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