Permissive HyperthErmiA Through Avoidance of Paracetamol in Known or Suspected Infection in the Intensive Care Unit (ICU)
A phase 2b randomised controlled trial investigating the safety and efficacy of intravenous paracetamol versus placebo (5% dextrose) in the treatment of fever in critically ill patients with known or suspected infection.
Medical Research Institute of New Zealand
700 participants
Mar 20, 2013
Interventional
Conditions
Summary
Fever is an adaptive response to infections which occurs widely in the animal kingdom. The suppression of fever increases the risk of mortality in animals, although the effect of antipyretics in critically ill patients is unknown. The objective of this study is to determine whether paracetamol influences the risk of mortality in critically ill patients with fever and known or suspected infection. A phase 2b double blind randomised placebo controlled trial of paracetamol will be undertaken in 700 patients with fever and known or suspected infection in New Zealand and Australia under the auspices of the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG). If either the aggressive or permissive antipyretic regimes influence outcomes including survival in patients with fever and infection, the findings will have a major impact on the burden of infectious disease in New Zealand and internationally. Pilot study registered at http://www.anzctr.org.au/ACTRN12611000981921.aspx
Eligibility
Inclusion Criteria6
- Patients are eligible to be included in the study only if they meet the following criteria at the time of randomisation:
- Age greater than or equal to16 years
- Standardised body temperature greater than or equal to 38.0 degrees within the previous 12 hours.
- Receiving antimicrobial therapy for a known or suspected infection (this does NOT include post-operative patients who are receiving antibiotics for the purposes of prophylaxis rather than treatment)
- any patient who is pregnant;
- previously randomised into the HEAT trial or previously eligible for enrolment during the current ICU admission but not enrolled in the study (i.e. patients who were not enrolled within 12 hours of onset of fever in association with satisfying other eligibility criteria may not be enrolled at a later point in the ICU admission)
Exclusion Criteria8
- Patients will be excluded from the study if they meet ANY of the following criteria:
- AST or ALT greater than five times the upper limit of normal OR bilirubin greater than twice the upper limit of normal OR any other contraindication to 4gm paracetamol per day
- a requirement for ongoing NSAID use (in excess of low dose aspirin);
- evidence of acute brain injury during the current hospital admission (defined as any acute traumatic brain injury, subarachnoid haemorrhage, acute ischaemic stroke, acute intracerebral haemorrhage, or acute intracranial infection); hyperthermic syndromes (including heat stroke; current biochemical evidence of thyrotoxicosis (thyroid function tests are not required prior to recruitment into the trial unless clinically indicated); malignant hyperthermia, neuroleptic malignant syndrome, or other drug-induced hyperthermia)
- admission to ICU following a cardiac arrest which is currently being treated with therapeutic hypothermia;
- there is a limitation of therapy order or aggressive treatment is deemed unsuitable
- patients who are moribund and, in whom, death is perceived to be imminent (within 24 hours);
- any patient with rhabdomyolysis that is deemed by the treating clinician to be clinically significant.
Interested in this trial?
Get notified about updates and connect with the research team.
Interventions
This study follows on from a previous pilot study with a similar design (http://www.anzctr.org.au/ACTRN12611000981921.aspx) After randomisation, the patient will receive paracetamol (1gm intravenously) or placebo 6 hourly until one of the following occurs: 1. the patient ceases antimicrobial therapy 2. the patient is discharged from ICU 3. the patient is deemed to have completed the course of study medication (as described below) 4. the patient reaches day 28 post randomisation (672 hours post randomisation) Provided that the patient remains on antimicrobial therapy and remains in ICU, they will receive paracetamol or placebo until at least the morning of study day 2. On the morning of study day 2 at 8 am the patient will be assessed. If the patient has not had a standardised body temperature of less than 37.5 degrees celsius for the previous 24 hours, they will continue to receive paracetamol or placebo 6 hourly and will be assessed by the research co-ordinator on each subsequent morning to determine if they have had a standardised body temperature of less than 37.5 degrees celsius for the previous 24 hours. If, at the time of assessment, the patient has had a standardised body temperature of less than 37.5 degrees celsius for the entire past 24 hours, further study treatment will be withheld. If the patient does not develop a fever of greater than or equal to 38 degrees celsius within 48 hours, they will be deemed to have completed the course of study medication. If the patient does develop another standardised body temperature of greater than or equal to 38 degrees celsius, the patient will restart study medication and, thereafter, they will be assessed each morning at 8 am to determine whether they a have had a standardised body temperature of less than 37.5 degrees celsius for a period of 24 hours at which point medication will be withheld and then stopped as described above. Once the patient has completed the course of study medication, they may receive open label paracetamol at the discretion of the treating clinician.
Locations(1)
View Full Details on ANZCTR
For the most up-to-date information, visit the official listing.
ACTRN12612000513819