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Gabay O, Miller H, Gruenbaum BF, Ashur A, Frenkel A, Zafarov A, Bichovsky Y, Koyfman L, Brotfain E. The hemodynamic effects of IV paracetamol in intensive care patients. J Intensive Care Soc 2025:17511437251327566. [PMID: 40160308 PMCID: PMC11948232 DOI: 10.1177/17511437251327566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025] Open
Abstract
Objective This retrospective observational study conducted in a general ICU aimed to evaluate the hemodynamic impact of IV paracetamol by monitoring blood pressure, urine output, and core temperature post-administration. Design The study was designed as a retrospective observational study in a general ICU setting. Setting The study was conducted in a general intensive care unit (ICU). Patients Data from 498 patients receiving IV paracetamol in various clinical contexts were analyzed. Interventions Patients received IV paracetamol for analgesia and fever reduction as part of their clinical care. Measurements and main results The study analyzed the hemodynamic effects of IV paracetamol by monitoring blood pressure, urine output, and core temperature post-administration. A significant decrease in mean systolic and diastolic blood pressure values was observed across different patient subgroups, notably 45-60 min post-infusion. An increase in noradrenaline dosage and a decrease in urine output indicated a decline in end-organ perfusion following IV paracetamol administration. Multivariate analysis identified associations between clinical factors (such as general anesthesia and cardiac conditions) and changes in blood pressure. Conclusions While IV paracetamol remains a valuable therapeutic option for pain and fever management, especially in hypertensive patients with specific conditions like traumatic brain injury and cerebral vascular accident, careful monitoring, and individualized dosing strategies are recommended in critically ill patients to maintain hemodynamic stability and optimize clinical outcomes. These findings contribute to enhancing our understanding of IV paracetamol hemodynamic effects and inform evidence-based practices for its use in ICU settings.
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Affiliation(s)
- Ohad Gabay
- Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Hodaya Miller
- Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | | | - Avia Ashur
- Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Amit Frenkel
- Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Adam Zafarov
- Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Yoav Bichovsky
- Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Leonid Koyfman
- Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Evgeni Brotfain
- Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
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Dannesboe J, Bastrup JA, Nielsen KH, Munck P, Thomsen MB, Hawkins CL, Jepps TA. Paracetamol metabolism by endothelial cells - Potential mechanism underlying intravenous paracetamol-induced hypotension. Pharmacol Res 2025; 211:107540. [PMID: 39653302 DOI: 10.1016/j.phrs.2024.107540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 11/24/2024] [Accepted: 12/05/2024] [Indexed: 12/16/2024]
Abstract
It was shown previously that a metabolite of acetaminophen (APAP), N-acetyl-p-benzoquinone imine (NAPQI), is a potent vasodilator, which could underlie the hypotension observed when APAP is administered intravenously. However, it is unknown whether APAP metabolism to NAPQI is possible in the vasculature. In this study, we examine the hypothesis that APAP is metabolized by cytochrome P450 enzymes within the endothelium, which may be accelerated in critically ill patients by the presence of elevated myeloperoxidase (MPO). Exposure of human coronary artery endothelial cells (HCAECs) to APAP resulted in the formation of protein-bound APAP adducts. Proteomic analysis of HCAECs exposed to APAP showed upregulation of CYP20A1, together with proteins involved in the pentose phosphate pathway and maintaining redox homeostasis. Proteomic analyses of mesenteric arteries from rats administered intravenous APAP are consistent with a key role of the vascular wall in APAP metabolism, with similar proteomic pathway changes identified in HCAECs. These changes occurred over a short timeframe and were not seen in the corresponding proteomic analyses of liver tissue. Intracellular thiols were depleted in HCAECs upon APAP treatment, which was partially attenuated by ketoconazole, consistent with the involvement of cytochrome P450 enzymes in the metabolism of APAP to a thiol-reactive metabolite such as NAPQI. Evidence was also obtained for the metabolism of APAP to a thiol-reactive intermediate by MPO in the absence of chloride ions, consistent with NAPQI formation. Taken together, these data provide a putative mechanism to explain the presentation of hypotension in critically ill patients following IV APAP administration.
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Affiliation(s)
- Johs Dannesboe
- Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N 2200, Denmark
| | - Joakim A Bastrup
- Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N 2200, Denmark
| | - Kathrine Holm Nielsen
- Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N 2200, Denmark
| | - Pelle Munck
- Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N 2200, Denmark
| | - Morten B Thomsen
- Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N 2200, Denmark
| | - Clare L Hawkins
- Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N 2200, Denmark
| | - Thomas A Jepps
- Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N 2200, Denmark.
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Sridharan K, Mulubwa M, Qader AM. Population Pharmacokinetic Modeling and Dose Optimization of Acetaminophen and its Metabolites Following Intravenous Infusion in Critically ill Adults. Eur J Drug Metab Pharmacokinet 2023; 48:531-540. [PMID: 37389726 DOI: 10.1007/s13318-023-00841-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/13/2023] [Indexed: 07/01/2023]
Abstract
BACKGROUND AND OBJECTIVE Acetaminophen (paracetamol) is a ubiquitously administered drug in critically ill patients. Considering the dearth of literature, we evaluated the population pharmacokinetics of intravenous acetaminophen and its principal metabolites (sulfate and glucuronide) in this population. METHODS Critically ill adults receiving intravenous acetaminophen were included in the study. One to three blood samples were withdrawn per patient for the estimation of acetaminophen, and its metabolites (acetaminophen glucuronide and acetaminophen sulfate). High-performance liquid chromatography was used for measuring serum concentrations. We used nonlinear mixed-effect modeling for estimating the primary pharmacokinetic parameters of acetaminophen and its metabolites. The effect of covariates was evaluated followed by dose optimization using Monte Carlo simulation. Patient factors such as demographic information, liver and renal function tests were used as covariates in population pharmacokinetic analysis. The therapeutic range for serum acetaminophen concentration was considered to be 66-132 μM, while 990 μM was considered as the threshold for toxic concentration. RESULTS Eighty-seven participants were recruited. A joint two-compartment acetaminophen pharmacokinetic model linked to glucuronide and sulfate metabolite compartments was used. The central and peripheral volume distributions were 7.87 and 8.87 L/70 kg, respectively. Estimated clearance (CL) was 0.58 L/h/70 kg, while intercompartmental clearance was 44.2 L/h/70 kg. The glucuronide and sulfate metabolite CL were 22 and 94.7 L/h/70 kg, respectively. Monte Carlo simulation showed that twice-daily administration of acetaminophen would result in a relatively higher proportion of patient population achieving and retaining serum concentrations in the therapeutic range, with reduced risk of concentrations remaining in the toxic range. CONCLUSION A joint pharmacokinetic model for intravenous acetaminophen and its principal metabolites in a critically ill patient population has been developed. Acetaminophen CL in this patient population is reduced. We propose a reduction in the frequency of administration to reduce the risk of supra-therapeutic concentrations in this population.
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Affiliation(s)
- Kannan Sridharan
- Department of Pharmacology & Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain.
| | - Mwila Mulubwa
- Drug Discovery and Development Centre (H3D), University of Cape Town, Observatory, Cape Town, 7925, South Africa
| | - Ali Mohamed Qader
- Salmaniya medical complex, Manama, Kingdom of Bahrain
- College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
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Rivasi G, Menale S, Turrin G, Coscarelli A, Giordano A, Ungar A. The Effects of Pain and Analgesic Medications on Blood Pressure. Curr Hypertens Rep 2022; 24:385-394. [PMID: 35704141 PMCID: PMC9509303 DOI: 10.1007/s11906-022-01205-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/06/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE OF REVIEW To review the blood pressure (BP) effects of pain and analgesic medications and to help interpret BP changes in people suffering from acute or chronic pain. RECENT FINDINGS Acute pain evokes a stress response which prompts a transient BP increase. Chronic pain is associated with impaired regulation of cardiovascular and analgesia systems, which may predispose to persistent BP elevation. Also analgesics may have BP effects, which vary according to the drug class considered. Data on paracetamol are controversial, while multiple studies indicate that non-steroidal anti-inflammatory drugs may increase BP, with celecoxib showing a lesser impact. Hypotension has been reported with opioid drugs. Among adjuvants, tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors could be pro-hypertensive due to potentiation of adrenergic transmission. Pain and analgesics may induce a clinically significant BP destabilization. The implications on hypertension incidence and BP control remain unclear and should be explored in future studies.
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Affiliation(s)
- Giulia Rivasi
- Hypertension Clinic, Syncope Unit, Division of Geriatric and Intensive Care Medicine, University of Florence and Azienda Ospedaliero Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy.
| | - Silvia Menale
- Hypertension Clinic, Syncope Unit, Division of Geriatric and Intensive Care Medicine, University of Florence and Azienda Ospedaliero Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy
| | - Giada Turrin
- Hypertension Clinic, Syncope Unit, Division of Geriatric and Intensive Care Medicine, University of Florence and Azienda Ospedaliero Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy
| | - Antonio Coscarelli
- Hypertension Clinic, Syncope Unit, Division of Geriatric and Intensive Care Medicine, University of Florence and Azienda Ospedaliero Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy
| | - Antonella Giordano
- Hypertension Clinic, Syncope Unit, Division of Geriatric and Intensive Care Medicine, University of Florence and Azienda Ospedaliero Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy
| | - Andrea Ungar
- Hypertension Clinic, Syncope Unit, Division of Geriatric and Intensive Care Medicine, University of Florence and Azienda Ospedaliero Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy
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Lee E, Song YJ, Jeon S, Lee J, Lee E, Lee JY, Lee E, Han MK, Jeong HG. Risk Factors for Intravenous Propacetamol-Induced Blood Pressure Drop in the Neurointensive Care Unit: A Retrospective Observational Study. Neurocrit Care 2021; 36:888-896. [PMID: 34791593 DOI: 10.1007/s12028-021-01390-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 10/25/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND Intravenous propacetamol is commonly used to control fever and pain in neurocritically ill patients in whom oral administration is often difficult. However, several studies reported that intravenous propacetamol may cause blood pressure drop. Thus, we aimed to investigate the occurrence and risk factors for intravenous propacetamol-induced blood pressure drop in neurocritically ill patients. METHODS This retrospective study included consecutive patients who were administered intravenous propacetamol in a neurointensive care unit at a single tertiary academic hospital between April 2013 and June 2020. The exact timing of intravenous propacetamol administration was collected from a database of the electronic barcode medication administration system. Blood pressure drop was defined as a systolic blood pressure below 90 mm Hg or a decrease by 30 mm Hg or more. Blood pressure, pulse rate, and body temperature were collected at baseline and within 2 h after intravenous propacetamol administration. The incidence of blood pressure drop was evaluated, and multivariable logistic regression analysis was performed to identify risk factors for blood pressure drop events. RESULTS A total of 16,586 instances of intravenous propacetamol administration in 4916 patients were eligible for this study. Intravenous propacetamol resulted in a significant decrease in systolic blood pressure (baseline 131.1 ± 17.8 mm Hg; within 1 h 124.6 ± 17.3 mm Hg; between 1 and 2 h 123.4 ± 17.4 mm Hg; P < 0.01). The incidence of blood pressure drop events was 13.5% within 2 h after intravenous propacetamol. Older age, lower or higher baseline systolic blood pressure, fever, higher Acute Physiology and Chronic Health Evaluation II score, and concomitant administration of vasopressors/inotropes or analgesics/sedatives were significant factors associated with the occurrence of blood pressure drop events after intravenous propacetamol administration. CONCLUSIONS Intravenous propacetamol can induce hemodynamic changes and blood pressure drop events in neurocritically ill patients. This study identified the risk factors for blood pressure drop events. On the basis of our results, judicious use of intravenous propacetamol is warranted for neurocritically ill patients with risk factors that make them more susceptible to hemodynamic changes.
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Affiliation(s)
- Eunah Lee
- Department of Pharmacy, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seoungnam-si, Gyeonggi-do, 13620, Republic of Korea
| | - Young Joo Song
- Department of Pharmacy, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seoungnam-si, Gyeonggi-do, 13620, Republic of Korea
| | - Sujeong Jeon
- Department of Pharmacy, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seoungnam-si, Gyeonggi-do, 13620, Republic of Korea
| | - Junghwa Lee
- Department of Pharmacy, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seoungnam-si, Gyeonggi-do, 13620, Republic of Korea
| | - Eunsook Lee
- Department of Pharmacy, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seoungnam-si, Gyeonggi-do, 13620, Republic of Korea
| | - Ju-Yeun Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Euni Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Moon-Ku Han
- Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, 08826, Republic of Korea
| | - Han-Gil Jeong
- Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, 08826, Republic of Korea. .,Division of Neurocritical Care, Department of Neurosurgery and Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea.
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Weinberg L, Chiam E, Karp J, Churilov L, Bellomo R. The hemodynamic effects of intravenous paracetamol (acetaminophen) in patients with chronic liver disease undergoing liver transplantation: a pilot study. BMC Res Notes 2021; 14:325. [PMID: 34429149 PMCID: PMC8383248 DOI: 10.1186/s13104-021-05749-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 08/18/2021] [Indexed: 12/04/2022] Open
Abstract
OBJECTIVE We performed a single-center double-blinded, randomized trial to investigate the hemodynamic effects of IV paracetamol in patients with chronic liver disease (CLD) undergoing liver transplantation surgery. Patients with CLD are particularly susceptible to hemodynamic derangements given their low systemic vascular resistance state. Accordingly, hypotension is common in this setting. The hemodynamic effects of IV paracetamol in patients undergoing elective liver transplantation are unknown, therefore we evaluated whether the intraoperative administration of IV paracetamol in patients with chronic liver disease undergoing liver transplantation results in adverse hemodynamic effects. The primary end point was a change in systolic blood pressure 30-min after the preoperative infusion. RESULTS Twenty-four participants undergoing liver transplantation surgery were randomly assigned to receive a single bolus of IV paracetamol (1 g paracetamol + 3.91 g mannitol per 100 mL) (n = 12) or placebo (0.9% Saline 100 mL) (n = 12). All participants completed their study intervention, and there were no breaches or violations of the trial protocol. Baseline characteristics were similar in both groups. There were no significant differences regarding surgical duration, intraoperative use of fluids, and intraoperative noradrenaline use. After the administration of paracetamol there were no significant differences observed in blood pressure or other hemodynamic parameters when compared to placebo.
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Affiliation(s)
- Laurence Weinberg
- Department of Anesthesia, Austin Health, Studley Rd, Heidelberg, VIC Australia
- Department of Surgery, The University of Melbourne, Austin Health, Victoria, Australia
| | - Elizabeth Chiam
- Department of Anesthesia, Austin Health, Studley Rd, Heidelberg, VIC Australia
| | - Jadon Karp
- Monash School of Medicine, Monash University, Victoria, Australia
| | - Leonid Churilov
- Department of Medicine (Austin Health) and Melbourne Brain Centre at Royal Melbourne Hospital, Melbourne Medical School, Parkville, Australia
- Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia
| | - Rinaldo Bellomo
- Department of Intensive Care, Austin Hospital, Heidelberg, VIC Australia
- Department of Critical Care, The Univesity of Melbourne, Victoria, Australia
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Young TL. A narrative review of paracetamol-induced hypotension: Keeping the patient safe. Nurs Open 2021; 9:1589-1601. [PMID: 34102027 PMCID: PMC8994964 DOI: 10.1002/nop2.943] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/01/2021] [Accepted: 04/28/2021] [Indexed: 12/21/2022] Open
Abstract
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.
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Affiliation(s)
- Tricia L Young
- Australia and Bairnsdale Regional Health Service, University of New England, Armadale, VIC, Australia
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van der Horst J, Manville RW, Hayes K, Thomsen MB, Abbott GW, Jepps TA. Acetaminophen (Paracetamol) Metabolites Induce Vasodilation and Hypotension by Activating Kv7 Potassium Channels Directly and Indirectly. Arterioscler Thromb Vasc Biol 2020; 40:1207-1219. [PMID: 32188278 DOI: 10.1161/atvbaha.120.313997] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Intravenous acetaminophen/paracetamol (APAP) is well documented to cause hypotension. Since the patients receiving intravenous APAP are usually critically ill, any severe hemodynamic changes, as with those associated with APAP, can be life-threatening. The mechanism underlying this dangerous iatrogenic effect of APAP was unknown. Approach and Results: Here, we show that intravenous APAP caused transient hypotension in rats, which was attenuated by the Kv7 channel blocker, linopirdine. APAP metabolite N-acetyl-p-benzoquinone imine caused vasodilatation of rat mesenteric arteries ex vivo. This vasodilatation was sensitive to linopirdine and also the calcitonin gene-related peptide antagonist, BIBN 4096. Further investigation revealed N-acetyl-p-benzoquinone imine stimulates calcitonin gene-related peptide release from perivascular nerves, causing a cAMP-dependent activation of Kv7 channels. We also show that N-acetyl-p-benzoquinone imine enhances Kv7.4 and Kv7.5 channels overexpressed in oocytes, suggesting that it can activate Kv7.4 and Kv7.5 channels directly, to elicit vasodilatation. CONCLUSIONS Direct and indirect activation of Kv7 channels by the APAP metabolite N-acetyl-p-benzoquinone imine decreases arterial tone, which can lead to a drop in blood pressure. Our findings provide a molecular mechanism and potential preventive intervention for the clinical phenomenon of intravenous APAP-dependent transient hypotension.
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Affiliation(s)
- Jennifer van der Horst
- From the Vascular Biology Group, Department of Biomedical Science (J.v.d.H., K.H., T.A.J.), University of Copenhagen, Denmark
| | - Rian W Manville
- Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine (R.W.M., G.W.A.)
| | - Katie Hayes
- From the Vascular Biology Group, Department of Biomedical Science (J.v.d.H., K.H., T.A.J.), University of Copenhagen, Denmark
| | - Morten B Thomsen
- Cardiac Electrophysiology Group, Department of Biomedical Science (M.B.T.), University of Copenhagen, Denmark
| | - Geoffrey W Abbott
- Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine (R.W.M., G.W.A.)
| | - Thomas A Jepps
- From the Vascular Biology Group, Department of Biomedical Science (J.v.d.H., K.H., T.A.J.), University of Copenhagen, Denmark
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Nahum E, Weissbach A, Kaplan E, Kadmon G. Hemodynamic effects of intravenous paracetamol in critically ill children with septic shock on inotropic support. J Intensive Care 2020; 8:14. [PMID: 32015882 PMCID: PMC6988254 DOI: 10.1186/s40560-020-0430-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Accepted: 01/15/2020] [Indexed: 12/13/2022] Open
Abstract
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.
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Affiliation(s)
- Elhanan Nahum
- 1Pediatric Intensive Care Unit, Schneider Children's Medical Center of Israel, 14 Kaplan St., 4920235 Petach Tikva, Israel.,2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Avichai Weissbach
- 1Pediatric Intensive Care Unit, Schneider Children's Medical Center of Israel, 14 Kaplan St., 4920235 Petach Tikva, Israel.,2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Eytan Kaplan
- 1Pediatric Intensive Care Unit, Schneider Children's Medical Center of Israel, 14 Kaplan St., 4920235 Petach Tikva, Israel.,2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gili Kadmon
- 1Pediatric Intensive Care Unit, Schneider Children's Medical Center of Israel, 14 Kaplan St., 4920235 Petach Tikva, Israel.,2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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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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Nahum E, Friedman M, Kaplan E, Weissbach A, Kadmon G. The Hemodynamic Effect of Intravenous Paracetamol in Children: A Retrospective Chart Review. Paediatr Drugs 2019; 21:177-183. [PMID: 31155693 DOI: 10.1007/s40272-019-00336-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
AIM Studies in adults have reported frequent episodes of blood pressure drops following intravenous paracetamol administration. We aimed to investigate the hemodynamic effects of intravenous paracetamol in critically ill children. METHODS The charts of 100 pediatric intensive care patients (age range 0.1-18 years) who were treated with intravenous paracetamol between March and September 2017 were retrospectively reviewed. A hemodynamic event was defined as a drop of > 15% in systolic or mean arterial blood pressure within 120 min after drug administration. Hypotension was defined as either a drop in systolic blood pressure (SBP) below the 5th percentile for age or a hemodynamic event associated with tachycardia, increased lactate level, or treatment with a fluid bolus or vasopressors. RESULTS A hemodynamic event was observed in 39 patients (39%). In these patients, SBP was in the pre-hypertension or hypertension values in 36/39 patients before paracetamol administration, median (IQR) SBP decreased from the 99th (95-99) percentile for age before to the 50th (50-95) percentile after paracetamol (p < 0.001) and mean heart rate was 137 bpm before treatment and 115 bpm after (p = 0.002). SBP values did not drop below the 5th percentile in any patient. In 15 patients diagnosed with shock on admission, paracetamol treatment did not cause an increase in vasopressor treatment after drug administration. CONCLUSIONS In the present study of critically ill pediatric patients, intravenous paracetamol administration was associated with a drop in SBP from high to normal values for age, possibly due to pain relief, with no evidence for a negative hemodynamic event.
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Affiliation(s)
- Elhanan Nahum
- Pediatric Intensive Care Unit, Schneider Children's Medical Center in Israel, 14 Kaplan Street, 4920235, Petach Tikva, Israel
| | - Matan Friedman
- Sackler Faculty of Medicine, Tel Aviv University, PC 39040, 69978, Tel Aviv, Israel
| | - Eytan Kaplan
- Pediatric Intensive Care Unit, Schneider Children's Medical Center in Israel, 14 Kaplan Street, 4920235, Petach Tikva, Israel
| | - Avichai Weissbach
- Pediatric Intensive Care Unit, Schneider Children's Medical Center in Israel, 14 Kaplan Street, 4920235, Petach Tikva, Israel
| | - Gili Kadmon
- Pediatric Intensive Care Unit, Schneider Children's Medical Center in Israel, 14 Kaplan Street, 4920235, Petach Tikva, Israel.
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12
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Maxwell EN, Johnson B, Cammilleri J, Ferreira JA. Intravenous Acetaminophen-Induced Hypotension: A Review of the Current Literature. Ann Pharmacother 2019; 53:1033-1041. [PMID: 31046402 DOI: 10.1177/1060028019849716] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
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.
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13
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Olmos M, Varela D, Klein F. ENFOQUE ACTUAL DE LA ANALGESIA, SEDACIÓN Y EL DELIRIUM EN CUIDADOS CRÍTICOS. REVISTA MÉDICA CLÍNICA LAS CONDES 2019. [DOI: 10.1016/j.rmclc.2019.03.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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14
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Nair A. Does mannitol contribute to hypotension after parenteral paracetamol administration in critical care? Anaesthesia 2018; 72:130. [PMID: 27988955 DOI: 10.1111/anae.13768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- A Nair
- Basavatarakam Indo-American Cancer Hospital and Research Institute, Hyderabad, India
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15
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Hanks F, McKenzie C. Paracetamol in intensive care - intravenous, oral or not at all? Anaesthesia 2018; 71:1136-40. [PMID: 27611037 DOI: 10.1111/anae.13517] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- F Hanks
- Critical Care, Guy's and St. Thomas' NHS Foundation Trust, London, UK.,Kings College, London, UK
| | - C McKenzie
- Critical Care, Guy's and St. Thomas' NHS Foundation Trust, London, UK. .,Kings College, London, UK.
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16
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Kang S, Durey A, Suh YJ, Kim AJ. Hemodynamic changes after propacetamol administration in patients with febrile UTI in the ED. Am J Emerg Med 2018; 36:935-941. [DOI: 10.1016/j.ajem.2017.10.054] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Revised: 10/20/2017] [Accepted: 10/24/2017] [Indexed: 11/16/2022] Open
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17
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Chiam E, Bellomo R, Churilov L, Weinberg L. The hemodynamic effects of intravenous paracetamol (acetaminophen) vs normal saline in cardiac surgery patients: A single center placebo controlled randomized study. PLoS One 2018; 13:e0195931. [PMID: 29659631 PMCID: PMC5901786 DOI: 10.1371/journal.pone.0195931] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Accepted: 03/09/2018] [Indexed: 11/18/2022] Open
Abstract
The hemodynamic effects of intravenous (IV) paracetamol in patients undergoing cardiac surgery are unknown. We performed a prospective single center placebo controlled randomized study with parallel group design in adult patients undergoing elective cardiac surgery. Participants received paracetamol (1 gram) IV or placebo (an equal volume of 0.9% saline) preoperatively followed by two postoperative doses 6 hours apart. The primary endpoint was the absolute change in systolic (SBP) 30 minutes after the preoperative infusion, analysed using an ANCOVA model. Secondary endpoints included absolute changes in mean arterial pressure (MAP) and diastolic blood pressure (DPB), and other key hemodynamic variables after each infusion. All other endpoints were analysed using random-effect generalized least squares regression modelling with individual patients treated as random effects. Fifty participants were randomly assigned to receive paracetamol (n = 25) or placebo (n = 25). Post preoperative infusion, paracetamol decreased SBP by a mean (SD) of 13 (18) mmHg, p = 0.02, compared to a mean (SD) of 1 (11) mmHg with saline. Paracetamol decreased MAP and DBP by a mean (SD) of 9 (12) mmHg and 8 (9) mmHg (p = 0.01 and 0.02), respectively, compared to a mean (SD) of 1 (8) mmHg and 0 (6) mmHg with placebo. Postoperatively, there were no significant differences in pressure or flow based hemodynamic parameters in both groups. This study provides high quality evidence that the administration of IV paracetamol in patients undergoing cardiac surgery causes a transient decrease in preoperative blood pressure when administered before surgery but no adverse hemodynamic effects when administered in the postoperative setting.
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Affiliation(s)
- Elizabeth Chiam
- Department of Surgery, The University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia
| | - Rinaldo Bellomo
- Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia
| | - Leonid Churilov
- The Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Heidelberg, Victoria, Australia
| | - Laurence Weinberg
- Department of Surgery, The University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia
- Anesthesia, Perioperative and Pain Medicine, The University of Melbourne, Victoria, Australia
- * E-mail:
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18
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Lee HJ, Suh YJ, Kim AJ, Han SB, Durey A. Hemodynamic changes in patients with influenza A after propacetamol infusion in the emergency department. Am J Emerg Med 2018. [DOI: 10.1016/j.ajem.2017.06.037] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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19
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Bos JC, Mistício MC, Nunguiane G, Mathôt RAA, van Hest RM, Prins JM. Paracetamol clinical dosing routine leads to paracetamol underexposure in an adult severely ill sub-Saharan African hospital population: a drug concentration measurement study. BMC Res Notes 2017; 10:671. [PMID: 29202789 PMCID: PMC5715499 DOI: 10.1186/s13104-017-3016-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 11/28/2017] [Indexed: 12/13/2022] Open
Abstract
Background Hospitals in sub-Saharan Africa (SSA) continue to receive high numbers of severely ill (HIV-infected) patients with physical pain that may suffer from hepatic and renal dysfunction. Paracetamol is widely used for pain relief in this setting but it is unknown whether therapeutic drug concentrations are attained. The aim of this study was to assess the occurrence of therapeutic, sub-therapeutic and toxic paracetamol concentrations in SSA adult hospital population. Methods In a cross-sectional study, plasma paracetamol concentrations were measured in patients with an oral prescription in a referral hospital in Mozambique. From August to November 2015, a maximum of four blood samples were drawn on different time points for paracetamol concentration measurement and biochemical analysis. Study endpoints were the percentage of participants with therapeutic (≥ 10 and ≤ 20 mg/L), sub-therapeutic (< 10 mg/L) and toxic (> 75 mg/L) concentrations. Results Seventy-six patients with a median age of 37 years, a body mass index of 18.2, a haemoglobin concentration of 10.3 g/dL and an albumin of 29 g/L yielded 225 samples. 13.4% of participants had one or more therapeutic paracetamol concentrations. 86.6% had a sub-therapeutic concentration at all time points and 70.2% had two or more concentrations below the lower limit of quantification. No potentially toxic concentrations were found. Conclusions Routine oral dosing practices in a SSA hospital resulted in substantial underexposure to paracetamol. Palliation is likely to be sub-standard and oral palliative drug pharmacokinetics and dispensing procedures in this setting need further investigation.
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Affiliation(s)
- Jeannet C Bos
- Division of Infectious Diseases, Department of Internal Medicine, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
| | - Mabor C Mistício
- Faculty of Health Sciences, Research Centre for Infectious Diseases (CIDI), Catholic University of Mozambique, Rua Marquês do Soveral 960, C.P. 821, Beira, Mozambique
| | - Ginto Nunguiane
- Faculty of Health Sciences, Research Centre for Infectious Diseases (CIDI), Catholic University of Mozambique, Rua Marquês do Soveral 960, C.P. 821, Beira, Mozambique
| | - Ron A A Mathôt
- Division of Clinical Pharmacology, Department of Hospital Pharmacy, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Reinier M van Hest
- Division of Clinical Pharmacology, Department of Hospital Pharmacy, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Jan M Prins
- Division of Infectious Diseases, Department of Internal Medicine, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
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20
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Ray S, Brick T, Raman S, Birrell PJ, Klein NJ, Peters MJ. Haemodynamic changes with paracetamol in critically-ill children. J Crit Care 2017; 40:108-112. [PMID: 28380408 DOI: 10.1016/j.jcrc.2017.03.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 03/22/2017] [Accepted: 03/29/2017] [Indexed: 11/28/2022]
Abstract
PURPOSE Paracetamol has been associated with a reduction in blood pressure, especially in febrile, critically-ill adults. We hypothesised that blood pressure would fall following administration of paracetamol in critically-ill children and this effect would be greater during fever and among children with a high body surface area to weight ratio. METHODS A 12-month prospective observational study of children (0-16years) admitted to paediatric intensive care, who underwent pulse contour analysis and received paracetamol concurrently. RESULTS Mean arterial blood pressure decreased significantly by 4.7% from baseline (95% CI 1.75-8.07%) in 31 children following 148 doses of paracetamol. The nadir was 2-hour post-dose. The effect was pronounced in children with fever at baseline (6.4%, 95% CI 2.8-10%), although this was not statistically significant. There was no simple relationship between this effect and body surface area to weight ratio. The association between a change in blood pressure and changes in heart rate or measured stroke volume was poor; therefore it was likely that a change in the systemic vascular resistance contributes most to this effect. CONCLUSION There is a significant but modest reduction in blood pressure post-paracetamol in critically-ill children. This is likely related to a change in systemic vascular resistance.
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Affiliation(s)
- Samiran Ray
- Paediatric Intensive Care Unit, Great Ormond Street Hospital, London, WC1N 3JH, UK; Respiratory, Anaesthesia and Critical Care Section, UCL Institute of Child Health, London, WC1N 1EH, UK.
| | - Thomas Brick
- Paediatric Intensive Care Unit, Great Ormond Street Hospital, London, WC1N 3JH, UK
| | - Sainath Raman
- Paediatric Intensive Care Unit, Great Ormond Street Hospital, London, WC1N 3JH, UK; Respiratory, Anaesthesia and Critical Care Section, UCL Institute of Child Health, London, WC1N 1EH, UK
| | - Paul J Birrell
- MRC Biostatistics Unit, Institute of Public Health, Cambridge, CB2 0SR, UK
| | - Nigel J Klein
- Infection, Inflammation and Rheumatology Section, UCL Institute of Child Health, London, WC1N 1EH, UK
| | - Mark J Peters
- Paediatric Intensive Care Unit, Great Ormond Street Hospital, London, WC1N 3JH, UK; Respiratory, Anaesthesia and Critical Care Section, UCL Institute of Child Health, London, WC1N 1EH, UK
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21
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Effects of IV Acetaminophen on Core Body Temperature and Hemodynamic Responses in Febrile Critically Ill Adults. Crit Care Med 2017; 45:1199-1207. [DOI: 10.1097/ccm.0000000000002340] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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22
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Fuster-Lluch O, Zapater-Hernández P, Gerónimo-Pardo M. Pharmacokinetic Study of Intravenous Acetaminophen Administered to Critically Ill Multiple-Trauma Patients at the Usual Dosage and a New Proposal for Administration. J Clin Pharmacol 2017; 57:1345-1352. [PMID: 28419483 DOI: 10.1002/jcph.903] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 03/02/2017] [Indexed: 11/11/2022]
Abstract
The pharmacokinetic profile of intravenous acetaminophen administered to critically ill multiple-trauma patients was studied after 4 consecutive doses of 1 g every 6 hours. Eleven blood samples were taken (predose and 15, 30, 45, 60, 90, 120, 180, 240, 300, and 360 minutes postdose), and urine was collected (during 6-hour intervals between doses) to determine serum and urine acetaminophen concentrations. These were used to calculate the following pharmacokinetic parameters: maximum and minimum concentrations, terminal half-life, area under serum concentration-time curve from 0 to 6 hours, mean residence time, volume of distribution, and serum and renal clearance of acetaminophen. Daily doses of acetaminophen required to obtain steady-state minimum (bolus dosing) and average plasma concentrations (continuous infusion) of 10 μg/mL were calculated (10 μg/mL is the presumed lower limit of the analgesic range). Data are expressed as median [interquartile range]. Twenty-two patients were studied, mostly young (age 44 [34-64] years) males (68%), not obese (weight 78 [70-84] kg). Acetaminophen concentrations and pharmacokinetic parameters were these: maximum concentration 33.6 [25.7-38.7] μg/mL and minimum concentration 0.5 [0.2-2.3] μg/mL, all values below 10 μg/mL and 8 below the detection limit; half-life 1.2 [1.0-1.9] hours; area under the curve for 6 hours 34.7 [29.7-52.7] μg·h/mL; mean residence time 1.8 [1.3-2.6] hours; steady-state volume of distribution 50.8 [42.5-66.5] L; and serum and renal clearance 28.8 [18.9-33.7] L/h and 15 [11-19] mL/min, respectively. Theoretically, daily doses for a steady-state minimum concentration of 10 μg/mL would be 12.2 [7.8-16.4] g/day (166 [112-202] mg/[kg·day]); for an average steady-state concentration of 10 μg/mL, they would be 6.9 [4.5-8.1] g/day (91 [59-111] mg/[kg·day]). In conclusion, administration of acetaminophen at the recommended dosage of 1 g per 6 hours to critically ill multiple-trauma patients yields serum concentrations below 10 μg/mL due to increased elimination. To reach the 10 μg/mL target, and from a strictly pharmacokinetic point of view, continuous infusion may be more feasible than bolus dosing. Such a change in dosing strategy requires appropriate, pharmacokinetic-pharmacodynamic and specific safety study.
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Affiliation(s)
- Oscar Fuster-Lluch
- Clinical Chemistry Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | | | - Manuel Gerónimo-Pardo
- Department of Anesthesiology, Resuscitation and Pain Therapy, Complejo Hospitalario Universitario, Albacete, Spain
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23
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Bae JI, Ahn S, Lee YS, Kim WY, Lee JH, Oh BJ, Lim KS. Clinically significant hemodynamic alterations after propacetamol injection in the emergency department: prevalence and risk factors. Intern Emerg Med 2017; 12:349-355. [PMID: 27165165 DOI: 10.1007/s11739-016-1460-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 04/28/2016] [Indexed: 10/21/2022]
Abstract
Propacetamol, a water-soluble prodrug form of paracetamol, is hydrolyzed by esterase to generate paracetamol in the blood. Each gram of propacetamol is equal to 0.5 g of paracetamol. It has been reported to cause hypotension in critically ill patients with a fever. We aimed to investigate the hemodynamic effects of propacetamol for the control of fever in patients with diverse severities of illness who were managed in the emergency department (ED). We also aimed to identify clinical factors related to significant hemodynamic alterations in ED patients. This was a retrospective study of 1507 ED patients who received propacetamol. Significant hemodynamic alterations were defined as systolic blood pressure (SBP) <90 mmHg or diastolic blood pressure (DBP) <60 mmHg, or a drop in SBP >30 mmHg, which required treatments with a bolus of fluid or vasopressor administration. Postinfusion SBP and DBP were significantly lower than the preinfusion SBP and DBP. A clinically significant drop in BP occurred in 162 (10.7 %) patients, and interventions were necessary. Among the predictors assessed, congestive heart failure (OR 6.21, 95 % CI 2.67-14.45) and chills (OR 3.10, 95 % CI 2.04-4.70) were independent factors for a significant hemodynamic change. Administration of propacetamol can provoke a reduction in BP in ED patients. This reduction was clinically significant for 10 % of infusions. Clinicians should be aware of this potential deleterious effect, especially in patients with congestive heart failure or who experience chills prior to the administration of propacetamol.
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Affiliation(s)
- June-Il Bae
- Department of Emergency Medicine, Asan Medical Center, College of Medicine, University of Ulsan, 388-1, Pungnap-dong, Songpa-gu, Seoul, 138-736, Korea
| | - Shin Ahn
- Department of Emergency Medicine, Asan Medical Center, College of Medicine, University of Ulsan, 388-1, Pungnap-dong, Songpa-gu, Seoul, 138-736, Korea.
| | - Yoon-Seon Lee
- Department of Emergency Medicine, Asan Medical Center, College of Medicine, University of Ulsan, 388-1, Pungnap-dong, Songpa-gu, Seoul, 138-736, Korea
| | - Won Young Kim
- Department of Emergency Medicine, Asan Medical Center, College of Medicine, University of Ulsan, 388-1, Pungnap-dong, Songpa-gu, Seoul, 138-736, Korea
| | - Jae Ho Lee
- Department of Emergency Medicine, Asan Medical Center, College of Medicine, University of Ulsan, 388-1, Pungnap-dong, Songpa-gu, Seoul, 138-736, Korea
| | - Bum Jin Oh
- Department of Emergency Medicine, Asan Medical Center, College of Medicine, University of Ulsan, 388-1, Pungnap-dong, Songpa-gu, Seoul, 138-736, Korea
| | - Kyung Soo Lim
- Department of Emergency Medicine, Asan Medical Center, College of Medicine, University of Ulsan, 388-1, Pungnap-dong, Songpa-gu, Seoul, 138-736, Korea
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24
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Lee HY, Ban GY, Jeong CG, Lee JH, Park SH, Kim SH, Lee YH, Ye YM. Propacetamol poses a potential harm of adverse hypotension in male and older patients. Pharmacoepidemiol Drug Saf 2017; 26:256-264. [DOI: 10.1002/pds.4159] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 12/02/2016] [Indexed: 12/17/2022]
Affiliation(s)
- Hyun-Young Lee
- Department of Statistics, Clinical Trial Center; Ajou University Medical Center; Korea
| | - Ga-Young Ban
- Department of Allergy and Clinical Immunology; Ajou University School of Medicine; Korea
- Regional Pharmacovigilance Center; Ajou University Medical Center; Suwon Korea
| | - Chang-Gyu Jeong
- Department of Allergy and Clinical Immunology; Ajou University School of Medicine; Korea
- Regional Pharmacovigilance Center; Ajou University Medical Center; Suwon Korea
| | - Ji-Ho Lee
- Department of Allergy and Clinical Immunology; Ajou University School of Medicine; Korea
- Regional Pharmacovigilance Center; Ajou University Medical Center; Suwon Korea
| | - Seung-Hee Park
- Regional Pharmacovigilance Center; Ajou University Medical Center; Suwon Korea
| | - Sang-Hee Kim
- Regional Pharmacovigilance Center; Ajou University Medical Center; Suwon Korea
| | - Young-Hee Lee
- Regional Pharmacovigilance Center; Ajou University Medical Center; Suwon Korea
| | - Young-Min Ye
- Department of Allergy and Clinical Immunology; Ajou University School of Medicine; Korea
- Regional Pharmacovigilance Center; Ajou University Medical Center; Suwon Korea
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25
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Acetaminophen-Induced Changes in Systemic Blood Pressure in Critically Ill Patients. Crit Care Med 2016; 44:2192-2198. [DOI: 10.1097/ccm.0000000000001954] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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26
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Ehieli E, Yalamuri S, Brudney CS, Pyati S. Analgesia in the surgical intensive care unit. Postgrad Med J 2016; 93:38-45. [PMID: 27777355 DOI: 10.1136/postgradmedj-2016-134047] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 07/10/2016] [Accepted: 08/27/2016] [Indexed: 01/30/2023]
Abstract
Critically ill patients are a heterogeneous group with diverse comorbidities and physiological derangements. The management of pain in the critically ill population is emerging as a standard of care in the intensive care unit (ICU). Pain control of critically ill patients in the ICU presents numerous challenges to intensivists. Inconsistencies in pain assessment, analgesic prescription and variation in monitoring sedation and analgesia result in suboptimal pain management. Inadequate pain control can have deleterious effects on several organ systems in critically ill patients. Therefore, it becomes incumbent on physicians and nurses caring for these patients to carefully evaluate their practice on pain management and adopt an optimal pain management strategy that includes a reduction in noxious stimuli, adequate analgesia and promoting education regarding sedation and analgesia to the ICU staff. Mechanistic approaches and multimodal analgesic techniques have been clearly demonstrated to be the most effective pain management strategy to improve outcomes. For example, recent evidence suggests that the use of short acting analgesics and analgesic adjuncts for sedation is superior to hypnotic based sedation in intubated patients. This review will address analgesia in the ICU, including opioid therapy, adjuncts, regional anaesthesia and non-pharmacological options that can provide a multimodal approach to treating pain.
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Affiliation(s)
- Eric Ehieli
- Department of Anesthesiology, Duke University Medical Center, Surgical Intensive Care Unit, Veterans Affairs Medical Center, Durham, North Carolina, USA
| | - Suraj Yalamuri
- Department of Anesthesiology, Duke University Medical Center, Surgical Intensive Care Unit, Veterans Affairs Medical Center, Durham, North Carolina, USA
| | - Charles S Brudney
- Department of Anesthesiology, Duke University Medical Center, Surgical Intensive Care Unit, Veterans Affairs Medical Center, Durham, North Carolina, USA
| | - Srinivas Pyati
- Department of Anesthesiology, Duke University Medical Center, Surgical Intensive Care Unit, Veterans Affairs Medical Center, Durham, North Carolina, USA
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27
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Kelly SJ, Moran JL, Williams PJ, Burns K, Rowland A, Miners JO, Peake SL. Haemodynamic effects of parenteral vs. enteral paracetamol in critically ill patients: a randomised controlled trial. Anaesthesia 2016; 71:1153-62. [DOI: 10.1111/anae.13562] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2016] [Indexed: 11/30/2022]
Affiliation(s)
- S. J. Kelly
- Department of Intensive Medicine; The Queen Elizabeth Hospital; Woodville South South Australia Australia
| | - J. L. Moran
- Department of Intensive Medicine; The Queen Elizabeth Hospital; Woodville South South Australia Australia
- School of Medicine; University of Adelaide; Adelaide South Australia Australia
| | - P. J. Williams
- Department of Intensive Medicine; The Queen Elizabeth Hospital; Woodville South South Australia Australia
- School of Medicine; University of Adelaide; Adelaide South Australia Australia
- School of Epidemiology and Preventive Medicine; Monash University; Melbourne Victoria Australia
| | - K. Burns
- Department of Clinical Pharmacology; Flinders University; School of Medicine; Bedford Park South Australia Australia
| | - A. Rowland
- Department of Clinical Pharmacology; Flinders University; School of Medicine; Bedford Park South Australia Australia
| | - J. O. Miners
- Department of Clinical Pharmacology; Flinders University; School of Medicine; Bedford Park South Australia Australia
| | - S. L. Peake
- Department of Intensive Medicine; The Queen Elizabeth Hospital; Woodville South South Australia Australia
- School of Medicine; University of Adelaide; Adelaide South Australia Australia
- School of Epidemiology and Preventive Medicine; Monash University; Melbourne Victoria Australia
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Ortlepp JR, Luethje F, Walz R. [Analgesia in intensive care medicine]. Med Klin Intensivmed Notfmed 2016; 111:6-13. [PMID: 26815840 DOI: 10.1007/s00063-015-0127-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 10/22/2015] [Accepted: 11/02/2015] [Indexed: 11/30/2022]
Abstract
BACKGROUND The administration of sedatives and analgesics on the intensive care unit (ICU) is routine daily practice. The correct discrimination between delirium, pain and anxiety or confusion is essential for the strategy and selection of medication. The correct pain therapy and sedation are essential for patient quality of life on the ICU and for the prognosis. OBJECTIVE The aim of this article is to present state of the art recommendations on the classification of pain and pain therapy on the ICU. MATERIAL AND METHODS An online search was carried out in PubMed for publications on the topics of "pain" and "ICU". RESULTS Critical care patients are frequently subjected to many procedures and situations which can cause pain. The perception of pain is, among other things, influenced by the degree of orientation, anxiety and the degree of sedation. The administration of analgesics and non-pharmacological approaches are effective in reducing the stress perceived by patients. DISCUSSION The main aim is improvement in the awareness of nursing and medical personnel for pain inducers and pain perception in ICU patients. The classification of pain must be made objectively. Therapeutic targets must be defined and in addition to the correct selection of pain medication, non-pharmacological approaches must also be consistently implemented.
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Affiliation(s)
- J R Ortlepp
- Klinik für Innere Medizin und Intensivmedizin, Asklepios Kliniken Schildautal, Karl-Herold-Str. 1, 38723, Seesen, Deutschland.
| | - F Luethje
- Internistische Intensivstation, Klinik für Innere Medizin und Intensivmedizin, Asklepios Kliniken Schildautal, Seesen, Deutschland
| | - R Walz
- Klinik für Anästhesiologie, Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland
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Chiam E, Weinberg L, Bailey M, McNicol L, Bellomo R. The haemodynamic effects of intravenous paracetamol (acetaminophen) in healthy volunteers: a double-blind, randomized, triple crossover trial. Br J Clin Pharmacol 2016; 81:605-12. [PMID: 26606263 DOI: 10.1111/bcp.12841] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Revised: 11/17/2015] [Accepted: 11/18/2015] [Indexed: 11/29/2022] Open
Abstract
AIM 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% in healthy volunteers. METHODS We performed a blinded, triple crossover, randomized trial of 24 adult healthy volunteers. Participants received i.v. paracetamol (1 g paracetamol +3.91 g mannitol 100 ml(-1) ), i.v. mannitol (3.91 g mannitol 100 ml(-1) ) and i.v. normal saline (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 min infusion period and over a 45 min observation period. Systemic vascular resistance index (SVRI) and cardiac index 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 -1.85 mmHg, 95% CI -2.6, -1.1, SBP -0.54 mmHg, 95% CI -1.7, 0.6 and DBP -1.92 mmHg, 95% CI -2.6, -1.2, P < 0.0001), associated with a transient reduction in SVRI and an increase in cardiac index. Changes were observed, but to a lesser extent with normal saline (MAP -0.15 mmHg, SBP +1.44 mmHg, DBP --0.73 mmHg, P < 0.0001), but not with mannitol (MAP +1.47 mmHg, SBP +4.03 mmHg, DBP +0.48 mmHg, P < 0.0001). CONCLUSIONS I.v. paracetamol caused a transient decrease in blood pressure immediately after infusion. These effects were not seen with mannitol or normal saline. 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 i.v. paracetamol and justifies controlled studies in the peri-operative and critical care setting.
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Affiliation(s)
- Elizabeth Chiam
- Department of Surgery, The University of Melbourne, Victoria
| | - Laurence Weinberg
- Department of Surgery and Centre for Anesthesia, Perioperative and Pain Medicine, The University of Melbourne, Victoria
| | - Michael Bailey
- Department of Epidemiology and Preventive Medicine, Monash University, Victoria
| | - Larry McNicol
- Department of Surgery, The University of Melbourne, Victoria.,Department of Anesthesia, Austin Hospital, The University of Melbourne, Victoria
| | - Rinaldo Bellomo
- The University of Melbourne, Victoria.,Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia
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Pacifici GM, Allegaert K. Clinical pharmacology of paracetamol in neonates: a review. CURRENT THERAPEUTIC RESEARCH 2015; 77:24-30. [PMID: 25709719 PMCID: PMC4329422 DOI: 10.1016/j.curtheres.2014.12.001] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 12/03/2014] [Indexed: 11/22/2022]
Abstract
Paracetamol is commonly used to control mild-to-moderate pain or to reduce opioid exposure as part of multimodal analgesia, and is the only compound recommended to treat fever in neonates. Paracetamol clearance is lower in neonates than in children and adults. After metabolic conversion, paracetamol is subsequently eliminated by the renal route. The main metabolic conversions are conjugation with glucuronic acid and with sulphate. In the urine of neonates sulphated paracetamol concentration is higher than the glucuronidated paracetamol level, suggesting that sulfation prevails over glucuronidation in neonates. A loading dose of 20 mg/kg followed by 10 mg/kg every 6 hours of intravenous paracetamol is suggested to achieve a compartment concentration of 11 mg/L in late preterm and term neonates. Aiming for the same target concentration, oral doses are similar with rectal administration of 25 to 30 mg/kg/d in preterm neonates of 30 weeks' gestation, 45 mg/kg/d in preterm infants of 34 weeks' gestation, and 60 mg/kg/d in term neonates are suggested. The above-mentioned paracetamol doses for these indications (pain, fever) are well tolerated in neonates, but do not result in a significant increase in liver enzymes, and do not affect blood pressure and have limited effects on heart rate. In contrast, the higher doses suggested in extreme preterm neonates to induce closure of the patent ductus arteriosus have not yet been sufficiently evaluated regarding efficacy or safety. Moreover, focussed pharmacovigilance to explore the potential causal association between paracetamol exposure during perinatal life and infancy and subsequent atopy is warranted.
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Affiliation(s)
- Gian Maria Pacifici
- Translational Department and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Karel Allegaert
- Neonatal Intensive Care Unit, Division of Woman and Child, University Hospitals Leuven, Leuven, Belgium
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31
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Messerer B, Grögl G, Stromer W, Jaksch W. [Pediatric perioperative systemic pain therapy: Austrian interdisciplinary recommendations on pediatric perioperative pain management]. Schmerz 2015; 28:43-64. [PMID: 24550026 DOI: 10.1007/s00482-013-1384-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND Many analgesics used in adult medicine are not licensed for pediatric use. Licensing limitations do not, however, justify that children are deprived of a sufficient pain therapy particularly in perioperative pain therapy. The treatment is principally oriented to the strength of the pain. Due to the degree of pain caused, intramuscular and subcutaneous injections should be avoided generally. NON-OPIOIDS The basis of systemic pain therapy for children are non-opioids and primarily non-steroidal anti-inflammatory drugs (NSAIDs). They should be used prophylactically. The NSAIDs are clearly more effective than paracetamol for acute posttraumatic and postoperative pain and additionally allow economization of opioids. Severe side effects are rare in children but administration should be carefully considered especially in cases of hepatic and renal dysfunction or coagulation disorders. Paracetamol should only be taken in pregnancy and by children when there are appropriate indications because a possible causal connection with bronchial asthma exists. To ensure a safe dosing the age, body weight, duration of therapy, maximum daily dose and dosing intervals must be taken into account. Dipyrone is used in children for treatment of visceral pain and cholic. According to the current state of knowledge the rare but severe side effect of agranulocytosis does not justify a general rejection for short-term perioperative administration. OPIOIDS In cases of insufficient analgesia with non-opioid analgesics, the complementary use of opioids is also appropriate for children of all age groups. They are the medication of choice for episodes of medium to strong pain and are administered in a titrated form oriented to effectiveness. If severe pain is expected to last for more than 24 h, patient-controlled anesthesia should be implemented but requires a comprehensive surveillance by nursing personnel. KETAMINE Ketamine is used as an adjuvant in postoperative pain therapy and is recommended for use in pediatric sedation and analgosedation.
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Affiliation(s)
- B Messerer
- Universitätsklinik für Anästhesiologie und Intensivmedizin, Medizinische Universität Graz, LKH-Universitätsklinikum Graz, Auenbruggerplatz 29, 8036, Graz, Österreich,
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Intravenous paracetamol for fever control in acute brain injury patients: cerebral and hemodynamic effects. Acta Neurochir (Wien) 2014; 156:1953-9; discussion 1959. [PMID: 24838770 DOI: 10.1007/s00701-014-2129-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Accepted: 05/02/2014] [Indexed: 10/25/2022]
Abstract
BACKGROUND Fever occurs frequently in acute brain injury patients, and its occurrence is associated with poorer outcomes. Paracetamol, an antipyretic frequently employed in patients with cerebral damage, may cause hypotension. We evaluated the cerebral and hemodynamic effects of intravenous (IV) paracetamol for the control of fever in Neuro-Intensive Care Unit (NICU) patients. METHODS This is a prospective observational study in which we enrolled 32 NICU patients: Subarachnoid Hemorrhage (SAH, n = 18), Traumatic Brain Injury (TBI, n = 10), Intracerebral Hemorrhage (ICH, n = 2) and Acute Ischemic Stroke (AIS, n = 2). RESULTS The administration of paracetamol resulted in a decrease of core body temperature (Tc) (p = 0,0001), mean arterial pressure (MAP) (p = 0,0006), cerebral perfusion pressure (CPP) (p = 0,0033), and jugular venous oxygen saturation (SjVO2) (p = 0.0193), and in an increase of arteriojugular venous differences of oxygen (AVDO2) (p = 0.0012). The proportion of patients who had an infusion of norepinephrine increased from 47 % to 75 % (p = 0.0039 McNemar Test). When intracranial pressure (ICP) at the start of paracetamol infusion (t-0) was compared with the measurement of ICP after 2 h, a significant correlation was observed (r = 0.669, p = 0.0002). This marked and significant correlation can be explained by the fact that for the higher levels of ICP assessed at t-0 (greater than 15 mmHg), we observed a marked reduction of ICP concomitant with the decrease of Tc. No problems related to norepinephrine administration and/or increase in dosage were observed. CONCLUSION Paracetamol administration is effective but exposes patients to hypotensive episodes that must be recognized and treated expeditiously to prevent further damage to the injured brain.
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Allegaert K, Olkkola KT, Owens KH, Van de Velde M, de Maat MM, Anderson BJ. Covariates of intravenous paracetamol pharmacokinetics in adults. BMC Anesthesiol 2014; 14:77. [PMID: 25342929 PMCID: PMC4165439 DOI: 10.1186/1471-2253-14-77] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2014] [Accepted: 09/11/2014] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Pharmacokinetic estimates for intravenous paracetamol in individual adult cohorts are different to a certain extent, and understanding the covariates of these differences may guide dose individualization. In order to assess covariate effects of intravenous paracetamol disposition in adults, pharmacokinetic data on discrete studies were pooled. METHODS This pooled analysis was based on 7 studies, resulting in 2755 time-concentration observations in 189 adults (mean age 46 SD 23 years; weight 73 SD 13 kg) given intravenous paracetamol. The effects of size, age, pregnancy and other clinical settings (intensive care, high dependency, orthopaedic or abdominal surgery) on clearance and volume of distribution were explored using non-linear mixed effects models. RESULTS Paracetamol disposition was best described using normal fat mass (NFM) with allometric scaling as a size descriptor. A three-compartment linear disposition model revealed that the population parameter estimates (between subject variability,%) were central volume (V1) 24.6 (55.5%) L/70 kg with peripheral volumes of distribution V2 23.1 (49.6%) L/70 kg and V3 30.6 (78.9%) L/70 kg. Clearance (CL) was 16.7 (24.6%) L/h/70 kg and inter-compartment clearances were Q2 67.3 (25.7%) L/h/70 kg and Q3 2.04 (71.3%) L/h/70 kg. Clearance and V2 decreased only slightly with age. Sex differences in clearance were minor and of no significance. Clearance, relative to median values, was increased during pregnancy (F(PREG) = 1.14) and decreased during abdominal surgery (F(ABDCL) = 0.715). Patients undergoing orthopaedic surgery had a reduced V2 (F(ORTHOV) = 0.649), while those in intensive care had increased V2 (F(ICV) = 1.51). CONCLUSIONS Size and age are important covariates for paracetamol pharmacokinetics explaining approximately 40% of clearance and V2 variability. Dose individualization in adult subpopulations would achieve little benefit in the scenarios explored.
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Affiliation(s)
- Karel Allegaert
- Department of Development and Regeneration, KU Leuven, Leuven, Belgium
- Neonatal Intensive Care Unit, University Hospitals Leuven, Herestraat 49, Leuven, Belgium
| | - Klaus T Olkkola
- Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
| | - Katie H Owens
- School of Pharmacy, University of Otago, Dunedin, New Zealand
| | - Marc Van de Velde
- Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
- Department of Anaesthesiology, University Hospital Leuven, Leuven, Belgium
| | - Monique M de Maat
- Department of Clinical Pharmacy, Rijnstate Hospital Arnhem, Arnhem, The Netherlands
| | - Brian J Anderson
- Department of Anaesthesiology, University of Auckland, Auckland, New Zealand
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Giamarellos-Bourboulis EJ, Spyridaki A, Savva A, Georgitsi M, Tsaganos T, Mouktaroudi M, Raftogiannis M, Antonopoulou A, Papaziogas V, Baziaka F, Sereti K, Christopoulos P, Marioli A, Kanni T, Maravitsa P, Pantelidou I, Leventogiannis K, Tsiaoussis P, Lymberopoulou K, Koutelidakis IM. Intravenous paracetamol as an antipyretic and analgesic medication: the significance of drug metabolism. J Pharmacol Sci 2014; 124:144-52. [PMID: 24553403 DOI: 10.1254/jphs.13133fp] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
One prospective, open-label, non-randomized study was conducted in 100 patients to define the antipyretic and analgesic effect of a new intravenous formulation of 1 g of paracetamol; 71 received paracetamol for the management of fever and 29 received paracetamol for pain relief after abdominal surgery or for neoplastic pain. Serial follow-up measurements of core temperature and of pain intensity were done for 6 h. Additional rescue medications were recorded for 5 days. Blood was sampled for the measurement of free paracetamol (APAP) and of glucuronide-APAP and N-sulfate-APAP by an HPLC assay. Defervescence, defined as core temperature below or equal to 37.1°C, was achieved in 52 patients (73.2%) within a median time of 3 h. Patients failing to become afebrile with the first dose of paracetamol became afebrile when administered other agents as rescue medications. Analgesia was achieved in 25 patients (86.4%) within a median time of 2 h. Serum levels of glucuronide-APAP were greater among non-responders to paracetamol. The presented results suggest that the intravenous formulation of paracetamol is clinically effective depending on drug metabolism.
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35
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Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF. The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology 2013; 21:201-32. [PMID: 23719833 DOI: 10.1007/s10787-013-0172-x] [Citation(s) in RCA: 358] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 04/18/2013] [Indexed: 02/06/2023]
Abstract
Paracetamol is used worldwide for its analgesic and antipyretic actions. It has a spectrum of action similar to that of NSAIDs and resembles particularly the COX-2 selective inhibitors. Paracetamol is, on average, a weaker analgesic than NSAIDs or COX-2 selective inhibitors but is often preferred because of its better tolerance. Despite the similarities to NSAIDs, the mode of action of paracetamol has been uncertain, but it is now generally accepted that it inhibits COX-1 and COX-2 through metabolism by the peroxidase function of these isoenzymes. This results in inhibition of phenoxyl radical formation from a critical tyrosine residue essential for the cyclooxygenase activity of COX-1 and COX-2 and prostaglandin (PG) synthesis. Paracetamol shows selectivity for inhibition of the synthesis of PGs and related factors when low levels of arachidonic acid and peroxides are available but conversely, it has little activity at substantial levels of arachidonic acid and peroxides. The result is that paracetamol does not suppress the severe inflammation of rheumatoid arthritis and acute gout but does inhibit the lesser inflammation resulting from extraction of teeth and is also active in a variety of inflammatory tests in experimental animals. Paracetamol often appears to have COX-2 selectivity. The apparent COX-2 selectivity of action of paracetamol is shown by its poor anti-platelet activity and good gastrointestinal tolerance. Unlike both non-selective NSAIDs and selective COX-2 inhibitors, paracetamol inhibits other peroxidase enzymes including myeloperoxidase. Inhibition of myeloperoxidase involves paracetamol oxidation and concomitant decreased formation of halogenating oxidants (e.g. hypochlorous acid, hypobromous acid) that may be associated with multiple inflammatory pathologies including atherosclerosis and rheumatic diseases. Paracetamol may, therefore, slow the development of these diseases. Paracetamol, NSAIDs and selective COX-2 inhibitors all have central and peripheral effects. As is the case with the NSAIDs, including the selective COX-2 inhibitors, the analgesic effects of paracetamol are reduced by inhibitors of many endogenous neurotransmitter systems including serotonergic, opioid and cannabinoid systems. There is considerable debate about the hepatotoxicity of therapeutic doses of paracetamol. Much of the toxicity may result from overuse of combinations of paracetamol with opioids which are widely used, particularly in USA.
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Affiliation(s)
- Garry G Graham
- Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, University of New South Wales, Sydney, Australia.
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Allegaert K. Clinical pharmacology of intravenous paracetamol in perinatal medicine. World J Anesthesiol 2013; 2:1-7. [DOI: 10.5313/wja.v2.i1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2012] [Accepted: 04/16/2013] [Indexed: 02/06/2023] Open
Abstract
Clinical pharmacology aims to predict drug-related effects based on compound and population specific pharmacokinetics (PK, concentration-time), and pharmacodynamics (PD, concentration-effect). Consequently, dosing needs to be based on the physiological characteristics of the individual patient. Pregnancy and early infancy hereby warrant focused assessment. The specific characteristics of both subpopulations will be illustrated based on observations on intravenous (iv) paracetamol PK and PD collected in these specific populations. At delivery, there is a significant higher paracetamol clearance (+ 45%, L/h) when compared to non-pregnant observations. This higher clearance is in part explained by a proportional increase in oxidative metabolite production, but mainly an increase in glucuronidation. When focusing on PD, an association between maternal paracetamol exposure and atopy in infancy and fetal gastroshizis has been reported. In early infancy, paracetamol clearance is significantly lower and mainly depends on size (weight 0.75), while also the distribution volume is higher (L/kg). Reports on hepatic tolerance, haemodynamic stability and impact of body temperature have been published while the concentration effect profile for analgesia seems to be similar between neonates and children. Similar to maternal exposure, there are reports on the association with atopy. Studies on the use of paracetamol to close the patent ductus arteriosus are ongoing. At least, these observations provide evidence on the need to study commonly administered anesthetics in such specific subpopulations with specific focus on both population specific PK and PD to further improve patient tailored pharmacotherapy.
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Pogatzki-Zahn EM, Schnabel A, Zahn PK. Room for improvement: unmet needs in postoperative pain management. Expert Rev Neurother 2012; 12:587-600. [PMID: 22550987 DOI: 10.1586/ern.12.30] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Postoperative pain treatment is an important healthcare issue. However, the management of pain in patients after surgery remains insufficient. In the present review, several key areas important for postoperative pain management are discussed. New findings about efficacy and side effects of nonopioid analgesics, such as paracetamol, NSAIDs and COX-2 inhibitors, are presented and discussed in light of acute, short-term application in the perioperative period. Second, new findings about postoperative pain management in patients with preoperative pain and chronic opioid consumption are reported. Third, feasibility of the transversus abdominal plane block as a new and promising regional anesthesia technique is discussed. Finally, potential predictors, mechanisms and preventive treatment strategies of persistent chronic pain after surgery are presented.
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Affiliation(s)
- Esther M Pogatzki-Zahn
- Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital of Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149 Muenster, Germany.
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Allegaert K, van den Anker J. Pharmacokinetics and pharmacodynamics of intravenous acetaminophen in neonates. Expert Rev Clin Pharmacol 2012; 4:713-8. [PMID: 22111857 DOI: 10.1586/ecp.11.50] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
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.
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Affiliation(s)
- Karel Allegaert
- Neonatal Intensive Care Unit, University Hospitals Leuven, Belgium.
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Krajčová A, Matoušek V, Duška F. Mechanism of paracetamol-induced hypotension in critically ill patients: a prospective observational cross-over study. Aust Crit Care 2012; 26:136-41. [PMID: 22424816 DOI: 10.1016/j.aucc.2012.02.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2011] [Revised: 02/05/2012] [Accepted: 02/14/2012] [Indexed: 11/27/2022] Open
Abstract
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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Affiliation(s)
- Adéla Krajčová
- 3rd Faculty of Medicine, Charles University, Prague, Czech Republic.
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Ortner C, Steiner I, Margeta K, Schulz M, Gustorff B. Dose response of tramadol and its combination with paracetamol in
UVB
induced hyperalgesia. Eur J Pain 2012; 16:562-73. [DOI: 10.1016/j.ejpain.2011.08.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- C.M. Ortner
- Department of AnesthesiologyGeneral Intensive Care and Pain ControlVienna Human Pain Research GroupMedical University Vienna Vienna Austria
- Department of Anesthesiology and Pain MedicineUniversity of Washington Seattle WA USA
| | - I. Steiner
- Institute for Medical StatisticsMedical University Vienna Vienna Austria
| | - K. Margeta
- Department of AnesthesiologyGeneral Intensive Care and Pain ControlVienna Human Pain Research GroupMedical University Vienna Vienna Austria
| | - M. Schulz
- Department of AnesthesiologyGeneral Intensive Care and Pain ControlVienna Human Pain Research GroupMedical University Vienna Vienna Austria
| | - B. Gustorff
- Department of AnesthesiologyGeneral Intensive Care and Pain ControlVienna Human Pain Research GroupMedical University Vienna Vienna Austria
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41
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Zahn P, Sabatowski R, Schug S, Stamer U, Pogatzki-Zahn E. Paracetamol für die perioperative Analgesie. Anaesthesist 2010; 59:940-52. [DOI: 10.1007/s00101-010-1773-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Allegaert K, Naulaers G. Haemodynamics of intravenous paracetamol in neonates. Eur J Clin Pharmacol 2010; 66:855-8. [PMID: 20607221 DOI: 10.1007/s00228-010-0860-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2010] [Accepted: 06/17/2010] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Reports on the haemodynamics of intravenous (iv) paracetamol in adult intensive care were recently published. We therefore wanted to explore the haemodynamics of iv paracetamol in neonates. METHODS Retrospective, pooled analysis of heart rate (bpm) and blood pressure (mean, systolic, diastolic) observations collected during iv paracetamol pharmacokinetic studies in neonates. Heart rate and blood pressure were recorded just before and 30, 60, 120, 180, 240, 300 and 360 min after iv paracetamol (paired, ANOVA). Clinical characteristics in hypotensive (mean mmHg < gestational age, weeks) cases were compared with controls (Mann-Whitney U test). RESULTS Based on observations in 72 neonates, heart rate decreased from 145 (SD 20) to 138 (21), 141 (20), 137 (20), 137 (22), 140 (20), 139 (20) and 140 (21) bpm (paired p < 0.05, ANOVA p = 0.36). There were no changes in systolic and diastolic pressure, but mean arterial pressure decreased from 46 (7) to 43 (8) mmHg at 60 min (paired p < 0.05, ANOVA p = 0.75). Eight neonates developed hypotension. These patients had lower pre-administration arterial pressure (38 vs 47 mmHg, p < 0.05). CONCLUSIONS In a setting of open label administration to alleviate (procedural) pain, haemodynamic effects of iv paracetamol in neonates remained modest. We suggest considering impaired haemodynamics to be a relative contra-indication for iv paracetamol in neonates.
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Affiliation(s)
- Karel Allegaert
- Neonatal Intensive Care Unit, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.
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