Effects of Intravenous Acetaminophen on Body Temperature and Hemodynamic Responses in Febrile Critically Ill Adults

Critical Illness Clinical Trial

— ICUFeverAPAP  

Official title:

Effects of Intravenous Acetaminophen on Body Temperature and Hemodynamic Responses in Febrile Critically Ill Adults: a Randomized Controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01869699
• Other study ID #: UCSF-ICUFever
• Status: Completed
• Phase: Phase 4
• First received: May 31, 2013
• Last updated: September 10, 2015
• Start date: September 2013
• Est. completion date: August 2015

Study information

• Verified date: September 2015
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to compare the effects of intravenous acetaminophen to placebo on body temperature and hemodynamic (heart rate and blood pressure) responses in febrile critically ill adult patients.

There are limited data to explain the variable and unpredictable antipyretic and hemodynamic response to acetaminophen in febrile ICU patients. The complex pathophysiology of critically ill patients, co-morbid conditions, the effect of multiple pharmacologic and non-pharmacologic care interventions, and/or the potential interferences with absorption of enteral or rectal formulations may be related to variations in the antipyretic response to acetaminophen. It is necessary for clinicians to have a better understanding of the therapy response and potential adverse effects of this commonly administered medication, especially the recently available IV formulation, in critically ill patients. Further research of the antipyretic response to acetaminophen in critically ill patients is warranted to inform evidence-based practice guidelines for fever management. Further randomized, placebo-controlled studies of hemodynamic responses to IV acetaminophen are also warranted.

Primary Hypothesis:

There is a significant reduction in time-weighted average core body temperature over 4 hours after administration of IV acetaminophen compared to placebo in febrile critically ill patients.

Secondary Hypotheses:

1. There is a significant reduction in time-weighted average heart rate over 4 hours after administration of IV acetaminophen compared to placebo in febrile critically ill patients.

2. There is a significant reduction in time-weighted mean arterial pressure over 4 hours after administration of IV acetaminophen compared to placebo in febrile critically ill patients.

Adult patients with fever (≥ 38.3ºCentigrade/101ºFarenheit) in the intensive care unit will be screened for eligibility and enrolled after informed consent. Patients will be randomized to receive IV acetaminophen 1 gram or normal saline 100 mLs. Body temperature, heart rate, and blood pressure will be measured at baseline and during the 4 hours post study drug administration.

Description:

Adult patients with fever (≥ 38.3ºCentigrade (C)/101ºFarenheit(F)) in the intensive care unit will be screened for eligibility and approached for informed consent. Enrolled patients will be stratified based on the leading etiology of their fever: either neurologic injury or infection and then randomized to receive IV acetaminophen 1 gram or normal saline 100 milliliters (mLs). Core body temperature will be measured using a zero-heat flow thermometry system (non-invasive, small disk on forehead). Patients will be monitored and data collected during the 4-hour post study drug administration period. A rescue protocol will be implemented if the temperature reaches ≥ 40 ºC during the study period and includes notification of primary team provider by the nurse and the pharmacist will contact them to inform the provider of study group (acetaminophen or placebo). The provider can decide whether to order antipyretic medication or physical cooling interventions at that time.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41
• Est. completion date: August 2015
• Est. primary completion date: August 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 18 years of age and older

• Patient in an intensive care unit

• Weight greater or equal to 50 kgs

• Fever: core body temperature greater than or equal to 38.3 degrees Celsius

• Clinically stable: no active resuscitation with fluids, blood products, or dose increases of vasoactive medications within 1 hour of study drug administration

Exclusion Criteria:

• Acetaminophen hypersensitivity

• Acute liver failure or acute liver injury

• Heat stroke, malignant hyperthermia, neuroleptic malignant syndrome

• Therapeutic cooling, physical cooling, extracorporeal blood circuit therapies

• Administration of acetaminophen-containing medications, non-steroidal anti-inflammatory drugs, or aspirin greater than 81 mg within specified times per drug prior to fever presentation

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Critical Illness
• Fever

Intervention

Drug:
• Acetaminophen
acetaminophen 1 gram/100mLs intravenously administered over 15 minutes
• Placebo
Normal saline placebo Normal saline 100 mLs intravenous, administered over 15 minutes

Locations

Country	Name	City	State
United States	UCSF Medical Center	San Francisco	California
United States	University of California, San Francisco Medical Center	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
University of California, San Francisco

Country where clinical trial is conducted

United States, 

References & Publications (13)

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

Circiumaru B, Baldock G, Cohen J. A prospective study of fever in the intensive care unit. Intensive Care Med. 1999 Jul;25(7):668-73. — 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

Frankenfield DC, Smith JS Jr, Cooney RN, Blosser SA, Sarson GY. Relative association of fever and injury with hypermetabolism in critically ill patients. Injury. 1997 Nov-Dec;28(9-10):617-21. — 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

Kett DH, Breitmeyer JB, Ang R, Royal MA. A randomized study of the efficacy and safety of intravenous acetaminophen vs. intravenous placebo for the treatment of fever. Clin Pharmacol Ther. 2011 Jul;90(1):32-9. doi: 10.1038/clpt.2011.98. Epub 2011 May 4. — View Citation

Laupland KB, Shahpori R, Kirkpatrick AW, Ross T, Gregson DB, Stelfox HT. Occurrence and outcome of fever in critically ill adults. Crit Care Med. 2008 May;36(5):1531-5. doi: 10.1097/CCM.0b013e318170efd3. — View Citation

Laupland KB, Zahar JR, Adrie C, Schwebel C, Goldgran-Toledano D, Azoulay E, Garrouste-Orgeas M, Cohen Y, Jamali S, Souweine B, Darmon M, Timsit JF. Determinants of temperature abnormalities and influence on outcome of critical illness. Crit Care Med. 2012 Jan;40(1):145-51. doi: 10.1097/CCM.0b013e31822f061d. — View Citation

Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsugu K, Uehara K, Dote K, Tajimi K, Morita K, Matsuo K, Hoshino K, Hosokawa K, Lee KH, Lee KM, Takatori M, Nishimura M, Sanui M, Ito M, Egi M, Honda N, Okayama N, Shime N, Tsuruta R, Nogami S, Yoon SH, Fujitani S, Koh SO, Takeda S, Saito S, Hong SJ, Yamamoto T, Yokoyama T, Yamaguchi T, Nishiyama T, Igarashi T, Kakihana Y, Koh Y; Fever and Antipyretic in Critically ill patients Evaluation (FACE) Study Group. Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Crit Care. 2012 Feb 28;16(1):R33. doi: 10.1186/cc11211. Erratum in: Crit Care. 2012;16(1):450. — 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

Niven DJ, Stelfox HT, Laupland KB. Antipyretic therapy in febrile critically ill adults: A systematic review and meta-analysis. J Crit Care. 2013 Jun;28(3):303-10. doi: 10.1016/j.jcrc.2012.09.009. Epub 2012 Nov 14. Review. — View Citation

Thompson HJ, Kagan SH. Clinical management of fever by nurses: doing what works. J Adv Nurs. 2011 Feb;67(2):359-70. doi: 10.1111/j.1365-2648.2010.05506.x. Epub 2010 Nov 2. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	blood pressure	time-weighted average blood pressure over 4 hours	4 hours post study drug administration	No
Primary	core body temperature	time-weighted average core body temperature over 4 hours	4 hours post study drug administration	No
Secondary	heart rate	time-weighted average heart rate over 4 hours	4 hours post study drug administration	No