Paracetamol in fever in critically ill patients—an update

Abstract

Fever, which is arbitrary defined as an increase in body temperature above 38.3°C, can affect up to 90% of patients admitted in intensive care unit. Induction of fever is mediated by the release of pyrogenic cytokines (tumor necrosis factor α, interleukin 1, interleukin 6, and interferons). Fever is associated with increased length of stay in intensive care unit and with a worse outcome in some subgroups of patients (mainly neurocritically ill patients). Although fever can increase oxygen consumption in unstable patients, on the contrary, it can activate physiologic systems that are involved in pathogens clearance. Treatments to reduce fever include the use of antipyretics. Thus, the reduction of fever might reduce the ability to develop an efficient host response. This balance, between harms and benefits, has to be taken into account every time we decide to treat or not to treat fever in a given patient. Among the antipyretics, paracetamol is one of the most common used. Paracetamol is a synthetic, nonopioid, centrally acting analgesic, and antipyretic drug. Its antipyretic effect occurs because it inhibits cyclooxygenase-3 and the prostaglandin synthesis, within the central nervous system, resetting the hypothalamic heat-regulation center. In this clinical review, we will summarize the use of paracetamol as antipyretic in critically ill patients (sepsis, trauma, neurological, and medical).

Introduction

Fever, defined as an increase in body temperature above 38.3°C, is a common finding in the critically ill patients, ranging between 30% up to 90% of the patients and may result from infectious and noninfectious (only inflammatory) causes [1]. In healthy subjects, thermoregulation maintains core body temperature within a narrow normal range, despite changes in environmental conditions. The center of thermoregulation has been identified in the preoptic area of hypothalamus; hypothalamic neurons elaborate 2 types of signals. The first one from peripheral neurons that are connected to thermoreceptors and the second from thermoreceptors located directly in the hypothalamus. A normal temperature is achieved by balancing heat production from muscles, hepatic metabolism, and heat loss to the environment [2]. Induction of fever is mediated by the release of pyrogenic cytokines (tumor necrosis factor α, interleukin 1, interleukin 6, and interferons) [3]. These cytokines are involved in immunologic activation and reaction against pathogens. According to the new Consensus Definitions for Sepsis and Septic Shock, sepsis is characterized by an aberrant and dysregulated host response, in addition to the presence of organ dysfunctions [4]. Fever is associated with increased length of stay in intensive care unit (ICU) and with a worse outcome in some subgroups of patients (mainly with traumatic brain injury, subarachnoid hemorrhage, and pancreatitis) [5], [6], [7], [8]. On the one hand, fever increases oxygen consumption in unstable patients, and on the other hand activates physiologic systems that are involved in pathogens clearance. Treatments to reduce body temperature may be utilized to reduce metabolic rate and hence, oxygen demand [9] or to reduce further brain cell death after brain injury or hemorrhage [10]. Furthermore, reduction of fever could reduce the ability of one patient to develop an efficient host response. This balance, between harms and benefits, has to be taken into account every time we decide to treat or not to treat fever in a given patient. The last Consensus Surviving Sepsis Campaign did not make any recommendations regarding the use of antipyretics. However, several drugs have been suggested for fever control; among them, paracetamol is one of the most common used one [11], [12], [13]. Paracetamol is a synthetic, nonopioid, centrally acting analgesic, and antipyretic drug. Paracetamol can be administered enterally or intravenously; also its precursor, the propacetamol, could be administered by the same routes. When administered, the propacetamol is quickly hydrolyzed to paracetamol and diethylglycine. Its antipyretic effect occurs because it inhibits cyclooxygenase-3 and the prostaglandin synthesis, within the central nervous system, resetting the hypothalamic heat-regulation center [3]. As for all the other drugs, hypersensitivity to paracetamol or to other molecules contained into the pharmacologic formulation is possible. The most serious acute adverse effect of overdosage of paracetamol is a potentially fatal hepatic necrosis. The mechanism involves paracetamol conversion to a toxic metabolite (NAPQI). It is eliminated by conjugation with glutathione and then further metabolized and excreted into the urine. In the setting of paracetamol overdose, hepatocellular levels of glutathione become depleted and NAPQI metabolite binds to cell macromolecules, leading to dysfunction of enzymatic systems and structural and metabolic derangement. For this reason, patients with liver impairment are always excluded from trial in which paracetamol is administered. In this clinical review, we will summarize the use of paracetamol as antipyretic in critically ill patients (sepsis, trauma, neurological, and medical).