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Abstract

Objectives: Acetaminophen is ubiquitously used as antipyretic/analgesic administered IV to patients undergoing surgery and to critically ill patients when enteral routes are not possible. Widely believed to be safe and free of adverse side effects, concerns have developed in adult literature regarding the association of IV acetaminophen and transient hypotension. We hypothesize that there are hemodynamic effects after IV acetaminophen in the PICU and assess the prevalence of such in a large pediatric cardiovascular ICU population using high-fidelity data. Design: Observational study analyzing an enormous set of continuous physiologic data including millions of beat to beat blood pressures surrounding medication administration. Setting: Quaternary pediatric cardiovascular ICU between January 1, 2013, and November 13, 2017. Patients: All patients less than or equal to 18 years old who received IV acetaminophen. Mechanical support devices excluded. Interventions: None. Measurements and main results: Physiologic vital sign data were analyzed in 5-minute intervals starting 60 minutes before through 180 minutes after completion. Hypotension defined as mean arterial pressure -15% from baseline and relative hypotension defined -10%. Only doses where patients received no other medications, including vasopressors, within the previous hour were included. t test and a correlation matrix were used to eliminate correlated factors before a logistic regression analysis was performed. Six-hundred eight patients received 777 IV acetaminophen doses. Median age was 8.8 months (interquartile range, 2-62 mo) with a dose of 12.5 mg/kg (interquartile range, 10-15 mg/kg). Data were normalized for age and reference values. One in 20 doses (5%) were associated with hypotension, and one in five (20%) associated with relative hypotension. Univariate analysis revealed hypotension associated with age, baseline mean arterial pressure, and skin temperature (p = 0.05, 0.01, and 0.09). Logistic regression revealed mean arterial pressure (p = 0.01) and age (p = 0.05) remained predictive for hypotension. Conclusions: In isolation of other medication, a hemodynamic response to IV acetaminophen has a higher prevalence in critically ill children with cardiac disease than previously thought and justifies controlled studies in the perioperative and critical care setting. The added impact on individual patient hemodynamics and physiologic instability will require further study.

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... [1][2][3] The parenteral formulation of acetaminophen was approved by The US Food and Drug Administration agency in November 2010 for acute pain and fever and has been frequently used since, especially in the perioperative period. 3,4 Manufacturer-listed adverse effects of intravenous acetaminophen report hypotension with an incidence of <1%. 5 However, several studies on critical care patients have demonstrated higher incidence of transient hypotension following acetaminophen administration. 4,[6][7][8][9][10][11] The different definitions of hypotension and studies limitations make it difficult to establish the severity and clinical implications of these transitory hypotensive recorded events. ...
... 3,4 Manufacturer-listed adverse effects of intravenous acetaminophen report hypotension with an incidence of <1%. 5 However, several studies on critical care patients have demonstrated higher incidence of transient hypotension following acetaminophen administration. 4,[6][7][8][9][10][11] The different definitions of hypotension and studies limitations make it difficult to establish the severity and clinical implications of these transitory hypotensive recorded events. 11 Hemodynamic changes associated with acetaminophen are not fully understood. ...
... Baseline variables were balanced between Table 1). Number of treatments with the study drug per patient was a median [Q1, Q3] of 6 [4,7] for acetaminophen and 6 [5,7] for placebo (Supplemental Digital Content, Figure 1, http://links. lww.com/AA/D400). ...
Article
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Background: Acetaminophen is commonly used as part of multimodal analgesia for acute pain. The intravenous formulation offers a more predictable bioavailability compared to oral and rectal acetaminophen. There have been reports of hypotension with intravenous acetaminophen attributable to centrally mediated and vasodilatory effects. We tested the hypothesis that in adults having abdominal surgery the use of intravenous acetaminophen versus placebo for postoperative pain management is associated with a decrease in mean arterial pressure (MAP) after its administration. Methods: This is a substudy of eFfect of intravenous ACetaminophen on posToperative hypOxemia after abdominal surgeRy (FACTOR) trial (NCT02156154). FACTOR trial randomly assigned adults undergoing abdominal surgery to either 1 g of acetaminophen or placebo every 6 hours during the first postoperative 48 hours. Continuous monitoring of blood pressure was obtained by noninvasive ViSi Mobile device (Sotera Wireless, Inc, San Diego, CA) at 15-second intervals during initial 48 hours postoperatively. We excluded patients without continuous monitoring data available. The primary outcome was the MAP difference between MAP 5 minutes before study drug administration (baseline) and MAP 30 minutes poststudy drug administration initiation. We used a linear mixed effects model to assess the treatment effect on MAP change. The secondary outcome was MAP area under baseline (AUB) during the 30 minutes after treatment. In a sensitivity analysis of change in MAP from predrug to postdrug administration, we instead used postdrug MAP as the outcome adjusting for the baseline MAP in the model. Results: Among 358 patients analyzed, 182 received acetaminophen and 176 placebo. The mean (standard deviation [SD]) of average MAP change was -0.75 (5.9) mm Hg for the treatment and 0.32 (6.3) mm Hg for the placebo. Acetaminophen was found to decrease the MAP from baseline more than placebo after drug administration. The estimated difference in mean change of MAP was -1.03 (95% confidence interval [CI] -1.60 to -0.47) mm Hg; P < .001. The sensitivity analysis showed postoperative MAP in the acetaminophen group was 1.33 (95% CI, 0.76-1.90) mm Hg lower than in the placebo group (P < .001). The median of MAP AUB was 33 [Q1 = 3.3, Q3 = 109] mm Hg × minutes for the treatment and 23 [1.6, 79] mm Hg × minutes for the placebo. Acetaminophen was found to increase the AUB with an estimated median difference of 15 (95% CI, 5-25) mm Hg × minutes (P = .003). Conclusions: Intravenous acetaminophen decreases MAP after its administration. However, this decrease does not appear to be clinically meaningful. Clinicians should not refrain to use intravenous acetaminophen for acute pain management because of worries of hypotension.
... [4][5][6][7] There are limited data on the acetaminophen-induced systemic blood pressure changes in children, but the effects appear to be similar, when compared with adults. [8][9][10][11] Interestingly, only the acetaminophen-related vascular effect on the systemic circulation has been evaluated at any age. Whether this drug can equally alter pulmonary vascular tone is currently unknown, but there is no reason to expect such effect to be unique to the systemic vasculature. ...
... 11 A large study in children with congenital heart disease showed that acetaminophen was associated with more frequent hypotension episodes. 8 Clinically relevant systemic hypotension was documented in 5% and a decrease in mean arterial pressure, from basal level, in 20% of the reported subjects. 8 Interestingly, skin temperature measurements of treated patients in the referred study 8 suggest that the acetaminophen-induced hypotension was secondary to systemic vasodilatation. ...
... 8 Clinically relevant systemic hypotension was documented in 5% and a decrease in mean arterial pressure, from basal level, in 20% of the reported subjects. 8 Interestingly, skin temperature measurements of treated patients in the referred study 8 suggest that the acetaminophen-induced hypotension was secondary to systemic vasodilatation. Finally, a recent metaanalysis concluded that intravenous acetaminophen is associated with clinically relevant hypotension in both critically ill children and adult subjects, and these risks should be considered when treating this population. ...
Article
Background: Acetaminophen is widely prescribed to both neonates and young children for a variety of reasons. In adults, therapeutic usage of acetaminophen induces systemic arterial pressure changes and exposure to high doses promotes tissue toxicity. The pulmonary vascular effects of acetaminophen at any age are unknown. Hypothesizing that, early in life, it promotes vasomotor tone changes via oxidative stress, we tested the in vitro acetaminophen effects on intrapulmonary and carotid arteries from newborn and adult rats. Methodology: We measured the acetaminophen dose-response in isometrically mounted arteries and pharmacologically evaluated the factors accounting for its vasomotor effects. Results: Acetaminophen induced concentration- and age-dependent vasomotor tone changes. Whereas a progressive increase in vasomotor tone was observed in the newborn, the adult arteries showed mostly vasorelaxation. Inhibition of endogenous nitric oxide generation with L-NAME and the use of the peroxynitrite decomposition catalyst FeTPPS (Fe(III)5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato chloride) mostly abolished the drug-induced increase in newborn pulmonary vasomotor tone CONCLUSIONS: In newborn rats, acetaminophen increases pulmonary vasomotor tone via peroxynitrite generation. Given its therapeutic usage, further clinical studies are warranted to assess the acetaminophen effects on the newborn pulmonary and systemic vascular resistance.
... 1,2 Intravenous (IV) acetaminophen has been widely used outside of the United States since 2002 and has been a relatively safe analgesic, with safety events predominantly associated with iatrogenic dosing errors. [3][4][5][6][7][8] In the United States, the parenteral preparation of acetaminophen was approved for management of pain and fever for children older than 2 years by the US Food and Drug Administration (FDA) in November 2010. 9 Since FDA approval, IV acetaminophen has been used alone and incorporated into multimodal pain regimens that use both opioid and non-opioid analgesic medications, particularly in postoperative care where enteral medications may not be appropriate. ...
... However, there is inadequate effectiveness data on these operative groups, with emerging literature revealing a possible hypotensive response following IV acetaminophen administration in pediatric cardiac surgery patients. 3,22,32,33 Studies using large data repositories such as Health Facts have limitations. First, medication use was implied from pharmacy records, not assessed through individual patient records. ...
Article
OBJECTIVE To 1) determine current intravenous (IV) acetaminophen use in pediatric inpatients; and 2) determine the association between opioid medication duration when used with or without IV acetaminophen. METHODS A retrospective analysis of pediatric inpatients exposed to IV acetaminophen from January 2011 to June 2016, using the national database Health Facts. RESULTS Eighteen thousand one hundred ninety-seven (2.0%) of 893,293 pediatric inpatients received IV acetaminophen for a median of 14 doses per patient (IQR, 8–56). A greater proportion of IV acetaminophen patients were admitted to the intensive care unit (ICU) (14.8% vs 5.1%, p < 0.0001), received positive pressure ventilation (2.0% vs 1.5%, p < 0.0001), had a higher hospital mortality rate (0.9% vs 0.3%, p < 0.0001), and were operative (35.5% vs 12.8%, p < 0.001) than those not receiving IV acetaminophen. The most common operations associated with IV acetaminophen use were musculoskeletal and digestive system operations. Prescription of IV acetaminophen increased over time, both in prescription rates and number of per patient doses. Of the 18,197 patients prescribed IV acetaminophen, 16,241 (89.2%) also were prescribed opioids during their hospitalization. A multivariate analysis revealed patients prescribed both IV acetaminophen and opioids had a 54.8% increase in opioid duration as compared with patients who received opioids alone. CONCLUSIONS This is the first study to assess IV acetaminophen prescription practices for pediatric inpatients. Intravenous acetaminophen prescription was greater in the non-operative pediatric inpatient population than operative patients. Intravenous acetaminophen prescription was associated with an increase in opioid duration as compared with patients who received opioids alone, suggesting that it is commonly used to supplement opioids for pain relief.
... Intravenous acetaminophen (also known as paracetamol) is the most widely used antipyretic and analgesic drug during intensive care worldwide [1]. Recently, in critically ill patients, including those presenting severe infections, acetaminophen administration has been associated with a decrease in blood pressure [2][3][4][5][6][7][8][9][10] and an increased incidence of hypotension lasting for approximately 2 h [4,5]; however, investigations are small and results are variable. Among critically ill patients with sepsis, those who develop hypotension have an increased risk of mortality [11]. ...
... The incidence of hypotension owing to acetaminophen administration varies widely [2][3][4][5][6][7][8][9][10], with several reasons for the diverse results reported, including small sample size, different definitions of hypotension, and differing [5,20]. Hyun Jong Lee et al. reported a high MAP at administration as a risk factor for hypotension following acetaminophen administration in relatively young patients with influenza A [10]. ...
Article
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Background Acetaminophen-induced hypotension has been reported in critically ill patients; however, it remains unclear whether mannitol, present as a stabilizing compound in acetaminophen formulations, affects hemodynamic changes. The objectives of this study were to clarify the direct effect of acetaminophen on blood pressure by comparing blood pressure changes after acetaminophen and intravenous immunoglobulin (IVIG) administration, both containing mannitol, in patients with sepsis and understand the risk factors for reduced blood pressure following acetaminophen administration. Methods This was a retrospective cohort study. Adult patients who were diagnosed with sepsis at Nippon Medical School Hospital, and who were undergoing continuous arterial blood pressure measurement and received intravenous acetaminophen or IVIG, were included. Results Overall, 185 patients were included, with 92 patients in the IVIG group and 93 in the acetaminophen group. The incidence of hypotension was 36.9% in the IVIG group (34 of 92 patients) and 58.0% in the acetaminophen group (54 of 93 patients) (OR = 8.26, p = 0.004). In a propensity score-matched cohort, 80 matched patients were selected. The incidence of hypotension was 37.5% in the IVIG group (15 of 40 patients) and 67.5% in the acetaminophen group (27 of 40 patients) (OR = 7.21, p = 0.007). Conclusions Acetaminophen induced substantially greater hypotension than IVIG in patients with sepsis, with both containing mannitol. Further studies are needed to clarify the effects on hemodynamics of mannitol contained in acetaminophen formulations.
... Fall in blood pressure was independently associated with younger age and higher blood pressure. In 16% of children with at least a 10% drop in mean blood pressure treatment was given either as a fluid bolus or a vasoactive infusion to increase the blood pressure [ Achuff 2019]. ...
... If fever further adds to haemodynamic compromise, then treatment is desirable.Treatment of fever can have its own consequences. Paracetamol is the most commonly used treatment for fever in children as shown in Chapter 2. In adults and children, paracetamol has been observed to decrease blood pressure [Schell-Chaple 017;Achuff 2019]. External cooling can cause vasoconstriction: studies of external cooling have reported a decrease in the need for vasoconstrictors ...
Conference Paper
Background: Fever is associated with improved mortality in critically ill adults with infection. Although infection is common in critically ill children, fever is treated, often with the aim to reduce oxygen consumption or improve oxygen delivery. This work tests the hypothesis that in critically ill children, fever impacts on outcomes by significantly imbalancing oxygen consumption and delivery. Methods: (i) A retrospective study of fever epidemiology in an unselected population of children admitted to the paediatric intensive care unit (PICU); (ii) A prospective study of fever epidemiology in children admitted to PICU with infection; (ii) A prospective study of the use of anti-pyretic interventions in children with infection and fever; (iv) A retrospective study exploring the effectiveness of paracetamol in reducing temperature; (v) A prospective study using indirect calorimetry to measure the changes in oxygen consumption with fever; (vi) Retrospective studies using high-resolution data and pulse-contour analysis to explore haemodynamic changes in children with fever and paracetamol; (vii) An observational study of the association between temperature and mortality in children admitted to PICU and children recruited to the FEAST study in sub-Saharan Africa. Results: (i) Fever occurred in 4066/10379 (40.1%) children in the first 48-hours of PICU admission. (ii) Seventy-seven of 140 children admitted with infection (55.0%) had a fever within the first 5-days of admission. (iii) 101/140 (72.1%) children were treated with anti-pyretic interventions, with paracetamol used in 99/101 (98.0%). The use of anti-pyretic interventions was correlated with temperature. (iv) Paracetamol was associated with a temperature decrease by 0.78oC (95% CI 074-0.82oC) in febrile children following the analysis of 4849 doses. (v) Changes in oxygen consumption with fever were variable, although the data could not be interpreted due to small numbers. (vi) A 1oC rise in temperature was associated with an 8.31/min (95% CI 8.30-8.33) rise in heart rate following an analysis of 7,39,466 data pairs from 170 children; and a 0.11 mmHg (95% CI 0.09-0.12) rise in mean arterial pressure following analysis of 5,212,439 pairs from 123 children. Rise in temperature was associated with a rise in the cardiac index but fall in the systemic vascular resistance. Paracetamol was associated with a drop in mean blood pressure by 3.02 mmHg (95% CI 1.56-4.47) following multi-variable analysis of 148 doses in 31 children. (vii) Maximum temperature in the first 24-hours of admission had a U-shaped relationship with mortality in 10125 PICU patients. The optimum temperature for survival was 38oC in those with unplanned admissions. Fever was similarly associated with improved survival in children with infection in sub-Saharan Africa without ICU provision. Conclusions: Fever is common in critically ill children. It is associated with near-equal increases in oxygen delivery and consumption. Given this, it is unlikely that an imbalance between oxygen consumption and delivery impacts on outcomes; fever was associated with a lower mortality compared to those with a maximum temperature of 36.5oC or below.
... Others, using pulse contour analysis, reported a significant, 4.7% reduction in MAP in critically ill children after paracetamol administration which they attributed to systemic vascular resistance [12]. Similarly, a study in children after cardiac surgery found that 1 in every 20 administrations of paracetamol (5%) was associated with a 15% drop in MAP from baseline [13]. However, this study, like the previous one [12], evaluated the change in MAP, not true hypotension. ...
... However, they included all routes of paracetamol administration, which may affect drug delivery and MAP change, and the reported decrease in MAP per se, which does not indicate true hypotension. Similarly, in pediatric patients with cardiac disease, Achuff Values given as mean ± SD, (IQR) unless otherwise indicated Δ delta, T 0 time immediately before paracetamol transfusion a mmHg below lowest normal systolic value for age Fig. 1 Systolic and mean arterial pressure changes from baseline, relative to lower limit of normal pressure, in patients required fluid bolus/VIS increment et al. [13] defined hypotension as a negative change of 15% compared to baseline, and relative hypotension as a negative change of 10%. Although they did not report true hypotensive values, they concluded that 16% of the children experienced hypotension since they required fluid bolus or a vasoactive drug increment. ...
Article
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Background: Treatment with intravenous paracetamol may impair hemodynamics in critically ill adults. Few data are available in children. The aim of this study was to investigate the frequency, extent, and risk factors of hypotension following intravenous paracetamol administration in children with septic shock on inotropic support. Methods: We retrospectively reviewed the electronic medical charts of all children aged 1 month to 18 years with septic shock who were treated with intravenous paracetamol while on inotropic support at the critical care unit of a tertiary pediatric medical center in 2013-2018. Data were collected on patient demographics, underlying disease, Pediatric Logistic Organ Dysfunction (PELOD) score, hemodynamic parameters before and up to 120 min after paracetamol administration, and need for inotropic support or intravenous fluid bolus. The main outcome measures were a change in blood pressure, hypotension, and hypotension requiring intervention. Results: The cohort included 45 children of mean age 8.9 ± 5.1 years. The mean inotropic support score was 12.1 ± 9.5. A total of 105 doses of paracetamol were administered. The lowest mean systolic pressure (108 ± 15 mmHg) was recorded at 60 min (p = 0.002). Systolic blood pressure decreased at 30, 60, 90, and 120 min after delivery of 50, 67, 61, and 59 drug doses, respectively. There were 5 events of systolic hypotension (decrease of 1 to 16 mmHg below systolic blood pressure hypotensive value). Mean arterial pressure decreased by ≥ 15% in 8 drug doses at 30 min (7.6%, mean - 19 ± 4 mmHg), 18 doses at 60 min (17.1%, mean - 20 ± 7 mmHg), 16 doses at 90 min (15.2%, mean - 20 ± 5 mmHg), and 17 doses at 120 min (16.2%, mean - 19 ± 5 mmHg). Mean arterial hypotension occurred at the respective time points in 2, 13, 10, and 9 drug doses. After 12 drug doses (11.4%), patients required an inotropic dose increment or fluid bolus. Conclusions: Hypotensive events are not uncommon in critically ill children on inotropic support treated with intravenous paracetamol, and physicians should be alert to their occurrence and the need for intervention.
... MAP and SBP were decreased postinfusion (−4.9 and −11.7 mm Hg, respectively), requiring initiation of fluid boluses or vasopressors in 26.2% of patients. 30 Retrospective Studies [34][35][36][37][38][39][40][41] Of the retrospective studies selected for this review, 3 were conducted in Korean patients presenting to the ED. [34][35][36] Results from these 3 studies indicate that a single dose of 1000 to 2000 mg propacetamol-a prodrug that is converted to acetaminophen by plasma esterase-results in a clinically significant reduction in SBP. ...
Article
Objective: Recent literature suggests that intravenous (IV) administration may cause hypotension in hospitalized patients; data further suggest that this effect is most pronounced in the critically ill. The purpose of this review is to identify and evaluate current literature that addresses the incidence and implications of IV acetaminophen–induced hypotension. Data Sources: A literature search of MEDLINE, Cochrane, and EMBASE databases was performed (2002-2019) using the following terms: acetaminophen, paracetamol, intravenous, and hypotension. Abstracts and peer-reviewed publications were reviewed. Study Selection and Data Extraction: Relevant English-language studies conducted in humans evaluating the hemodynamic effects of IV acetaminophen were considered. Data Synthesis: A majority of the 19 studies included in this review identified a statistically significant drop in hemodynamic variables after the administration of 500 to 1000 mg IV acetaminophen as measured by changes in systolic blood pressure, diastolic blood pressure, or mean arterial pressure. Of the trials reporting vasopressor use, the authors found a significant increase in vasopressor requirements following IV acetaminophen administration. Relevance to Patient Care and Clinical Practice: This review represents the first comprehensive review of IV acetaminophen-induced hypotension. The findings raise the question of whether IV acetaminophen is an appropriate choice for inpatient pain or temperature management in the critically ill. Conclusions: Available evidence indicates that the administration of IV acetaminophen may be harmful in the critically ill. Additional monitoring is likely required when using IV acetaminophen in this specific population, particularly if a patient is hemodynamically unstable prior to administration.
Chapter
Paracetamol (acetaminophen) is analgesic and antipyretic that is widely used to relieve mild to moderate pain and fever. This drug is an acetaniline derivative and was first used in 1883 in Europe. The most commonly used route for introducing paracetamol in addition to oral and rectal administration is intravenous route. Mechanism of this drug including inhibition of COX pathways, nitric oxide, and modulating endocannabinoid system. Intravenous use of paracetamol is carried out in critically ill patients, postsurgical patients, and pediatric patients that need immediate pain treatment. The use of Intravenous paracetamol has the advantage of being absorbed more quickly by the body than the oral or rectal routes. Intravenous use of paracetamol also makes it possible for little first-pass metabolism in the liver and higher bioavailability compared to the other routes (i.e., oral and rectal). However, intravenous use of paracetamol has also been reported to cause hemodynamic changes and also need careful deliberations due to effectiveness and cost considerations.
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Aim To understand the prevalence and epidemiology of paracetamol-induced hypotension and clinical implications for contemporaneous practice. Design Narrative review. Methods In May and June 2020, an open-date literature search of English publications indexed in ProQuest, PubMed, and EBSCO was conducted with the search terms ‘acetaminophen’ and ‘hypotension’ and related search combinations (‘paracetamol’, ‘propacetamol’, ‘low blood pressure’, ‘fever’, ‘sepsis’, and ‘shock’) to identify peer-reviewed publications of blood pressure changes after paracetamol administration in humans. Results A pattern of blood pressure reduction following the administration of paracetamol is demonstrated in the 27 studies included in this review. Haemodynamic intervention often followed persistent blood pressure reduction, and was greatest in febrile critically ill patients who received parenteral paracetamol.
Article
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Paracetamol (also known as Acetaminophen) is an antipyretic, non-opioid analgesic, and non-steroidal anti-inflammatory drug (NSAID), and is one of the most commonly used medications worldwide. In recent years, IV paracetamol has been frequently used in hospitalized patients to reduce fever and pain. Significant adverse reactions associated with intravenous paracetamol are extremely rare. Typically reported adverse events include hypotension, malaise, hypersensitivity reaction, liver enzyme elevation, and thrombocytopenia. We present herein a case of IV paracetamol infusion-related severe hypotension and cardiac arrest.
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Background: Acetaminophen is a common therapy for fever in patients in the intensive care unit (ICU) who have probable infection, but its effects are unknown. Methods: We randomly assigned 700 ICU patients with fever (body temperature, ≥38°C) and known or suspected infection to receive either 1 g of intravenous acetaminophen or placebo every 6 hours until ICU discharge, resolution of fever, cessation of antimicrobial therapy, or death. The primary outcome was ICU-free days (days alive and free from the need for intensive care) from randomization to day 28. Results: The number of ICU-free days to day 28 did not differ significantly between the acetaminophen group and the placebo group: 23 days (interquartile range, 13 to 25) among patients assigned to acetaminophen and 22 days (interquartile range, 12 to 25) among patients assigned to placebo (Hodges-Lehmann estimate of absolute difference, 0 days; 96.2% confidence interval [CI], 0 to 1; P=0.07). A total of 55 of 345 patients in the acetaminophen group (15.9%) and 57 of 344 patients in the placebo group (16.6%) had died by day 90 (relative risk, 0.96; 95% CI, 0.66 to 1.39; P=0.84). Conclusions: Early administration of acetaminophen to treat fever due to probable infection did not affect the number of ICU-free days. (Funded by the Health Research Council of New Zealand and others; HEAT Australian New Zealand Clinical Trials Registry number, ACTRN12612000513819.).
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To study the association between paracetamol administration in intensive care unit (ICU) and mortality in critically ill patients. We conducted a multicenter retrospective observational study in four ICUs. We obtained information on paracetamol use, body temperature, demographic, clinical and outcome data from each hospital's clinical information system and admissions and discharges database. We performed statistical analysis to assess the association between paracetamol administration and hospital mortality. We studied 15,818 patients with 691,348 temperature measurements from 4 ICUs. Of these patients, 10,046 (64%) received at least one gram of paracetamol. Patients who received paracetamol had lower in-hospital mortality (10% vs. 20%, p <0.001) and survivors were more likely to have received paracetamol (66% vs. 46%; p < 0.001). However, paracetamol-treated patients were also more likely to be admitted to ICU after surgery (70% vs. 51%; p < 0.001) and/or after elective surgery (55% vs. 37%; p < 0.001). On multivariate logistic regression analysis including a propensity score for paracetamol treatment, we found a significant and independent association between the use of paracetamol and reduced in-hospital mortality (Adjusted odds ratio 0.60 [95%CI 0.53-0.68], p < 0.001). Cox-proportional hazards analysis showed that patients who received paracetamol also had a significantly longer time to death (Adjusted hazard ratio 0.51 [95%CI 0.46-0.56], P <0.001). The association between paracetamol and decreased mortality and/or time to death was broadly consistent across surgical and medical patients. It remained present after adjusting for paracetamol administration as a time dependent variable. However, when such time-dependent analysis was performed, the association of paracetamol with outcome lost statistical significance in the presence of fever, suspected infection and in patients in the lower tertiles of Acute Physiology and Chronic Health Evaluation (APACHE II) scores. Paracetamol administration is common in ICU and appears independently associated with reduced in-hospital mortality and time to death after adjustment for multiple potential confounders and propensity score. This association, however, was modified by the presence of fever, suspected infection and lesser illness severity and may represent the effect of indication bias.
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Pain is a predictable consequence following operations, but the management of postoperative pain is another challenge for anesthesiologists and inappropriately controlled pain may lead to unwanted outcomes in the postoperative period. Opioids are indeed still at the mainstream of postoperative pain control, but solely using only opioids for postoperative pain management may be connected with risks of complications and adverse effects. As a consequence, the concept of multimodal analgesia has been proposed and is recommended whenever possible. Acetaminophen is one of the most commonly used analgesic and antipyretic drug for its good tolerance and high safety profiles. The introduction of intravenous form of acetaminophen has led to a wider flexibility of its use during peri- and postoperative periods, allowing the early initiation of multimodal analgesia. Many studies have revealed the efficacy, safety and opioid sparing effects of intravenous acetaminophen. Intravenous ibuprofen has also shown to be well tolerated and demonstrated to have significant opioid sparing effects during the postoperative period. However, the number of randomized controlled trials confirming the efficacy and safety is small and should be used in caution in certain group of patients. Intravenous acetaminophen and ibuprofen are important options for multimodal postoperative analgesia, improving pain and patient satisfaction.
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Hypertension is a leading cause of morbidity and mortality worldwide. Individuals with hypertension are at an increased risk for stroke, heart disease and kidney failure. Essential hypertension results from a combination of genetic and lifestyle factors. One such lifestyle factor is diet, and its role in the control of blood pressure has come under much scrutiny. Just as increased salt and sugar are known to elevate blood pressure, other dietary factors may have antihypertensive effects. Studies including the Optimal Macronutrient Intake to Prevent Heart Disease (OmniHeart) study, Multiple Risk Factor Intervention Trial (MRFIT), International Study of Salt and Blood Pressure (INTERSALT) and Dietary Approaches to Stop Hypertension (DASH) study have demonstrated an inverse relationship between dietary protein and blood pressure. One component of dietary protein that may partially account for its antihypertensive effect is the nonessential amino acid cysteine. Studies in hypertensive humans and animal models of hypertension have shown that N-acetylcysteine, a stable cysteine analogue, lowers blood pressure, which substantiates this idea. Cysteine may exert its antihypertensive effects directly or through its storage form, glutathione, by decreasing oxidative stress, improving insulin resistance and glucose metabolism, lowering advanced glycation end products, and modulating levels of nitric oxide and other vasoactive molecules. Therefore, adopting a balanced diet containing cysteine-rich proteins may be a beneficial lifestyle choice for individuals with hypertension. An example of such a diet is the DASH diet, which is low in salt and saturated fat; includes whole grains, poultry, fish and nuts; and is rich in vegetables, fruits and low-fat dairy products.
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Objective: To elucidate the mechanism of hypotension following intravenous administration of paracetamol (acetaminophen) to patients on the Intensive Care Unit. Design: Prospective observational cross-over study. Setting: Intensive Care Unit, University Hospital Královské Vinohrady, Prague, Czech Republic. Methods: Ventilated critically ill patients monitored by PiCCO and administered intravenous paracetamol at the same time were eligible for the study. We recorded haemodynamic indices, as well as core and peripheral temperatures, continuously for 3 h after the dose of paracetamol. Ranitidine was then used as a control drug known not to influence haemodynamics. Results: We included 6 subjects, and recorded 48 cycles of observations after administration of paracetamol, and 35 cycles after administration of the control drug. Haemodynamic parameters were not different at the baseline and administration of control drug did not result in any change in haemodynamics. After intravenous paracetamol, mean arterial pressure (MAP) dropped by 7% (p<0.001) with a nadir at the 19th minute. In 22 measurement cycles (45%) we noted >15% reduction in MAP with paracetamol. Analysis of these cycles suggests that hypotension with paracetamol can be caused by reduction of both cardiac index and systemic vascular resistance. In febrile cycles paracetamol caused narrowing of the gradient between central and peripheral temperatures suggesting skin vasodilation. These changes were not correlated to a change of systemic vascular resistance at any time point. Conclusion: Hypotension with intravenous paracetamol in critically ill patients is caused by a reduction of both cardiac output and systemic vascular resistance. We did not demonstrate any relation between haemodynamic changes and antipyretic action of paracetamol. A possibility that cardiac output is reduced with paracetamol might be clinically important.
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Although heart rate and respiratory rate in children are measured routinely in acute settings, current reference ranges are not based on evidence. We aimed to derive new centile charts for these vital signs and to compare these centiles with existing international ranges. We searched Medline, Embase, CINAHL, and reference lists for studies that reported heart rate or respiratory rate of healthy children between birth and 18 years of age. We used non-parametric kernel regression to create centile charts for heart rate and respiratory rate in relation to age. We compared existing reference ranges with those derived from our centile charts. We identified 69 studies with heart rate data for 143,346 children and respiratory rate data for 3881 children. Our centile charts show decline in respiratory rate from birth to early adolescence, with the steepest fall apparent in infants under 2 years of age; decreasing from a median of 44 breaths per min at birth to 26 breaths per min at 2 years. Heart rate shows a small peak at age 1 month. Median heart rate increases from 127 beats per min at birth to a maximum of 145 beats per min at about 1 month, before decreasing to 113 beats per min by 2 years of age. Comparison of our centile charts with existing published reference ranges for heart rate and respiratory rate show striking disagreement, with limits from published ranges frequently exceeding the 99th and 1st centiles, or crossing the median. Our evidence-based centile charts for children from birth to 18 years should help clinicians to update clinical and resuscitation guidelines. National Institute for Health Research, Engineering and Physical Sciences Research Council.
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We studied the pharmacokinetics of paracetamol and determine the incidence of hypotension after intravenous administration in medium- (MCU) and intensive care (ICU) patients. All patients on the ICU/MCU starting with paracetamol i.v. were included, yielding 38 patients. Blood samples were collected at predetermined time points to determine paracetamol serum concentration. The number of patients with a clinically relevant reduction in systolic blood pressure (SBP) and the number of patients that needed intervention to regain an acceptable blood pressure level were assessed. Overall, pharmacokinetic data were roughly comparable with earlier publications, but differences were noted in the subgroup ICU patients. Also, there was a trend to a larger peak serum concentration (p = 0.052) and a significantly smaller volume of distribution (p = 0.033) in MCU patients compared with ICU patients. Twenty-two percent (22%) and 33% of patients had a clinically relevant reduction in systolic blood pressure (SBP) 15 and 30 min after start of paracetamol infusion, respectively. In six patients (16%), an intervention was needed to correct blood pressure. Overall, SBP was significantly reduced at T = 15 min and 30 min postinfusion (p < 0.003 at both time points) when compared with SBP at the start of paracetamol infusion. Further research on differences in paracetamol pharmacokinetics between ICU and MCU patients is warranted, as these differences might result in differences in efficacy. Furthermore, administration of paracetamol i.v. as potential cause of hypotension in the critically ill patient must not be overlooked.
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Physiologic alterations in critically ill patients can significantly affect the pharmacokinetics of drugs used in the critically ill patient population. Understanding these pharmacokinetic changes is essential relative to optimizing drug therapy. This article outlines the major differences seen in the absorption, distribution, metabolism, and excretion of drugs in critically ill patients. Important strategies for drug therapy dosing and monitoring in these patients are also addressed.
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Systolic blood pressure (SBP) and mean arterial pressure (MAP) are essential evaluation elements in ill children, but there is wide variation among different sources defining systolic hypotension in children, and there are no normal reference values for MAP. Our goal was to calculate the 5th percentile SBP and MAP values in children from recently updated data published by the task force working group of the National High Blood Pressure Education Program and compare these values with the lowest limit of acceptable SBP and MAP defined by different sources. Mathematical analysis of clinical database. The 50th and 95th percentile SBP values from task force data were used to derive the 5th percentile value for children from 1 to 17 yrs of age stratified by height percentiles. MAP values were calculated using a standard mathematical formula. Calculated SBP values were compared with systolic hypotension definitions from other sources. Linear regression analysis was applied to create simple formulas to estimate 5th percentile SBP and 5th and 50th percentile MAP for different age groups at the 50th height percentile. A 9-21% range in both SBP and MAP values was noted for different height percentiles in the same age groups. The 5th percentile SBP values used to define hypotension by different sources are higher than our calculated values in children but are lower than our calculated values in adolescents. Clinical formulas for calculation of SBP and MAP (mm Hg) in normal children are as follows: SBP (5th percentile at 50th height percentile) = 2 x age in years + 65, MAP (5th percentile at 50th height percentile) = 1.5 x age in years + 40, and MAP (50th percentile at 50th height percentile) = 1.5 x age in years + 55. We developed new estimates for values of 5th percentile SBP and created a table of normal MAP values for reference. SBP is significantly affected by height, which has not been considered previously. Although the estimated lower limits of SBP are lower than currently used to define hypotension, these values are derived from normal healthy children and are likely not appropriate for critically ill children. Our data suggest that the current values for hypotension are not evidence-based and may need to be adjusted for patient height and, most important, for clinical condition. Specifically, we suggest that the definition of hypotension derived from normal children should not be used to define the SBP goal; a higher target SBP is likely appropriate in many critically ill and injured children. Further studies are needed to evaluate the appropriate threshold values of SBP for determining hypotension.
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Introduction Haemodynamically unstable patients can experience potentially hazardous changes in vital signs related to the exchange of depleted syringes of epinephrine to full syringes. The purpose was to determine the measured effects of epinephrine syringe exchanges on the magnitude, duration, and frequency of haemodynamic disturbances in the hour after an exchange event (study) relative to the hours before (control). Materials and methods Beat-to-beat vital signs recorded every 2 seconds from bedside monitors for patients admitted to the paediatric cardiovascular ICU of Texas Children’s Hospital were collected between 1 January, 2013 and 30 June, 2015. Epinephrine syringe exchanges without dose/flow change were obtained from electronic records. Time, magnitude, and duration of changes in systolic blood pressure and heart rate were characterised using Matlab. Significant haemodynamic events were identified and compared with control data. Results In all, 1042 syringe exchange events were found and 850 (81.6%) had uncorrupted data for analysis. A total of 744 (87.5%) exchanges had at least 1 associated haemodynamic perturbation including 2958 systolic blood pressure and 1747 heart-rate changes. Heart-rate perturbations occurred 37% before exchange and 63% after exchange, and 37% of systolic blood pressure perturbations happened before syringe exchange, whereas 63% occurred after syringe exchange with significant differences found in systolic blood pressure frequency (p<0.001), duration (p<0.001), and amplitude (p<0.001) compared with control data. Conclusions This novel data collection and signal processing analysis showed a significant increase in frequency, duration, and magnitude of systolic blood pressure perturbations surrounding epinephrine syringe exchange events.
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Objective: To determine the effects of IV acetaminophen on core body temperature, blood pressure, and heart rate in febrile critically ill patients. Design: Randomized, double-blind, placebo-controlled clinical trial. Setting: Three adult ICUs at a large, urban, academic medical center. Patients: Forty critically ill adults with fever (core temperature, ≥ 38.3°C). Intervention: An infusion of acetaminophen 1 g or saline placebo over 15 minutes. Measurement and main results: Core temperature and vital signs were measured at baseline and at 5-15-minute intervals for 4 hours after infusion of study drug. The primary outcome was time-weighted average core temperature adjusted for baseline temperature. Secondary outcomes included adjusted time-weighted average heart rate, blood pressure, and respiratory rate, along with changes-over-time for each. Baseline patient characteristics were similar in those given acetaminophen and placebo. Patients given acetaminophen had an adjusted time-weighted average temperature that was 0.47°C less than those given placebo (95% CI, -0.76 to -0.18; p = 0.002). The acetaminophen group had significantly lower adjusted time-weighted average systolic blood pressure (-17 mm Hg; 95% CI, -25 to -8; p < 0.001), mean arterial pressure (-7 mm Hg; 95% CI, -12 to -1; p = 0.02), and heart rate (-6 beats/min; 95% CI, -10 to -1; p = 0.03). Changes-over-time temperature, blood pressure, and heart rate outcomes were also significantly lower at 2 hours, but not at 4 hours. Conclusions: Among febrile critically ill adults, treatment with acetaminophen decreased temperature, blood pressure, and heart rate. IV acetaminophen thus produces modest fever reduction in critical care patients, along with clinically important reductions in blood pressure.
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Purpose: Researchers recently suggested intravenous paracetamol as a potential cause of hypotension. We aimed to investigate risk factors of paracetamol- and propacetamol-associated adverse drug reactions (ADRs) in Korean individuals. Methods: All adverse hypotension cases, regardless of suspected drug, and all ADRs associated with paracetamol and propacetamol use were collected from the Korea Adverse Event Reporting System database between 2011 and 2014. The seriousness, causality, and type of ADR were classified. Results: Of 4,771 cases of adverse hypotension, 403 (8.4%) were reported to be related to propacetamol. This was comparable to the rate of hypotension associated with fentanyl (454, 9.5%), the major suspected drug of hypotension. Paracetamol-associated hypotension accounted for merely 1.2% (55 cases) of all hypotension cases. Among ADRs associated with propacetamol use, hypotension was the most common (37.1%), whereas cutaneous reactions were the primary paracetamol-associated ADR. Propacetamol/paracetamol-associated hypotension was frequently recorded in older patients (≥54 years) (53.9 ± 25.8 vs. 42.8 ± 21.7, P < 0.001) and taking more concomitant drugs (1.9 ± 5.0 vs. 1.1 ± 3.2, P < 0.001). Also, compared with other ADRs associated by propacetamol/paracetamol, hypotension was more commonly assessed as a serious outcome (27.3% vs. 11.4%, P < 0.001). Regarding concomitant medications, the risk for hypotension associated with propacetamol was significantly increased in patients simultaneously taking antibacterials (J01), cold preparations (R05), drugs for acid related disorders (A02), blood substitutes (B05), or antithrombotics (B01). Conclusions: Propacetamol was found to be a major suspected drug of pharmacologically associated hypotension in Korea. Older and male patients taking medications in combination with propacetamol/paracetamol should undergo monitoring of their blood pressure. Copyright © 2017 John Wiley & Sons, Ltd.
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Paracetamol is a commonly used drug in the intensive care unit. There have been reports in the literature of an association with significant hypotension, a potentially important interaction for labile critically ill patients. Route of administration may influence the incidence of hypotension. This single-centre, prospective, open-label, randomised, parallel-arm, active-control trial was designed to determine the incidence of hypotension following the administration of paracetamol to critically ill patients. Fifty adult patients receiving paracetamol for analgesia or pyrexia were randomly assigned to receive either the parenteral or enteral formulation of the drug. Paracetamol concentrations were measured at baseline and at multiple time points over 24 h. The maximal plasma paracetamol concentration was significantly different between routes; 156 vs. 73 micromol.l−1 [p = 0.0005] following the first dose of parenteral or enteral paracetamol, respectively. Sixteen hypotensive events occurred in 12 patients: parenteral n = 12; enteral n = 4. The incident rate ratio for parenteral vs. enteral paracetamol was 2.94 (95% CI 0.97–8.92; p = 0.06). The incidence of hypotension associated with paracetamol administration is higher than previously reported and tends to be more frequent with parenteral paracetamol.
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Objectives: We sought to assess the incidence of acetaminophen-induced hypotension. Our secondary objectives were to describe systemic hemodynamic changes and factors associated with this complication. Design: Prospective observational study. Setting: Three ICUs. Patients: Adult patients requiring IV acetaminophen infusion. Arterial pressure was monitored via an arterial catheter for 3 hours. Hypotension was defined as a decrease in the mean arterial pressure of greater than or equal to 15% compared with the baseline. Results: Overall, 160 patients were included in this study. Eighty-three patients (51.9%) experienced acetaminophen-induced hypotension according to our definition. In patients with acetaminophen-induced hypotension, the nadir mean arterial pressure was 64 mm Hg (95% CI, 54-74). Hypotension was observed 30 minutes (95% CI, 15-71) after acetaminophen infusion. Changes in mean arterial pressure were closely correlated with decreases in the diastolic arterial pressure (r = 0.92) and to a lesser extent with changes in the pulse pressure (r = 0.18) and heart rate (r = 0.09). Changes in the body temperature were not correlated with changes in mean arterial pressure (r = 0.0002; p = 0.85). None of the patients' baseline characteristics (shock, use of angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers, lactates, renal replacement therapy, chronic heart disease, and indication for acetaminophen infusion) or clinically relevant characteristics (baseline severity according to Logistic Organ Dysfunction score, need for vasopressors, use of antihypertensive agents, need for mechanical ventilation, or changes in the body temperature) were independently associated with acetaminophen-induced hypotension. Among patients with acetaminophen-induced hypotension, 29 (34.9%) required therapeutic intervention. Conclusions: Half of the patients who received IV injections of acetaminophen developed hypotension, and up to one third of the observed episodes necessitated therapeutic intervention. Adequately powered randomized studies are needed to confirm our findings, provide an accurate estimation of the consequences of acetaminophen-induced hypotension, and assess the pathophysiologic mechanisms involved.
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Introduction: The haemodynamic effects of intravenous paracetamol have not been systematically investigated. We compared the physiological effects of intravenous mannitol-containing paracetamol, and an equivalent dosage of mannitol, and normal saline 0.9% (NS) in healthy volunteers. Methods: We performed a blinded, triple crossover, randomized trial of 24 adult healthy volunteers. Participants received IV paracetamol (1 g paracetamol + 3.91 g mannitol/100 mL), IV mannitol (3.91 g mannitol/100 mL), and IV NS (100 mL). Composite primary end points were changes in mean arterial pressure (MAP), systolic blood pressure (SBP) and diastolic blood pressure (DBP) measured pre-infusion, during a 15 minute infusion period, and over a 45 minute observation period. Systemic vascular resistance index (SVRI), cardiac index (CI) were measured at the same time points. Results: Infusion of paracetamol induced a transient yet significant decrease in blood pressures from pre-infusion values (MAP -1.85mmHg (95% CI: -2.6 to -1.1), SBP -0.54mmHg (95% CI: -1.7 to 0.6) and DBP -1.92mmHg (95% CI: -2.6 to -1.2); p<0.0001), associated with a transient reduction in SVRI and an increase in CI. Changes were observed, but to a lesser extent with NS (MAP -0.15mmHg, SBP +1.44mmHg, DBP -0.73mmHg p<0.0001), but not with mannitol (MAP +1.47mmHg, SBP +4.03mmHg, DBP +0.48mmHg; p<0.0001). Conclusions: IV paracetamol caused a transient decrease in blood pressures immediately after infusion. These effects were not seen with mannitol or NS. The physiological mechanism was consistent with vasodilatation. This study provides plausible physiological data in a healthy volunteer setting, supporting transient changes in haemodynamic variables with IV paracetamol and justifies controlled studies in the peri-operative and critical care setting. This article is protected by copyright. All rights reserved.
Article
The objective was to study the antipyretic and hemodynamic effects of three different drugs used to treat fever in critically ill patients.Methods Design and setting: Prospective, observational study in a 16-bed, general ICU of a university hospital. Patient population: We studied 150 patients who had a febrile episode (temperature >38° C): 50 received paracetamol, 50 metamizol and 50 dexketoprofen. Interventions: None. Body temperature, systolic, diastolic and mean arterial pressure, heart rate, central venous pressure and oxygen saturation were determined at baseline and at 30, 60 and 120 minutes after infusion of the drug. Additionally, we recorded temperature 180 minutes after starting drug infusion. Diuresis and the need for or change of dose of vasodilator or vasoconstrictor drugs were also recorded.ResultsPatient characteristics, baseline temperature and hemodynamics were similar in all groups. We observed a significant decrease of at least 1 °C in temperature after 180 minutes in 38 patients treated with dexketoprofen (76%), in 36 with metamizol (72%), and in 20 with paracetamol (40%) (p < 0.001). After 120 minutes, the mean decrease in mean arterial pressure was 8.5 ± 13.6 mmHg with paracetamol, 14.9 ± 11.8 mmHg with metamizol, and 16.8 ± 13.7 mmHg with dexketoprofen (p = 0.005).Conclusions Dexketoprofen was the most effective antipyretic agent at the doses tested. Although all three drugs reduced mean arterial pressure, the reduction with paracetamol was less pronounced.
Article
Background: Intravenous (IV) paracetamol is commonly used in the postoperative period for the treatment of mild to moderate pain. The main pathways for paracetamol metabolism are glucuronidation, sulfation, and oxidation, accounting for approximately 55%, 30%, and 10% of urinary metabolites, respectively. The aim of this study was to describe the pharmacokinetics of IV paracetamol and its metabolites in adult patients after major abdominal surgery. Methods: Twenty patients were given 1 g of paracetamol by IV infusion at induction of anesthesia (Interval 1) and every 6 hours thereafter, with the final dose given at 48-72 hours (Interval 2). Plasma and urine samples were collected for up to 8 hours after infusion for both intervals. The samples were analyzed by high-performance liquid chromatography to determine the amount of paracetamol and its metabolites. The data were modeled in Phoenix WinNonlin using a user-defined ASCII parent-metabolite model with linear disposition, to obtain the estimates for volume of distribution, metabolic and urinary clearance. Results: Mean (95% confidence interval) metabolic clearance to paracetamol glucuronide increased from 0.06 (0.05-0.08) to 0.14 (0.11-0.18) L · h⁻¹ · kg⁻¹, P value <0.001 and urinary clearance increased from 0.08 (0.07-0.09) to 0.14 (0.10-0.17) L · h⁻¹ · kg⁻¹, P value 0.002. The mean (95% confidence interval) volume of distribution of paracetamol increased from 0.17 (0.12-0.21) to 0.43 (0.27-0.59) L · kg⁻¹, P value 0.032. Conclusions: After major abdominal surgery, there were apparent increases in the metabolic conversion to paracetamol glucuronide and its urinary clearance suggesting potential induction of paracetamol glucuronidation.
Effective analgesia in neonates is still hampered owing to a lack of data on pharmacokinetics and pharmacodynamics of analgesics. In this article, the consecutive steps taken to document aspects of disposition (pharmacokinetics and metabolism) and safety (hepatic tolerance, hemodynamic stability and effects on body temperature) during exposure to intravenous acetaminophen in neonates are summarized. Based on these data, dosing suggestions were formulated. However, we have to be aware that such dosing suggestions are - at present - without any validated pharmacodynamic correlates since the applicability of a fixed acetaminophen target concentration (10 mg·l(-1)) in neonates of different subpopulations remains to be documented. In addition, the number of observations in extreme preterm neonates is limited. Finally, epidemiological data suggest a link between perinatal acetaminophen exposure and an increased risk to developing asthma. Consequently, well designed and appropriately powered pharmacodynamic studies in neonates are urgently required, with specific emphasis on extreme preterm neonates.
Article
To determine the relationship between paracetamol administration and skin blood flow (skBF) and blood pressure (BP) in critically ill patients treated for fever. Prospective, observational study. Intensive care units of university teaching hospital. 29 adults (17 males and 12 females), aged 58±15 years treated with enteral or intravenous paracetamol for fever. APACHE II score was 17.2±8.3 and admission classifications were 41% medical (n=12), 31% surgical (n=9), and 28% neurological intervention (n=8). Thirty healthy afebrile volunteers were also studied after ingesting 1g paracetamol. Temperature, BP and skBF (laser Doppler flowmetry perfusion units) were recorded 15 min prior to administration of paracetamol, at administration (T0) and then for every 15 min for 60 min. Cutaneous vascular conductance (CVC=skBF/mean arterial pressure) was calculated. Thirty data sets were recorded from 29 patients. Temperature at T0 was 38.7±0.6°C. BP decreased over the study period whilst skBF and CVC increased (repeated measured ANOVA, p<.05). Systolic BP decreased significantly (p<.01) at all post-administration times and was 90±13% of T0 at 60 min. CVC was 128±48% of T0 at 60 min. Systolic BP fell by a clinically significant amount (≥15%) in 17 patients (59%) and hypotension was treated during 33% (n=10) of the observation periods. BP and skBF did not change significantly in afebrile volunteers. Paracetamol induced increases in skBF consistent with its antipyretic action and may be associated with significant falls in BP in the critically ill.
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Intravenous paracetamol (rINN)/intravenous acetaminophen (USAN) is an analgesic and antipyretic agent, recommended worldwide as a first-line agent for the treatment of pain and fever in adults and children. ▴ In double-blind clinical trials, single or multiple doses of intravenous paracetamol 1 g generally provided significantly better analgesic efficacy than placebo treatment (as determined by primary efficacy endpoints) in adult patients who had undergone dental, orthopaedic or gynaecological surgery. ▴ Furthermore, where evaluated, intravenous paracetamol 1 g generally showed similar analgesic efficacy to a bioequivalent dose of propacetamol, and a reduced need for opioid rescue medication. ▴ In paediatric surgical patients, recommended doses of intravenous paracetamol 15 mg/kg were not significantly different from propacetamol 30 mg/kg for the treatment of pain, and showed equivocal analgesic efficacy compared with intramuscular pethidine 1 mg/kg in several randomized, active comparator-controlled studies. ▴ In a randomized, noninferiority study in paediatric patients with an infection-induced fever, intravenous paracetamol 15 mg/kg treatment was shown to be no less effective than propacetamol 30 mg/kg in terms of antipyretic efficacy. ▴ Intravenous paracetamol was well tolerated in clinical trials, having a tolerability profile similar to placebo. Additionally, adverse reactions emerging from the use of the intravenous formulation of paracetamol are extremely rare (<1/10000).
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Through 30 years of widespread use, acetaminophen has been shown to be a remarkably safe medication in therapeutic dosages. The potential for acetaminophen to produce cardiovascular toxicities is very low. However, acetaminophen has been demonstrated to produce symptoms of anaphylaxis, including hypotension, in sensitive individuals. This article describes two critically ill patients in whom transient episodes of hypotension reproducibly developed after administration of acetaminophen. Other symptoms of allergic reactions were not clinically detectable. The hypotensive episodes were severe enough to require vasopressor administration. The reports illustrate the need for clinicians to consider acetaminophen in patients with hypotension of unknown origin.
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Intravenous acetaminophen injection (paracetamol) is marketed in Europe for the management of acute pain. A repeated-dose, randomized, double-blind, placebo-controlled, three-parallel group study was performed to evaluate the analgesic efficacy and safety of intravenous acetaminophen as compared with its prodrug (propacetamol) and placebo. Propacetamol has been available in many European countries for more than 20 yr. After orthopedic surgery, patients reporting moderate to severe pain received either 1 g intravenous acetaminophen, 2 g propacetamol, or placebo at 6-h intervals over 24 h. Patients were allowed "rescue" intravenous patient-controlled analgesia morphine. Pain intensity, pain relief, and morphine use were measured at selected intervals. Safety was monitored through adverse event reporting, clinical examination, and laboratory testing. One hundred fifty-one patients (intravenous acetaminophen: 49; propacetamol: 50; placebo: 52) received at least one dose of study medication. The intravenous acetaminophen and propacetamol groups differed significantly from the placebo group regarding pain relief from 15 min to 6 h (P < 0.05) and median time to morphine rescue (intravenous acetaminophen: 3 h; propacetamol: 2.6 h; placebo: 0.8 h). Intravenous acetaminophen and propacetamol significantly reduced morphine consumption over the 24-h period: The total morphine doses received over 24 h were 38.3 +/- 35.1 mg for intravenous acetaminophen, 40.8 +/- 30.2 mg for propacetamol, and 57. 4 +/- 52.3 mg for placebo, corresponding to decreases of -33% (19 mg) and -29% (17 mg) for intravenous acetaminophen and propacetamol, respectively. Drug-related adverse events were reported in 8.2%, 50% (most of them local), and 17.3% of patients treated with intravenous acetaminophen, propacetamol, and placebo, respectively. Intravenous acetaminophen, 1 g, administered over a 24-h period in patients with moderate to severe pain after orthopedic surgery provided rapid and effective analgesia and was well tolerated.