2.Acute brain injury

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• Paracetamol 1g (or 100ml 5% dextrose placebo) every 6 hours

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When to stop study treatment

1. Fever resolves2. The patient ceases antimicrobial therapy3. The patient is discharged from ICU4. The patient reaches day 285. Develops a contraindication to

paracetamol

InterventionD

ESIGN

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15 months

InterventionD

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The primary outcome• 28 day ICU free survival

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#HEATtrialThe largest trial ever to investigate the world’s most commonly administered drug

↑ or ↓ ICU-free days?

↑ or ↓ 90-day mortality?

Study results coming soon...

www.criticalcarereviews.com

@DogICUma

paul.young@ccdhb.org.nz