The HEAT TrialPermissive HyperthErmiA

Through Avoidance of Paracetamol in Known or Suspected Infection in ICU

Paul Young, Richard Beasley, Manoj Saxena, Colin McArthur, Seton Henderson, Shay McGuinness, Ross Freebairn, Frank van Haren, John Myburgh, Rinaldo Bellomo, Steve Webb, Lynn Andrews, Diane Mackle

ANZCTRN: 12611000981921Ethics Approval: MEC/11/01/004 Funding: Health Research Council of New Zealand Ref: 11/593

The HEAT Trial

Protocol overview and the patient study folder

The HEAT Trial

The HEAT Trial Hypothesis

Permissive hyperthermia improves

survival and reduces organ

dysfunction in septic patients in ICU.

The HEAT Trial

DesignMulti-centre

New Zealand and Australia

Randomised

Double-blind

Placebo-controlled

Phase 2 trial

N= 700 patients

PatientsIntensive care admission with infection + fever

InterventionIntravenous paracetamol

Comparator5% dextrose

OutcomeICU free days at day 28

The HEAT Trial

Overview

Inclusion criteria1. Age&≥16&years

2. Standardised,body,temperature,(axillary*)&≥38.0oC&temperature&within&the&previous&12&hours.

3. Receiving&an>microbial&therapy&for&a&known&or&suspected&infec>on• NOT&postGopera>ve&prophylaxis

*Axillary thermometry will be standardised across all participating sites to ensure consistency with temperature measurement.

The HEAT Trial

Potential problemUse of the wrong thermometer The H

EAT Trial

Potential solutions1. Attach a study thermometer to the outside

of the patient study file

2. Affix a sticker onto the chart of randomised patients to remind the bedside nurse to record axillary temperatures.

The HEAT Trial

Exclusion Criteria1. ALT&>&&5*&upper&limit&of&normal&at&the&>me&of&randomisa>on,or,&

Bilirubin&>&2*&upper&limit&of&normal,&OR,&any&other&contraindica>on&to&4gm&of&paracetamol&per&day

2. Requirement&for&ongoing&NSAID&use&(in&excess&of&low&dose&aspirin)&&

3. Acute&brain&injury,&heat&stroke,&malignant&hyperthermia,&neurolep>c&malignant&syndrome&(or&other&drugGinduced&hyperthermia),&thyrotoxicosis,&cardiac&arrest&which&is&currently&being&treated&with&therapeu>c&hypothermia&&

4. Moribund&pa>ents,&Pregnancy,&Clinically&significant&rhabdomyolysis.&

5. Pa>ent&who&fulfilled&all&inclusion&criteria&in&another&ICU&and&spent&>12&hours&in&the&other&ICU&

The HEAT Trial

Study TreatmentParacetamol 1g (or 100ml 5% dextrose placebo) every 6 hours until temperature less than 37.5°C for 24 hours

If T > 38°C within 48 hours of ceasing study medication, then re-start study medicationSee Flowchart on next slide

The HEAT Trial

Cessation of Study Treatment

1. The&pa)ent&is&deemed&to&have&completed&the&course&

of&study&medica)on&(as&per&flowchart)&

2. The&pa)ent&ceases&an)microbial&therapy

3. The&pa)ent&is&discharged&from&ICU

4. The&pa)ent&reaches&day&28

5. Develops&a&contraindica)on&to&paracetamol

The HEAT Trial

The HEAT Trial

Potential problemDetermining whether or not to administer study medication is simple (but only if you know how!)

The HEAT Trial

SolutionWe have designed a simple checklist to be kept at the bedside to determine whether to administer study medication or not

We suggest one to one training with all ACNMs to ensure they understand the checklist

The HEAT Trial

Concomitant Treatments

1. Any&medica)on&containing&paracetamol&or&a&nonH

steroidal&an)Hinflammatory&drug/COXH2&inhibitor&

may&not&be&given&to&the&pa)ent&un)l&they&have&

completed&the&course&of&study&medica)on.&

a) LowHdose&aspirin&allowed&

2. Physical&cooling&therapies&are&not&used&for&

temperatures&of&less&than&39.5&oC.&&

a) Above&this&temperature,&cooling&is&allowed&at&the&discre)on&

of&the&trea)ng&clinician.

The HEAT Trial

Potential problemNo cold flannels on the forehead for patient comfort The H

EAT Trial

SolutionExplain the rationale to the nurse and the patient The H

EAT Trial

Primary Outcome Variable

The&number&of&‘alive&ICUHfree&days’&to&study&day&28.&&

The&number&of&ICUGfree&days&will&be&calculated&as&28&minus&the&number&of&days&in&ICU&(excluding&days&of&ICU&readmission).&&

Pa)ents&who&die&will&be&counted&as&having&zero&ICU&

free&days.

The HEAT Trial

Power Calculation700 patients

2 day increase in the number of ICU Free days (measured at day 28)

80% power, alpha of 0.05 Increase in the number of days of ‘ICU-free survival to day 28’ from 16.0±9.2 to 18±9.2 daysAllowing for a 5% drop-out rate

The HEAT Trial

Secondary Outcome Variables

1. Temperature&indices,&

2. Liver&func)on,&CK,&CRP&

3. Acute&kidney&injury&(based&on&RIFLE&criteria)&

4. Organ&support&–&free&days&(Day&28)

5. Mortality&(Day&28&&&Day&90)

The HEAT Trial