Safety and Efficacy of Acetaminophen in the Intensive Care Unit. (SEA-ICU)

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.

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.

This group consists of stable but febrile ICU patients (temp >38.3°C). Participants in this group will receive a one-time dose of placebo via the enteral route (via the gut), after which vital signs (including continuous measures of core temperature, heart rate, and blood pressure) will be monitored for 4 hours.

This group consists of stable but febrile ICU patients (temp >38.3°C). Participants in this group will receive a one-time does of acetaminophen 650mg via the enteral route (via the gut), after which vital signs (including continuous measures of core temperature, heart rate, and blood pressure) will be monitored for 4 hours.

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.

systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressures (MAP) will be monitored for 4 hours 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.

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.

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

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: 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. 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.

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