IV Propacetamol on Blood Pressure in Febrile Critically Ill Patients
Study Objectives. To investigate the effect of intravenous propacetamol, a parenteral bioprecursor of acetaminophen, on systemic blood pressure in critically ill patients with fever, and to establish the prevalence and clinical significance of this effect.
Design. Prospective, observational study.
Setting. A six-bed medical-surgical intensive care unit (ICU) of a university-affiliated tertiary care hospital in Israel.
Patients. Fourteen critically ill patients (aged 17–83 yrs) with sepsis and fever (body temperature ≥ 38°C) who received an intravenous infusion of propacetamol 2 g over 15–20 minutes every 6 hours as needed to reduce fever.
Measurements and Results. Demographic data, including degree of sepsis, were collected at baseline (before propacetamol infusion). Blood pressure, heart rate, body temperature, and need for fluid or vasopressor therapy were recorded at baseline, at end of infusion, and at 15, 30, 45, 60, 90, and 120 minutes after propacetamol administration. The drug was administered on 72 occasions in the 14 patients. Mean ± SE systolic, diastolic, and mean arterial pressures recorded 15 minutes after propacetamol administration were significantly lower than baseline measurements: 123 ± 29 versus 148 ± 33, 62 ± 12 versus 70 ± 15, and 83 ± 16 versus 97 ± 19 mm Hg, respectively (p<0.05). In 24 (33%) of the 72 infusions, systolic blood pressure decreased to below 90 mm Hg and required intervention with fluid bolus administration on six occasions; a fluid bolus was accompanied by a dosage increase or initiation of a norepinephrine infusion on 18 occasions. No correlation, however, was noted between the degree of decrease in mean arterial pressure and decrease in temperature (r=0.01), or the degree of decrease in mean arterial pressure and decrease in heart rate (r=0.23), at each data collection time point, as measured by linear regression.
Conclusion. Intravenous propacetamol, given in antipyretic doses, caused a significant decrease in blood pressure 15 minutes after administration in febrile critically ill patients. This drug-induced hypotension was clinically relevant in that interventions to control blood pressure were required. Thus, clinicians should be aware of this potential deleterious effect, particularly in specific populations such as critically ill patients.
Pyrexia in critically ill patients is very common. Most of these patients have an infection, with fever being one of the most recognized systemic host responses to the invading microorganism. Although there is a debate about the role of this physiopathologic response in fighting the infection, most practitioners in the intensive care unit will try to reduce the fever, as every increase in body temperature of 1°C above 37°C increases oxygen consumption by 6–10%.
Many of our critically ill patients with fever have problems absorbing enterally administered drugs, or at least, absorption is unpredictable. Therefore, when we want to lower body temper-ature in these patients, we prefer an intravenous preparation with a good safety profile to circum-vent this questionable enteric absorption. The relatively well-known intravenous antipyretic and analgesic drug dypirone is not an option in most countries because of its rare but potentially lethal adverse effect on bone marrow. Propacetamol, a parenteral bioprecursor of acetaminophen, was recently introduced for use in intensive care units (ICUs) for the treatment of fever in critically ill patients. Because acetaminophen is poorly soluble and unstable in aqueous solution, it has been administered parenterally as the water-soluble prodrug, propacetamol hydrochloride, which is readily cleaved in the blood by esterases into acetaminophen and pharmacologically inactive diethylglycine. Thus, the pharmacologic and pharmacokinetic profile of propacetamol is identical to that of acetaminophen. A dose of 2 g of intravenous propacetamol is bioequivalent to 1 g of intravenous acetaminophen. The maximum plasma concentration after intravenous infusion of acetaminophen 1 g is about 30 mg/L, occurring at 15 minutes (i.e., end of infusion).
It is our ICU's practice to attempt to reduce a patient's body temperature when it reaches 38°C. Preliminary observations by our staff have noted that when defervescence started, approximately 15 minutes after propacetamol administration, many patients demonstrated a significant decrease in blood pressure that sometimes necessitated an intervention (i.e., fluid bolus administration and/or initiation or increase of vasopressor therapy). Published data regarding acetaminophen's or its precursor's effects on blood pressure are limited and controversial. Some studies showed no decrease in blood pressure, and others demonstrated significant decreases in blood pressure, although mostly on an anecdotal basis and usually after oral administration. Thus, we sought to validate prospectively our preliminary observation that propacetamol therapy reduces blood pressure in febrile patients in the ICU and to establish the prevalence and clinical significance of this phenomenon.
Abstract and Introduction
Abstract
Study Objectives. To investigate the effect of intravenous propacetamol, a parenteral bioprecursor of acetaminophen, on systemic blood pressure in critically ill patients with fever, and to establish the prevalence and clinical significance of this effect.
Design. Prospective, observational study.
Setting. A six-bed medical-surgical intensive care unit (ICU) of a university-affiliated tertiary care hospital in Israel.
Patients. Fourteen critically ill patients (aged 17–83 yrs) with sepsis and fever (body temperature ≥ 38°C) who received an intravenous infusion of propacetamol 2 g over 15–20 minutes every 6 hours as needed to reduce fever.
Measurements and Results. Demographic data, including degree of sepsis, were collected at baseline (before propacetamol infusion). Blood pressure, heart rate, body temperature, and need for fluid or vasopressor therapy were recorded at baseline, at end of infusion, and at 15, 30, 45, 60, 90, and 120 minutes after propacetamol administration. The drug was administered on 72 occasions in the 14 patients. Mean ± SE systolic, diastolic, and mean arterial pressures recorded 15 minutes after propacetamol administration were significantly lower than baseline measurements: 123 ± 29 versus 148 ± 33, 62 ± 12 versus 70 ± 15, and 83 ± 16 versus 97 ± 19 mm Hg, respectively (p<0.05). In 24 (33%) of the 72 infusions, systolic blood pressure decreased to below 90 mm Hg and required intervention with fluid bolus administration on six occasions; a fluid bolus was accompanied by a dosage increase or initiation of a norepinephrine infusion on 18 occasions. No correlation, however, was noted between the degree of decrease in mean arterial pressure and decrease in temperature (r=0.01), or the degree of decrease in mean arterial pressure and decrease in heart rate (r=0.23), at each data collection time point, as measured by linear regression.
Conclusion. Intravenous propacetamol, given in antipyretic doses, caused a significant decrease in blood pressure 15 minutes after administration in febrile critically ill patients. This drug-induced hypotension was clinically relevant in that interventions to control blood pressure were required. Thus, clinicians should be aware of this potential deleterious effect, particularly in specific populations such as critically ill patients.
Introduction
Pyrexia in critically ill patients is very common. Most of these patients have an infection, with fever being one of the most recognized systemic host responses to the invading microorganism. Although there is a debate about the role of this physiopathologic response in fighting the infection, most practitioners in the intensive care unit will try to reduce the fever, as every increase in body temperature of 1°C above 37°C increases oxygen consumption by 6–10%.
Many of our critically ill patients with fever have problems absorbing enterally administered drugs, or at least, absorption is unpredictable. Therefore, when we want to lower body temper-ature in these patients, we prefer an intravenous preparation with a good safety profile to circum-vent this questionable enteric absorption. The relatively well-known intravenous antipyretic and analgesic drug dypirone is not an option in most countries because of its rare but potentially lethal adverse effect on bone marrow. Propacetamol, a parenteral bioprecursor of acetaminophen, was recently introduced for use in intensive care units (ICUs) for the treatment of fever in critically ill patients. Because acetaminophen is poorly soluble and unstable in aqueous solution, it has been administered parenterally as the water-soluble prodrug, propacetamol hydrochloride, which is readily cleaved in the blood by esterases into acetaminophen and pharmacologically inactive diethylglycine. Thus, the pharmacologic and pharmacokinetic profile of propacetamol is identical to that of acetaminophen. A dose of 2 g of intravenous propacetamol is bioequivalent to 1 g of intravenous acetaminophen. The maximum plasma concentration after intravenous infusion of acetaminophen 1 g is about 30 mg/L, occurring at 15 minutes (i.e., end of infusion).
It is our ICU's practice to attempt to reduce a patient's body temperature when it reaches 38°C. Preliminary observations by our staff have noted that when defervescence started, approximately 15 minutes after propacetamol administration, many patients demonstrated a significant decrease in blood pressure that sometimes necessitated an intervention (i.e., fluid bolus administration and/or initiation or increase of vasopressor therapy). Published data regarding acetaminophen's or its precursor's effects on blood pressure are limited and controversial. Some studies showed no decrease in blood pressure, and others demonstrated significant decreases in blood pressure, although mostly on an anecdotal basis and usually after oral administration. Thus, we sought to validate prospectively our preliminary observation that propacetamol therapy reduces blood pressure in febrile patients in the ICU and to establish the prevalence and clinical significance of this phenomenon.
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