Safety and Efficacy of Acetaminophen in the Intensive Care Unit.

Critical Illness Clinical Trial

— SEA-ICU  

Official title:

Safety and Antipyretic Efficacy of Acetaminophen in the Febrile Intensive Care Unit Patient.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02280239
• Other study ID #: H13-01160
• Status: Terminated
• Phase: Phase 4
• Start date: May 2015
• Est. completion date: February 2016

Study information

• Verified date: November 2022
• Source: University of British Columbia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The intensive care unit (ICU) team needs to know what effects acetaminophen has in critically ill patients. Acetaminophen is better known as Tylenol. It is the drug given to reduce fever. Most research that has looked at how safe and effective this drug is, has been done with healthy people. Those studies tell us it is safe and works well to bring down fever.

This may not be true for the ICU patient. Some research found acetaminophen was not as good at reducing fever as expected in the ICU. Fever helps to fight infection so it may help patients get better, but it is also stressful. When you have fever, you to need more oxygen, and your heart beats faster. If you have a fever after brain injury, you are less likely to make a full recovery. In patients with brain injury, a weak heart or trouble breathing we should treat fever. If we can predict how well acetaminophen will reduce fever, we can decide if this drug is enough, or other treatments are also needed.

If you do not have problems with your brain, heart, or lungs, it is safe to not treat fever. When you give this drug to treat fever, the body cools itself by sweating, and bringing hot blood to the skin's surface. These changes do not affect healthy people. Research suggests ICU patients may be at risk for sudden drop in blood pressure.

Our study will answer 2 questions: 1) When acetaminophen is given to treat fever in ICU patients, are they more likely to have a drop in blood pressure? 2) How much will acetaminophen reduce fever in ICU patients? We will study ICU patients with a fever who can safely get, or not get this drug. This information will help us decide when and how to treat fever in the ICU.

Description:

In the ICU, fever is commonly treated with 650 mg acetaminophen every 4 hours with the hopes of reducing fever burden, thereby also reducing metabolic demand. Acetaminophen is thought to be a safe and effective antipyretic. This assumption has not been tested in the critically ill despite its widespread use. Observational studies report critically ill patients experience hypotension, sometimes severe enough to require treatment; other studies indicate acetaminophen may not be as effective at reducing fever burden in the critically ill.

OBJECTIVES:

• To see if 650mg acetaminophen, given to febrile critically ill patients affects blood pressure; by comparing the incidence of hypotension severe enough to require treatment in the way of a fluid bolus (500cc or greater) or increase in vasoactive drugs (increase in norepinephrine by 5mcg or greater); by assessing for changes in mean arterial pressure and systolic blood pressure.

• To quantify the degree of fever suppression achieved by 650mg acetaminophen in the febrile critically ill population.

RESEARCH PROPOSAL:

Patients admitted into Vancouver Hospital's ICU are eligible for this study if they have a new fever and meet the inclusion/exclusion criteria. Study participants will be randomly assigned into one of 2 study arms, the control group and the 650mg group. Study participants in the control group will receive 2 capsules of placebo and the 650mg group will receive 2 capsules of 325mg acetaminophen. Data (continuous measures of temperature, heart rate and blood pressure) will be collected from the time of the study drug administration until 6 hours post. All patients, health care workers, and researchers will be blinded to which arm the patient is enrolled in until the end of the study. The incidence of fluid bolus administration, increases in vasoactive drug use, will be recorded and compared. We will also compare blood pressure data, and fever burden between the 2 groups.

INCLUSION/EXCLUSION CRITERIA To be included the subject must be admitted to the ICU; have an arterial line as standard of care; have at least 2 hours of a temperature greater than 38.3°C; within 24 hours of fever onset or ICU admission; be hemodynamically stable, and not received any drugs with known antipyretic effects at least 6 hours prior to initiating the study. Patients are excluded if they have an acute brain injury, liver dysfunction, cardiac dysfunction, requiring greater than 50% fraction of inspired oxygen (FiO); mechanical ventilation is permitted, any extracorporeal blood treatments (dialysis, plasmapheresis, etc.), injury to more than 20% of the skin (i.e. burn patient), or the responsible physician is opposed to enrolment.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 10
• Est. completion date: February 2016
• Est. primary completion date: February 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Generally to be considered for this study one must be critically ill, febrile, and can safely either receive acetaminophen or have acetaminophen withheld. Also one must not have conditions that would alter normal drug absorption or normal thermoregulation. Specifically the eligibility criteria are:

INCLUSION CRITERIA:

• Adult patients (> 18 years) admitted to Intensive Care Unit at Vancouver Hospital with a core temperature > 38.3 °C for 2 or more consecutive hours, but not longer than 48 hours*

• Continuous arterial pressure monitor in place at the time of intervention and data collection

• Patients may only participate in the study once

• To remain in the ICU for the entire study period (2 hours prior to drug administration to 4 hours post drug administration)

EXCLUSION CRITERIA:

• Significant liver dysfunction

• Acute neurological injury

• Seizure disorder

• Cardiomyopathy, elevated cardiac enzymes indicative of an acute cardiac injury, electrocardiogram (ECG) changes indicative of cardiac ischemia (i.e., ST segment elevation/depression)

• Hemodynamic instability (requiring fluid boluses, or change/initiation of vasopressors. Patients receiving steady doses of vasopressor support may be included)

• Severe hypoxemia, (fraction of inspired oxygen (FiO2) requirements of more than 60% to maintain hemoglobin oxygen saturation (SaO2) > 90% or partial pressure of oxygen in the blood (PaO2) > 70)

• Temperature > 40.0 °C

• Receiving external cooling

• Haemodialysis, plasma exchange, or any treatment where the blood is taken out of the body and processed

• Acute thermal injury to skin (i.e., burn)

• Gut malabsorption (i.e., receiving < 40% required calories enterally)

• Receiving medications that have known antipyretic effects (acetaminophen, ibuprofen, steroids, etc.)

• Physician opposed to enrolment in the study

NOTE: in response to very low enrollment 2 exclusion criteria were changed on Nov 5, 2015. These were:

1. patients no longer needed to recieve 40% of required calories enterally, instead patients who were not receiving any caloric intake via the gut could be enrolled as long as they were still permitted to receive oral medications.

2. patients no longer had to have acetaminophen discontinued upon enrollment. They could not be receiving it regularly but could still receive acetaminophen on an as needed (PRN) basis as long as it could be safely withheld for up to 12 hours if they developed a fever.

Related Conditions & MeSH terms

• Critical Illness
• Fever

Intervention

Drug:
• Acetaminophen
one-time dose of acetaminophen 650mg given via the enteral route (via the gut)
• Placebo
one-time dose of placebo (identical capsule) given via the enteral route (via the gut)

Locations

Country	Name	City	State
Canada	Vancouver Hospital	Vancouver	British Columbia

Sponsors (2)

Lead Sponsor	Collaborator
University of British Columbia	Vancouver Coastal Health Research Institute

Country where clinical trial is conducted

Canada, 

References & Publications (16)

Allegaert K, Naulaers G. Haemodynamics of intravenous paracetamol in neonates. Eur J Clin Pharmacol. 2010 Sep;66(9):855-8. doi: 10.1007/s00228-010-0860-z. Epub 2010 Jul 4. — View Citation

Bendjelid K, Soubirou JL, Bohe J. [Systemic arterial hypotension induced by paracetamol administration: nurse's anecdotes or facts from the intensive care unit?]. Ann Fr Anesth Reanim. 2000 Jun;19(6):499. French. — View Citation

Boyle M, Hundy S, Torda TA. Paracetamol administration is associated with hypotension in the critically ill. Aust Crit Care. 1997 Dec;10(4):120-2. — View Citation

Boyle M, Nicholson L, O'Brien M, Flynn GM, Collins DW, Walsh WR, Bihari D. Paracetamol induced skin blood flow and blood pressure changes in febrile intensive care patients: An observational study. Aust Crit Care. 2010 Nov;23(4):208-14. doi: 10.1016/j.aucc.2010.06.004. Epub 2010 Jul 22. — View Citation

Cruz P, Garutti I, Díaz S, Fernández-Quero L. [Metamizol versus propacetamol: comparative study of the hemodynamic and antipyretic effects in critically ill patients]. Rev Esp Anestesiol Reanim. 2002 Oct;49(8):391-6. Spanish. — View Citation

Danguy des Déserts M, Nguyen BV, Giacardi C, Commandeur D, Paleiron N. [Acetaminophen-induced hypotension after intravenous and oral administration]. Ann Fr Anesth Reanim. 2010 Apr;29(4):313-4. doi: 10.1016/j.annfar.2010.02.006. Epub 2010 Mar 12. French. — View Citation

de Maat MM, Tijssen TA, Brüggemann RJ, Ponssen HH. Paracetamol for intravenous use in medium--and intensive care patients: pharmacokinetics and tolerance. Eur J Clin Pharmacol. 2010 Jul;66(7):713-9. doi: 10.1007/s00228-010-0806-5. Epub 2010 Mar 19. — View Citation

Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R; SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004 May 27;350(22):2247-56. — View Citation

Gozzoli V, Treggiari MM, Kleger GR, Roux-Lombard P, Fathi M, Pichard C, Romand JA. Randomized trial of the effect of antipyresis by metamizol, propacetamol or external cooling on metabolism, hemodynamics and inflammatory response. Intensive Care Med. 2004 Mar;30(3):401-7. Epub 2004 Jan 13. — View Citation

Greenberg RS, Chen H, Hasday JD. Acetaminophen has limited antipyretic activity in critically ill patients. J Crit Care. 2010 Jun;25(2):363.e1-7. doi: 10.1016/j.jcrc.2009.07.005. Epub 2009 Sep 24. — View Citation

Hersch M, Raveh D, Izbicki G. Effect of intravenous propacetamol on blood pressure in febrile critically ill patients. Pharmacotherapy. 2008 Oct;28(10):1205-10. doi: 10.1592/phco.28.10.1205. — View Citation

Krajcová A, Matoušek V, Duška F. Mechanism of paracetamol-induced hypotension in critically ill patients: a prospective observational cross-over study. Aust Crit Care. 2013 Aug;26(3):136-41. doi: 10.1016/j.aucc.2012.02.002. Epub 2012 Mar 14. — View Citation

Mackenzie I, Forrest K, Thompson F, Marsh R. Effects of acetaminophen administration to patients in intensive care. Intensive Care Med. 2000 Sep;26(9):1408. — View Citation

Mrozek S, Constantin JM, Futier E, Zenut M, Ghardes G, Cayot-Constantin S, Bonnard M, Ait-Bensaid N, Eschalier A, Bazin JE. [Acetaminophene-induced hypotension in intensive care unit: a prospective study]. Ann Fr Anesth Reanim. 2009 May;28(5):448-53. doi: 10.1016/j.annfar.2009.01.018. Epub 2009 Mar 21. French. — View Citation

Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-87. doi: 10.1056/NEJMoa067373. — View Citation

Vincent JL, Weil MH. Fluid challenge revisited. Crit Care Med. 2006 May;34(5):1333-7. Review. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinically Significant Hypotension	Clinically significant hypotension is defined as an acute drop in mean arterial pressure requiring treatment. Treatment is defined as either a 500 cc (or greater) fluid bolus and/or an increase in inotrope support of greater than 5 mcg/min over baseline.	4 hours post acetaminophen administration
Secondary	Blood Pressure	systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressures (MAP) will be monitored for 4 hours post intervention	4 hours post intervention
Secondary	Equivalent-dose of Vasoactive Medication Post Intervention	Total dose of all vasoactive medications will be converted to total Equidose value (with the formula 10 mcg/min norepinephrine ˜ 5 mcg/kg/min dopamine ˜ 10 mcg/min epinephrine ˜ 1 mcg/min phenylephrine ˜ 0.02 u/min vasopressin as per Russell et al. (2008)) before comparing the treatment and control groups; Only 2 of the 6 participants were on low-dose vasoactive medications, (i.e., one was on norepinephrine and the other was on milrinone) therefore the pre-planned conversion calculation was not done.	4 hours post intervention
Secondary	Equivalent-volume Fluid Administered Post Intervention	Total crystalloid and colloid fluid will be converted the the equi-volume dose (with the ratio 1.4:1 (as per Finfer et al.(2004) & Vincent and Weil (2006) before making comparisons between the treatment and control groups.	4 hours post intervention
Secondary	Fever Burden	Continuous measurements of core body temperature will be recorded for 6 hours. Fever burden (FB) is defined as area between the 6 hour temperature curve and 38.3°C cut-off and it is reported in °C-hour.; PRE-INTERVENTION FB: is reported for a 2 hour period. POST-INTERVENTION FB: post-intervention fever burden is reported for a 6 hour period and average hourly fever burden.; Peak Temperature: is the highest recorded temperature for the study period in °C Minimum Temperature: is the lowest recorded temperature for the study period in °C	6 hours post intervention