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1.  Correction: PAIS: paracetamol (acetaminophen) in stroke; protocol for a randomized, double blind clinical trial. [ISCRTN74418480] 
The Paracetamol (Acetaminophen) In Stroke (PAIS) study is a phase III multicenter, double blind, randomized, placebo-controlled clinical trial of high-dose acetaminophen in patients with acute stroke. The trial compares treatment with a daily dose of 6 g acetaminophen, started within 12 hours after the onset of symptoms, with matched placebo. The purpose of this study is to assess whether treatment with acetaminophen for 3 days will result in improved functional outcome through a modest reduction in body temperature and prevention of fever.
The previously planned statistical analysis based on a dichotomization of the scores on the modified Rankin Scale (mRS) may not make the most efficient use of the available baseline information. Therefore, the planned primary analysis of the PAIS study has been changed from fixed dichotomization of the mRS to a sliding dichotomy analysis.
Instead of taking a single definition of good outcome for all patients, the definition is tailored to each individual patient's baseline prognosis on entry into the trial.
The protocol change was initiated because of both advances in statistical approaches and to increase the efficiency of the trial by improving statistical power.
Trial Registration
Current Controlled Trials [ISCRTN74418480]
PMCID: PMC2600816  PMID: 18983661
2.  Effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute ischemic stroke PISA, a phase II double-blind, randomized, placebo-controlled trial [ISRCTN98608690] 
Body temperature is a strong predictor of outcome in acute stroke. In a previous randomized trial we observed that treatment with high-dose acetaminophen (paracetamol) led to a reduction of body temperature in patients with acute ischemic stroke, even when they had no fever. The purpose of the present trial was to study whether this effect of acetaminophen could be reproduced, and whether ibuprofen would have a similar, or even stronger effect.
Seventy-five patients with acute ischemic stroke confined to the anterior circulation were randomized to treatment with either 1000 mg acetaminophen, 400 mg ibuprofen, or placebo, given 6 times daily during 5 days. Treatment was started within 24 hours from the onset of symptoms. Body temperatures were measured at 2-hour intervals during the first 24 hours, and at 6-hour intervals thereafter.
No difference in body temperature at 24 hours was observed between the three treatment groups. However, treatment with high-dose acetaminophen resulted in a 0.3°C larger reduction in body temperature from baseline than placebo treatment (95% CI: 0.0 to 0.6 °C). Acetaminophen had no significant effect on body temperature during the subsequent four days compared to placebo, and ibuprofen had no statistically significant effect on body temperature during the entire study period.
Treatment with a daily dose of 6000 mg acetaminophen results in a small, but potentially worthwhile decrease in body temperature after acute ischemic stroke, even in normothermic and subfebrile patients. Further large randomized clinical trials are needed to study whether early reduction of body temperature leads to improved outcome.
PMCID: PMC152640  PMID: 12657165
3.  PISA. The effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute stroke: Protocol for a phase II double-blind randomised placebo-controlled trial [ISRCTN98608690] 
During the first days after stroke, one to two fifths of the patients develop fever or subfebrile temperatures. Body temperature is a strong prognostic factor after stroke. Pharmacological reduction of temperature in patients with acute ischaemic stroke may improve their functional outcome. Previously, we studied the effect of high dose (6 g daily) and low dose (3 g daily) paracetamol (acetaminophen) in a randomised placebo-controlled trial of 75 patients with acute ischemic stroke. In the high-dose paracetamol group, mean body temperature at 12 and 24 hours after start of treatment was 0.4°C lower than in the placebo group. The effect of ibuprofen, another potent antipyretic drug, on body-core temperature in normothermic patients has not been studied.
The aim of the present trial is to study the effects of high-dose paracetamol and ibuprofen on body temperature in patients with acute ischaemic stroke, and to study the safety of these treatments.
Seventy-five (3 × 25) patients with acute ischaemic stroke confined to the anterior circulation will be randomised to treatment with either: 400 mg ibuprofen, 1000 mg acetaminophen, or with placebo 6 times daily during 5 days. Body-temperatures will be measured with a rectal electronic thermometer at the start of treatment and after 24 hours. An infrared tympanic thermometer will be used to monitor body temperature at 2-hour intervals during the first 24 hours and at 12-hour intervals thereafter. The primary outcome measure will be rectal temperature at 24 hours after the start of treatment. The study results will be analysed on an intent-to-treat basis, but an on-treatment analysis will also be performed. No formal interim analysis will be carried out.
PMCID: PMC101394  PMID: 11918829
4.  Inflammatory Markers and Poor Outcome after Stroke: A Prospective Cohort Study and Systematic Review of Interleukin-6 
PLoS Medicine  2009;6(9):e1000145.
In a prospective cohort study of patient outcomes following stroke, William Whiteley and colleagues find that markers of inflammatory response are associated with poor outcomes. However, addition of these markers to existing prognostic models does not improve outcome prediction.
The objective of this study was to determine whether: (a) markers of acute inflammation (white cell count, glucose, interleukin-6, C-reactive protein, and fibrinogen) are associated with poor outcome after stroke and (b) the addition of markers to previously validated prognostic models improves prediction of poor outcome.
Methods and Findings
We prospectively recruited patients between 2002 and 2005. Clinicians assessed patients and drew blood for inflammatory markers. Patients were followed up by postal questionnaire for poor outcome (a score of>2 on the modified Rankin Scale) and death through the General Register Office (Scotland) at 6 mo. We performed a systematic review of the literature and meta-analysis of the association between interleukin-6 and poor outcome after stroke to place our study in the context of previous research. We recruited 844 patients; mortality data were available in 844 (100%) and functional outcome in 750 (89%). After appropriate adjustment, the odds ratios for the association of markers and poor outcome (comparing the upper and the lower third) were interleukin-6, 3.1 (95% CI: 1.9–5.0); C-reactive protein, 1.9 (95% CI: 1.2–3.1); fibrinogen, 1.5 (95% CI: 1.0–2.36); white cell count, 2.1 (95% CI: 1.3–3.4); and glucose 1.3 (95% CI: 0.8–2.1). The results for interleukin-6 were similar to other studies. However, the addition of inflammatory marker levels to validated prognostic models did not materially improve model discrimination, calibration, or reclassification for prediction of poor outcome after stroke.
Raised levels of markers of the acute inflammatory response after stroke are associated with poor outcomes. However, the addition of these markers to a previously validated stroke prognostic model did not improve the prediction of poor outcome. Whether inflammatory markers are useful in prediction of recurrent stroke or other vascular events is a separate question, which requires further study.
Please see later in the article for the Editors' Summary
Editors' Summary
Every year, 15 million people have a stroke. In the US alone, someone has a stroke every 40 seconds and someone dies from a stroke every 3–4 minutes. Stroke occurs when the blood supply to the brain is suddenly interrupted by a blood clot blocking a blood vessel in the brain (ischemic stroke, the commonest type of stroke) or by a blood vessel in the brain bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and confusion or trouble speaking or understanding speech. Anyone experiencing these symptoms should seek medical assistance immediately because prompt treatment can limit the damage to the brain. Risk factors for stroke include age (three-quarters of strokes occur in people over 65 years old), high blood pressure, and heart disease.
Why Was This Study Done?
Many people are left with permanent disabilities after a stroke. An accurate way to predict the likely long-term outcome (prognosis) for individual patients would help clinicians manage their patients and help relatives and patients come to terms with their changed circumstances. Clinicians can get some idea of their patients' likely outcomes by assessing six simple clinical variables. These include the ability to lift both arms and awareness of the present situation. But could the inclusion of additional variables improve the predictive power of this simple prognostic model? There is some evidence that high levels in the blood of inflammatory markers (for example, interleukin-6 and C-reactive protein) are associated with poor outcomes after stroke—inflammation is the body's response to infection and to damage. In this prospective cohort study, the researchers investigate whether inflammatory markers are associated with poor outcome after stroke and whether the addition of these markers to the six-variable prognostic model improves its predictive power. Prospective cohort studies enroll a group of participants and follow their subsequent progress.
What Did the Researchers Do and Find?
The researchers recruited 844 patients who had had a stroke (mainly mild ischemic strokes) in Edinburgh. Each patient was assessed soon after the stroke by a clinician and blood was taken for the measurement of inflammatory markers. Six months after the stroke, the patient or their relatives completed a postal questionnaire that assessed their progress. Information about patient deaths was obtained from the General Register Office for Scotland. Dependency on others for the activities of daily life or dying was recorded as a poor outcome. In their statistical analysis of these data, the researchers found that raised levels of several inflammatory markers increased the likelihood of a poor outcome. For example, after allowing for age and other factors, individuals with interleukin-6 levels in the upper third of the measured range were three times as likely to have a poor outcome as patients with interleukin-6 levels in the bottom third of the range. A systematic search of the literature revealed that previous studies that had looked at the potential association between interleukin-6 levels and outcome after stroke had found similar results. Finally, the researchers found that the addition of inflammatory marker levels to the six-variable prognostic model did not substantially improve its ability to predict outcome after stroke for this cohort of patients.
What Do These Findings Mean?
These findings provide additional support for the idea that increased levels of inflammatory markers are associated with a poor outcome after stroke. However, because patients with infections were not excluded from the study, infection may be responsible for part of the observed association. Importantly, these findings also show that although the inclusion of inflammatory markers in the six variable prognostic model slightly improves its ability to predict outcome, the magnitude of this improvement is too small to warrant the use of these markers in routine practice. Whether the measurement of inflammatory markers might be useful in the prediction of recurrent stroke—at least a quarter of people who survive a stroke will have another one within 5 years—requires further study.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Len Kritharides
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); the Know Stroke site provides educational materials about stroke prevention, treatment, and rehabilitation (in English and Spanish)
The Internet Stroke Center provides detailed information about stroke for patients, families and health professionals (in English and Spanish)
The UK National Health Service also provides information for patients and their families about stroke (in several languages)
MedlinePlus provides links to further resources and advice about stroke (in English and Spanish)
The six simple variable model for prediction of death or disability after stroke is available here:
PMCID: PMC2730573  PMID: 19901973
5.  Single dose oral paracetamol (acetaminophen) for postoperative pain in adults 
This is an updated version of the original Cochrane review published in Issue 1, 2004 - this original review had been split from a previous title on ‘Single dose paracetamol (acetaminophen) with and without codeine for postoperative pain’. The last version of this review concluded that paracetamol is an effective analgesic for postoperative pain, but additional trials have since been published. This review sought to evaluate the efficacy and safety of paracetamol using current data, and to compare the findings with other analgesics evaluated in the same way.
To assess the efficacy of single dose oral paracetamol for the treatment of acute postoperative pain.
Search methods
We searched The Cochrane Library, MEDLINE, EMBASE, the Oxford Pain Relief Database and reference lists of articles to update an existing version of the review in July 2008.
Selection criteria
Randomised, double-blind, placebo-controlled clinical trials of paracetamol for acute postoperative pain in adults.
Data collection and analysis
Two review authors independently assessed trial quality and extracted data. Area under the “pain relief versus time” curve was used to derive the proportion of participants with paracetamol or placebo experiencing at least 50% pain relief over four to six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated, with 95% confidence intervals (CI). The proportion of participants using rescue analgesia over a specified time period, and time to use, were sought as measures of duration of analgesia. Information on adverse events and withdrawals was also collected.
Main results
Fifty-one studies, with 5762 participants, were included: 3277 participants were treated with a single oral dose of paracetamol and 2425 with placebo. About half of participants treated with paracetamol at standard doses achieved at least 50% pain relief over four to six hours, compared with about 20% treated with placebo. NNTs for at least 50% pain relief over four to six hours following a single dose of paracetamol were as follows: 500 mg NNT 3.5 (2.7 to 4.8); 600 to 650 mg NNT 4.6 (3.9 to 5.5); 975 to 1000 mg NNT 3.6 (3.4 to 4.0). There was no dose response. Sensitivity analysis showed no significant effect of trial size or quality on this outcome.
About half of participants needed additional analgesia over four to six hours, compared with about 70% with placebo. Five people would need to be treated with 1000 mg paracetamol, the most commonly used dose, to prevent one needing rescue medication over four to six hours, who would have needed it with placebo. Adverse event reporting was inconsistent and often incomplete. Reported adverse events were mainly mild and transient, and occurred at similar rates with 1000 mg paracetamol and placebo. No serious adverse events were reported. Withdrawals due to adverse events were uncommon and occurred in both paracetamol and placebo treatment arms.
Authors’ conclusions
A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.
PMCID: PMC4163965  PMID: 18843665
Acetaminophen [*administration & dosage; adverse effects]; Analgesics, Non-Narcotic [*administration & dosage; adverse effects]; Pain, Postoperative [*drug therapy]; Randomized Controlled Trials as Topic; Adult; Humans
6.  A randomized, double-blind, placebo-controlled, multiple-dose, parallel-group clinical trial to assess the effects of teduglutide on gastric emptying of liquids in healthy subjects 
BMC Gastroenterology  2014;14:25.
Teduglutide, a recombinant analog of human glucagon-like peptide (GLP)-2, is a novel therapy recently approved for the treatment of adult patients with short bowel syndrome who are dependent on parenteral support. Previous studies assessing the effect of GLP-2 on gastric emptying in humans have yielded inconsistent results, with some studies showing no effect and others documenting a GLP-2–dependent delay in gastric emptying. The primary objective of this study was to assess the effect of teduglutide on gastric emptying of liquids in healthy subjects, as measured by the pharmacokinetics of acetaminophen.
This double-blind, parallel-group, single-center study enrolled and randomized 36 healthy subjects (22 men, 14 women) to receive subcutaneous doses of teduglutide 4 mg or placebo (2:1 ratio; 23:13) once daily on Days 1 through 10 in the morning. Gastric emptying of a mixed nutrient liquid meal was assessed by measuring acetaminophen levels predose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 3.5, 4, 5, 6, 8, 10, 12, and 14 hours after administration of 1000 mg acetaminophen on Days 0 and 10. The primary study endpoint was a pharmacokinetic analysis of acetaminophen absorption in subjects receiving teduglutide or placebo.
No significant differences in gastric emptying of liquids (acetaminophen area under the concentration [AUC] vs time curve from time 0 to the last measurable concentration, AUC extrapolated to infinity, maximum concentration [Cmax], and time to Cmax) were observed on Day 10 in subjects receiving teduglutide 4 mg versus subjects receiving placebo. There were no serious adverse events (AEs), deaths, or discontinuations due to an AE reported during the study.
Teduglutide 4 mg/day for 10 days does not affect gastric emptying of liquids in healthy subjects as measured by acetaminophen pharmacokinetics. No unexpected safety signals were observed.
Trial registration
This study was registered at, identifier NCT01209351.
PMCID: PMC3928318  PMID: 24517114
Teduglutide; Gastric emptying; Pharmacokinetics; Pharmacodynamics
7.  Perioperative Intravenous Acetaminophen Attenuates Lipid Peroxidation in Adults Undergoing Cardiopulmonary Bypass: A Randomized Clinical Trial 
PLoS ONE  2015;10(2):e0117625.
Cardiopulmonary bypass (CPB) lyses erythrocytes and induces lipid peroxidation, indicated by increasing plasma concentrations of free hemoglobin, F2-isoprostanes, and isofurans. Acetaminophen attenuates hemeprotein-mediated lipid peroxidation, reduces plasma and urine concentrations of F2-isoprostanes, and preserves kidney function in an animal model of rhabdomyolysis. Acetaminophen also attenuates plasma concentrations of isofurans in children undergoing CPB. The effect of acetaminophen on lipid peroxidation in adults has not been studied. This was a pilot study designed to test the hypothesis that acetaminophen attenuates lipid peroxidation in adults undergoing CPB and to generate data for a clinical trial aimed to reduce acute kidney injury following cardiac surgery.
Methods and Results
In a prospective double-blind placebo-controlled clinical trial, sixty adult patients were randomized to receive intravenous acetaminophen or placebo starting prior to initiation of CPB and for every 6 hours for 4 doses. Acetaminophen concentrations measured 30 min into CPB and post-CPB were 11.9±0.6 μg/mL (78.9±3.9 μM) and 8.7±0.3 μg/mL (57.6±2.0 μM), respectively. Plasma free hemoglobin increased more than 15-fold during CPB, and haptoglobin decreased 73%, indicating hemolysis. Plasma and urinary markers of lipid peroxidation also increased during CPB but returned to baseline by the first postoperative day. Acetaminophen reduced plasma isofuran concentrations over the duration of the study (P = 0.05), and the intraoperative plasma isofuran concentrations that corresponded to peak hemolysis were attenuated in those subjects randomized to acetaminophen (P = 0.03). Perioperative acetaminophen did not affect plasma concentrations of F2-isoprostanes or urinary markers of lipid peroxidation.
Intravenous acetaminophen attenuates the increase in intraoperative plasma isofuran concentrations that occurs during CPB, while urinary markers were unaffected.
Trial Registration NCT01366976
PMCID: PMC4338200  PMID: 25705899
8.  Associations between Stroke Mortality and Weekend Working by Stroke Specialist Physicians and Registered Nurses: Prospective Multicentre Cohort Study 
PLoS Medicine  2014;11(8):e1001705.
In a multicenter observational study, Benjamin Bray and colleagues evaluate whether weekend rounds by stroke specialist physicians, or the ratio of registered nurses to beds on weekends, is associated with patient mortality after stroke.
Please see later in the article for the Editors' Summary
Observational studies have reported higher mortality for patients admitted on weekends. It is not known whether this “weekend effect” is modified by clinical staffing levels on weekends. We aimed to test the hypotheses that rounds by stroke specialist physicians 7 d per week and the ratio of registered nurses to beds on weekends are associated with mortality after stroke.
Methods and Findings
We conducted a prospective cohort study of 103 stroke units (SUs) in England. Data of 56,666 patients with stroke admitted between 1 June 2011 and 1 December 2012 were extracted from a national register of stroke care in England. SU characteristics and staffing levels were derived from cross-sectional survey. Cox proportional hazards models were used to estimate hazard ratios (HRs) of 30-d post-admission mortality, adjusting for case mix, organisational, staffing, and care quality variables. After adjusting for confounders, there was no significant difference in mortality risk for patients admitted to a stroke service with stroke specialist physician rounds fewer than 7 d per week (adjusted HR [aHR] 1.04, 95% CI 0.91–1.18) compared to patients admitted to a service with rounds 7 d per week. There was a dose–response relationship between weekend nurse/bed ratios and mortality risk, with the highest risk of death observed in stroke services with the lowest nurse/bed ratios. In multivariable analysis, patients admitted on a weekend to a SU with 1.5 nurses/ten beds had an estimated adjusted 30-d mortality risk of 15.2% (aHR 1.18, 95% CI 1.07–1.29) compared to 11.2% for patients admitted to a unit with 3.0 nurses/ten beds (aHR 0.85, 95% CI 0.77–0.93), equivalent to one excess death per 25 admissions. The main limitation is the risk of confounding from unmeasured characteristics of stroke services.
Mortality outcomes after stroke are associated with the intensity of weekend staffing by registered nurses but not 7-d/wk ward rounds by stroke specialist physicians. The findings have implications for quality improvement and resource allocation in stroke care.
Please see later in the article for the Editors' Summary
Editors' Summary
In a perfect world, a patient admitted to hospital on a weekend or during the night should have as good an outcome as a patient admitted during regular working hours. But several observational studies (investigations that record patient outcomes without intervening in any way; clinical trials, by contrast, test potential healthcare interventions by comparing the outcomes of patients who are deliberately given different treatments) have reported that admission on weekends is associated with a higher mortality (death) rate than admission on weekdays. This “weekend effect” has led to calls for increased medical and nursing staff to be available in hospitals during the weekend and overnight to ensure that the healthcare provided at these times is of equal quality to that provided during regular working hours. In the UK, for example, “seven-day working” has been identified as a policy and service improvement priority for the National Health Service.
Why Was This Study Done?
Few studies have actually tested the relationship between patient outcomes and weekend physician or nurse staffing levels. It could be that patients who are admitted to hospital on the weekend have poor outcomes because they are generally more ill than those admitted on weekdays. Before any health system introduces potentially expensive increases in weekend staffing levels, better evidence that this intervention will improve patient outcomes is needed. In this prospective cohort study (a study that compares the outcomes of groups of people with different baseline characteristics), the researchers ask whether mortality after stroke is associated with weekend working by stroke specialist physicians and registered nurses. Stroke occurs when the brain's blood supply is interrupted by a blood vessel in the brain bursting (hemorrhagic stroke) or being blocked by a blood clot (ischemic stroke). Swift treatment can limit the damage to the brain caused by stroke, but of the 15 million people who have a stroke every year, about 6 million die within a few hours and another 5 million are left disabled.
What Did the Researchers Do and Find?
The researchers extracted clinical data on 56,666 patients who were admitted to stroke units in England over an 18-month period from a national stroke register. They obtained information on the characteristics and staffing levels of the stroke units from a biennial survey of hospitals admitting patients with stroke, and information on deaths among patients with stroke from the national register of deaths. A quarter of the patients were admitted on a weekend, almost half the stroke units provided stroke specialist physician rounds seven days per week, and the remainder provided rounds five days per week. After adjustment for factors that might have affected outcomes (“confounders”) such as stroke severity and the level of acute stroke care available in each stroke unit, there was no significant difference in mortality risk between patients admitted to a stroke unit with rounds seven days/week and patients admitted to a unit with rounds fewer than seven days/week. However, patients admitted on a weekend to a stroke unit with 1.5 nurses/ten beds had a 30-day mortality risk of 15.2%, whereas patients admitted to a unit with 3.0 nurses/ten beds had a mortality risk of 11.2%, a mortality risk difference equivalent to one excess death per 25 admissions.
What Do These Findings Mean?
These findings show that the provision of stroke specialist physician rounds seven days/week in stroke units in England did not influence the (weak) association between weekend admission for stroke and death recorded in this study, but mortality outcomes after stroke were associated with the intensity of weekend staffing by registered nurses. The accuracy of these findings may be affected by the measure used to judge the level of acute care available in each stroke unit and by residual confounding. For example, patients admitted to units with lower nursing levels may have shared other unknown characteristics that increased their risk of dying after stroke. Moreover, this study considered the impact of staffing levels on mortality only and did not consider other relevant outcomes such as long-term disability. Despite these limitations, these findings support the provision of higher weekend ratios of registered nurses to beds in stroke units, but given the high costs of increasing weekend staffing levels, it is important that controlled trials of different models of physician and nursing staffing are undertaken as soon as possible.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Meeta Kerlin
Information about plans to introduce seven-day working into the National Health Service in England is available; the 2013 publication “NHS Services—Open Seven Days a Week: Every Day Counts” provides examples of how hospitals across England are working together to provide routine healthcare services seven days a week; a “Behind the Headlines” article on the UK National Health Service Choices website describes a recent observational study that investigated the association between admission to hospital on the weekend and death, and newspaper coverage of the study's results; the Choices website also provides information about stroke for patients and their families, including personal stories
A US nurses' site includes information on the association of nurse staffing with patient safety
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); its Know Stroke site provides educational materials about stroke prevention, treatment, and rehabilitation, including personal stories (in English and Spanish); the US National Institute of Health SeniorHealth website has additional information about stroke
The Internet Stroke Center provides detailed information about stroke for patients, families, and health professionals (in English and Spanish)
PMCID: PMC4138029  PMID: 25137386
9.  Scottish and Newcastle Antiemetic Pre-treatment for paracetamol poisoning study (SNAP) 
Paracetamol (acetaminophen) poisoning remains the commonest cause of acute liver injury in Europe and North America. The intravenous (IV) N-acetylcysteine (NAC) regimen introduced in the 1970s has continued effectively unchanged. This involves 3 different infusion regimens (dose and time) lasting over 20 hours. The same weight-related dose of NAC is used irrespective of paracetamol dose. Complications include frequent nausea and vomiting, anaphylactoid reactions and dosing errors. We designed a randomised controlled study investigating the efficacy of antiemetic pre-treatment (ondansetron) using standard NAC and a modified, shorter, regimen.
We designed a double-blind trial using a 2 × 2 factorial design involving four parallel groups. Pre-treatment with ondansetron 4 mg IV was compared against placebo on nausea and vomiting following the standard (20.25 h) regimen, or a novel 12 h NAC regimen in paracetamol poisoning. Each delivered 300 mg/kg bodyweight NAC. Randomisation was stratified on: paracetamol dose, perceived risk factors, and time to presentation. The primary outcome was the incidence of nausea and vomiting following NAC. In addition the frequency of anaphylactoid reactions and end of treatment liver function documented. Where clinically necessary further doses of NAC were administered as per standard UK protocols at the end of the first antidote course.
This study is primarily designed to test the efficacy of prophylactic anti-emetic therapy with ondansetron, but is the first attempt to formally examine new methods of administering IV NAC in paracetamol overdose. We anticipate, from volunteer studies, that nausea and vomiting will be less frequent with the new NAC regimen. In addition as anaphylactoid response appears related to plasma concentrations of both NAC and paracetamol anaphylactoid reactions should be less likely. This study is not powered to assess the relative efficacy of the two NAC regimens, however it will give useful information to power future studies. As the first formal randomised clinical trial in this patient group in over 30 years this study will also provide information to support further studies in patients in paracetamol overdose, particularly, when linked with modern novel biomarkers of liver damage, patients at different toxicity risk.
Trial registration
EudraCT number 2009-017800-10, IdentifierNCT01050270
PMCID: PMC3626543  PMID: 23556549
Paracetamol; Acetylcysteine; Overdose; Antidotes; Hepatotoxicity
10.  The effect of preoperative intravenous paracetamol administration on postoperative fever in pediatrics cardiac surgery 
Post-operative fever is a common complication of cardiac operations, which is known to be correlated with a greater degree of cognitive dysfunction 6 weeks after cardiac surgery. The aim of the present study was to examine efficacy and safety of single dose intravenous Paracetamol in treatment of post-operative fever in children undergoing cardiac surgery.
Materials and Methods:
In this randomised, double-blind, placebo-controlled clinical trial, 80 children, aged 1-12 years, presenting for open heart surgery were entered in the trial and randomly allocated into two groups: Placebo and Paracetamol. After induction of anaesthesia, 15 mg/kg intravenous Paracetamol solution was infused during 1 h in the Paracetamol group. Patients in placebo group received 15 mg/kg normal saline infusion during the same time. Since the end of operation until next 24 h in intensive care unit, axillary temperature of the two group patients was recorded in 4-h intervals. Any fever that occurred during this period had been treated with Paracetamol suppository (125 mg) and the amount of antipyretic drug consumption for each patient had been recorded. In order to examine the safety of Paracetamol, patients were evaluated for drug complication at the same time.
Mean axillary temperature during first 24 h after operation was significantly lower in Paracetamol group compared with placebo group (P = 0.001). Overall fever incidence during 24 h after operation was higher in placebo group compared with Paracetamol group (P = 0.012). Of Paracetamol group patients, 42.5% compared with 15% of placebo group participants had no consumption of antipyretic agent (Paracetamol suppository) during 24 h after operation (P = 0.001).
This study suggests that single dose administration of intravenous Paracetamol before paediatric cardiac surgeries using cardiopulmonary bypass; reduce mean body temperature in the first 24 h after operation.
PMCID: PMC4178333  PMID: 25298601
Cardiac surgery; paracetamol; paediatric; post-operative fever
11.  Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study 
Critical Care  2012;16(1):R33.
Fever is frequently observed in critically ill patients. An independent association of fever with increased mortality has been observed in non-neurological critically ill patients with mixed febrile etiology. The association of fever and antipyretics with mortality, however, may be different between infective and non-infective illness.
We designed a prospective observational study to investigate the independent association of fever and the use of antipyretic treatments with mortality in critically ill patients with and without sepsis. We included 1,425 consecutive adult critically ill patients (without neurological injury) requiring > 48 hours intensive care admitted in 25 ICUs. We recorded four-hourly body temperature and all antipyretic treatments until ICU discharge or 28 days after ICU admission, whichever occurred first. For septic and non-septic patients, we separately assessed the association of maximum body temperature during ICU stay (MAXICU) and the use of antipyretic treatments with 28-day mortality.
We recorded body temperature 63,441 times. Antipyretic treatment was given 4,863 times to 737 patients (51.7%). We found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen independently increased 28-day mortality for septic patients (adjusted odds ratio: NSAIDs: 2.61, P = 0.028, acetaminophen: 2.05, P = 0.01), but not for non-septic patients (adjusted odds ratio: NSAIDs: 0.22, P = 0.15, acetaminophen: 0.58, P = 0.63). Application of physical cooling did not associate with mortality in either group. Relative to the reference range (MAXICU 36.5°C to 37.4°C), MAXICU ≥ 39.5°C increased risk of 28-day mortality in septic patients (adjusted odds ratio 8.14, P = 0.01), but not in non-septic patients (adjusted odds ratio 0.47, P = 0.11).
In non-septic patients, high fever (≥ 39.5°C) independently associated with mortality, without association of administration of NSAIDs or acetaminophen with mortality. In contrast, in septic patients, administration of NSAIDs or acetaminophen independently associated with 28-day mortality, without association of fever with mortality. These findings suggest that fever and antipyretics may have different biological or clinical or both implications for patients with and without sepsis.
Trial registration NCT00940654
PMCID: PMC3396278  PMID: 22373120
body temperature; antipyretic; fever; critical illness; mortality
12.  Interrupted Time-Series Analysis of Regulations to Reduce Paracetamol (Acetaminophen) Poisoning 
PLoS Medicine  2007;4(4):e105.
Paracetamol (acetaminophen) poisoning is the leading cause of acute liver failure in Great Britain and the United States. Successful interventions to reduced harm from paracetamol poisoning are needed. To achieve this, the government of the United Kingdom introduced legislation in 1998 limiting the pack size of paracetamol sold in shops. Several studies have reported recent decreases in fatal poisonings involving paracetamol. We use interrupted time-series analysis to evaluate whether the recent fall in the number of paracetamol deaths is different to trends in fatal poisoning involving aspirin, paracetamol compounds, antidepressants, or nondrug poisoning suicide.
Methods and Findings
We calculated directly age-standardised mortality rates for paracetamol poisoning in England and Wales from 1993 to 2004. We used an ordinary least-squares regression model divided into pre- and postintervention segments at 1999. The model included a term for autocorrelation within the time series. We tested for changes in the level and slope between the pre- and postintervention segments. To assess whether observed changes in the time series were unique to paracetamol, we compared against poisoning deaths involving compound paracetamol (not covered by the regulations), aspirin, antidepressants, and nonpoisoning suicide deaths. We did this comparison by calculating a ratio of each comparison series with paracetamol and applying a segmented regression model to the ratios. No change in the ratio level or slope indicated no difference compared to the control series. There were about 2,200 deaths involving paracetamol. The age-standardised mortality rate rose from 8.1 per million in 1993 to 8.8 per million in 1997, subsequently falling to about 5.3 per million in 2004. After the regulations were introduced, deaths dropped by 2.69 per million (p = 0.003). Trends in the age-standardised mortality rate for paracetamol compounds, aspirin, and antidepressants were broadly similar to paracetamol, increasing until 1997 and then declining. Nondrug poisoning suicide also declined during the study period, but was highest in 1993. The segmented regression models showed that the age-standardised mortality rate for compound paracetamol dropped less after the regulations (p = 0.012) but declined more rapidly afterward (p = 0.031). However, age-standardised rates for aspirin and antidepressants fell in a similar way to paracetamol after the regulations. Nondrug poisoning suicide declined at a similar rate to paracetamol after the regulations were introduced.
Introduction of regulations to limit availability of paracetamol coincided with a decrease in paracetamol-poisoning mortality. However, fatal poisoning involving aspirin, antidepressants, and to a lesser degree, paracetamol compounds, also showed similar trends. This raises the question whether the decline in paracetamol deaths was due to the regulations or was part of a wider trend in decreasing drug-poisoning mortality. We found little evidence to support the hypothesis that the 1998 regulations limiting pack size resulted in a greater reduction in poisoning deaths involving paracetamol than occurred for other drugs or nondrug poisoning suicide.
Analysis of mortality rates for paracetamol poisoning in England and Wales does not support the view that regulations limiting pack size have been responsible for a reduction in deaths.
Editors' Summary
Paracetamol—known as acetaminophen in the United States—is a cheap and effective painkiller. It is widely used to relieve minor aches and pains as well as fevers and headaches. Recommended doses of paracetamol are considered safe in humans, but overdoses are toxic and can cause liver failure and death. Because this drug is very easy to get hold of, there are many overdoses each year, either accidental or deliberate. In the UK, paracetamol poisoning is the most common cause of acute liver failure. Toward the end of 1998, new laws were introduced in the UK to try to reduce the number of paracetamol overdoses. These laws said that pharmacies could not sell packs of paracetamol containing more than 32 tablets and other shops could not sell packs with more than 16 tablets. One of the reasons behind the introduction of this law was that many suicides are not preplanned and, therefore, if it was harder for people to get hold of or keep large quantities of tablets, they might be less likely to attempt suicide or accidentally overdose.
Why Was This Study Done?
Following the introduction of these new laws, the number of deaths caused by paracetamol overdose in the UK dropped. However, it is possible that the drop in deaths came about for a variety of different reasons and not just as a result of the new laws on paracetamol pack size. For example, the suicide rate might have been falling anyway due to other changes in society and the fall in death rate from paracetamol might just have been part of that trend. It is important to find out whether the legal changes that were introduced to address a public health problem did in fact bring about a change for the better. This knowledge would also be relevant to other countries that are considering similar changes.
What Did the Researchers Do and Find?
The researchers used data from the Office of National Statistics, which holds information on drug poisoning deaths in England and Wales. These data were then broken down by the type of drug that was mentioned on the death certificate. The researchers compared death rates involving the following drugs: paracetamol; paracetamol-containing compounds (which were not subject to the new pack size laws); aspirin; antidepressant drugs; and then finally non-drug poisoning suicides. The reason for comparing death rates involving paracetamol against death rates involving other drugs, or non-drug suicide, was that this method would allow the researchers to see if the drop in paracetamol deaths followed overall trends in the poisoning or suicide rates or not. If the paracetamol death rate dropped following introduction of the new laws but the rates of other types of poisoning or suicide did not, then there would be a link between the new laws and a fall in paracetamol suicides. The researchers compared these death data within specific time periods before the end of 1998 (when the new laws on paracetamol pack size were introduced) and after.
Overall, there were nearly 2,200 deaths involving paracetamol between 1993 and 2004. The number of deaths per year involving paracetamol dropped substantially when comparing the periods of time before the end of 1998 and after it. However, the number of deaths per year involving any drug, and the non-drug suicides, also fell during this period of time. When comparing the trends for paracetamol deaths with other poisoning or suicide deaths, the researchers did not find any statistical evidence that the fall in paracetamol deaths was any different to the overall trend in poisoning or suicide death rates.
What Do These Findings Mean?
Although the paracetamol death rate fell immediately following the new laws on pack size, this study suggests the link might just be coincidence. The researchers could not find any data supporting the idea that the new laws caused a drop in paracetamol deaths. However, this was an observational study, not a true experimental one: the researchers here were clearly not able to set up equivalent “experimental” and “control” groups for comparison. It is very difficult to prove or disprove conclusively that new laws such as this are, or are not, effective.
Additional Information.
Please access these Web sites via the online version of this summary at
Information is available from Medline Plus about suicide
Wikipedia has an entry on paracetamol (note that Wikipedia is an internet encyclopedia anyone can edit)
Information about regulation of drugs in the UK is available from the Medicines and Healthcare Regulatory Agency
The Office for National Statistics provides key economic and social data about the UK, and is involved in many other important projects
PMCID: PMC1845154  PMID: 17407385
13.  Temporal profile of body temperature in acute ischemic stroke: relation to stroke severity and outcome 
BMC Neurology  2012;12:123.
Pyrexia after stroke (temperature ≥37.5°C) is associated with poor prognosis, but information on timing of body temperature changes and relationship to stroke severity and subtypes varies.
We recruited patients with acute ischemic stroke, measured stroke severity, stroke subtype and recorded four-hourly tympanic (body) temperature readings from admission to 120 hours after stroke. We sought causes of pyrexia and measured functional outcome at 90 days. We systematically summarised all relevant previous studies.
Amongst 44 patients (21 males, mean age 72 years SD 11) with median National Institute of Health Stroke Score (NIHSS) 7 (range 0–28), 14 had total anterior circulation strokes (TACS). On admission all patients, both TACS and non-TACS, were normothermic (median 36.3°C vs 36.5°C, p=0.382 respectively) at median 4 hours (interquartile range, IQR, 2–8) after stroke; admission temperature and NIHSS were not associated (r2=0.0, p=0.353). Peak temperature, occurring at 35.5 (IQR 19.0 to 53.8) hours after stroke, was higher in TACS (37.7°C) than non-TACS (37.1°C, p<0.001) and was associated with admission NIHSS (r2=0.20, p=0.002). Poor outcome (modified Rankin Scale ≥3) at 90 days was associated with higher admission (36.6°C vs. 36.2°C p=0.031) and peak (37.4°C vs. 37.0°C, p=0.016) temperatures. Sixteen (36%) patients became pyrexial, in seven (44%) of whom we found no cause other than the stroke.
Normothermia is usual within the first 4 hours of stroke. Peak temperature occurs at 1.5 to 2 days after stroke, and is related to stroke severity/subtype and more closely associated with poor outcome than admission temperature. Temperature-outcome associations after stroke are complex, but normothermia on admission should not preclude randomisation of patients into trials of therapeutic hypothermia.
PMCID: PMC3607983  PMID: 23075282
Ischemic stroke; Tympanic body temperature; Pyrexia; Outcome; OCSP
14.  MR CLEAN, a multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands: study protocol for a randomized controlled trial 
Trials  2014;15:343.
Endovascular or intra-arterial treatment (IAT) increases the likelihood of recanalization in patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion. However, a beneficial effect of IAT on functional recovery in patients with acute ischemic stroke remains unproven. The aim of this study is to assess the effect of IAT on functional outcome in patients with acute ischemic stroke. Additionally, we aim to assess the safety of IAT, and the effect on recanalization of different mechanical treatment modalities.
A multicenter randomized clinical trial with blinded outcome assessment. The active comparison is IAT versus no IAT. IAT may consist of intra-arterial thrombolysis with alteplase or urokinase, mechanical treatment or both. Mechanical treatment refers to retraction, aspiration, sonolysis, or use of a retrievable stent (stent-retriever). Patients with a relevant intracranial proximal arterial occlusion of the anterior circulation, who can be treated within 6 hours after stroke onset, are eligible. Treatment effect will be estimated with ordinal logistic regression (shift analysis); 500 patients will be included in the trial for a power of 80% to detect a shift leading to a decrease in dependency in 10% of treated patients. The primary outcome is the score on the modified Rankin scale at 90 days. Secondary outcomes are the National Institutes of Health stroke scale score at 24 hours, vessel patency at 24 hours, infarct size on day 5, and the occurrence of major bleeding during the first 5 days.
If IAT leads to a 10% absolute reduction in poor outcome after stroke, careful implementation of the intervention could save approximately 1% of all new stroke cases from death or disability annually.
Trial registration
NTR1804 (7 May 2009)/ISRCTN10888758 (24 July 2012).
Electronic supplementary material
The online version of this article (doi:10.1186/1745-6215-15-343) contains supplementary material, which is available to authorized users.
PMCID: PMC4162915  PMID: 25179366
Alteplase; Urokinase; Endovascular treatment; Acute ischemic stroke; Randomized controlled trial; Stent; Thrombectomy
15.  Effect of acetaminophen and fluvastatin on post-dose symptoms following infusion of zoledronic acid 
Osteoporosis International  2010;22(8):2337-2345.
A randomized, double-blind, placebo-controlled study assessed the efficacy of acetaminophen or fluvastatin in preventing post-dose symptoms (increases in body temperature or use of rescue medication) following a single infusion of the intravenous (IV) bisphosphonate zoledronic acid (ZOL). Acetaminophen, but not fluvastatin, significantly reduced the incidence and severity of post-dose symptoms.
Transient symptoms including myalgia and pyrexia have been reported post-infusion of IV bisphosphonates, typically starting the day after infusion and resolving within several days. The cause is unknown but may be related to transient cytokine elevations. Statins’ potential to block release of these cytokines has been hypothesized. This study was aimed to evaluate efficacy of acetaminophen and fluvastatin in preventing/reducing post-dose symptoms following ZOL 5 mg infusion.
Randomized, double-blind, placebo-controlled study of efficacy of acetaminophen or fluvastatin in preventing increases in body temperature or use of rescue medication (ibuprofen) following a single ZOL infusion. Bisphosphonate-naive postmenopausal women with low bone mass (N = 793) were randomized into three treatment groups and given 650 mg acetaminophen or 80 mg fluvastatin or placebo 45 min before ZOL infusion. The acetaminophen group continued taking 650 mg acetaminophen every 6 h over the next 3 days, and the other two groups took matching placebo according to the same schedule. Subjects recorded body temperature, symptoms in a diary. Inflammatory cytokines and C-reactive protein (CRP) were measured at baseline, 24, and 72 h in a study subset.
Acetaminophen four times/day significantly reduced the incidence and severity of post-dose symptoms following ZOL infusion. Single-dose fluvastatin 80 mg prior to ZOL infusion did not prevent/reduce post-dose symptoms. Cytokine levels increased by 24 h and returned towards baseline by 72 h, similar to the pattern for post-infusion symptoms. CRP levels increased from baseline to 72 h.
Acetaminophen four times/day for 3 days significantly reduced the incidence and severity of post-dose symptoms following ZOL infusion.
PMCID: PMC3132314  PMID: 21116816
Cytokines; Fluvastatin; Inflammatory biomarkers; Osteoporosis; Post-dose symptoms; Zoledronic acid
16.  Patient Preference for Placebo, Acetaminophen (paracetamol) or Celecoxib Efficacy Studies (PACES): two randomised, double blind, placebo controlled, crossover clinical trials in patients with knee or hip osteoarthritis 
Annals of the Rheumatic Diseases  2004;63(8):931-939.
Background: Acetaminophen (paracetamol) is recommended as the initial pharmacological treatment for knee or hip osteoarthritis. However, survey and clinical trial data indicate greater efficacy for non-steroidal anti-inflammatory drugs and cyclo-oxygenase-2 specific inhibitors.
Design: Two randomised, double blind, placebo controlled, crossover multicentre clinical trials, Patient Preference for Placebo, Acetaminophen or Celecoxib Efficacy Studies (PACES).
Patients: Osteoarthritis of knee or hip.
Intervention: "Wash out" of treatment; randomisation; 6 weeks of celecoxib 200 mg/day, acetaminophen 1000 mg four times a day, or placebo; second "wash out;" crossover to 6 weeks of second treatment.
Measurements: Western Ontario McMaster Osteoarthritis Index (WOMAC), visual analogue pain scale, patient preference between two treatments.
Results: Celecoxib was more efficacious than acetaminophen in both periods in both studies; WOMAC and pain scale scores differed at p<0.05 in period II and both periods combined of PACES-a and in periods I and II and both periods combined in PACES-b, but not in period I of PACES-a. Acetaminophen was more efficacious than placebo, generally p<0.05 in PACES-b, and >0.05 in PACES-a. Patient preferences were 53% celecoxib v 24% acetaminophen in PACES-a (p<0.001) and 50% v 32% in PACES-b (p = 0.009); 37% acetaminophen v 28% placebo in PACES-a (p = 0.340) and 48% v 24% in PACES-b (p = 0.007). No clinically or statistically significant differences were seen in adverse events or tolerability among the three treatment groups.
Conclusions: Greater efficacy was seen for celecoxib v acetaminophen v placebo, while adverse events and tolerability were similar. Variation in results and statistical significance in the two different trials are of interest.
PMCID: PMC1755088  PMID: 15082468
17.  Effects of Suppository Acetaminophen, Bupivacaine Wound Infiltration, and Caudal Block With Bupivacaine on Postoperative Pain in Pediatric Inguinal Herniorrhaphy 
Anesthesiology and Pain Medicine  2012;1(4):243-247.
The control of postoperative pain is important in children, and poor pain control leads to organ dysfunction and behavioral problems.
We compared the analgesic effects of suppository acetaminophen, bupivacaine wound infiltration, and caudal block with bupivacaine on postoperative pain in pediatric inguinal herniorrhaphy.
Patients and Methods:
In this double-blinded, randomized controlled clinical trial, 90 children of American Society of Anesthesiologists (ASA) grade I-II, aged between 3 months and 7 years, and scheduled for elective unilateral inguinal herniorrhaphy under general anesthesia were assigned to three equal groups. Patients in the first group received 20 mg/kg of suppository acetaminophen. In the second group, 2 mg/kg of 0.5% bupivacaine was infiltrated in the incisional site, and in the third group, a caudal block was performed with 0.75 mL/kg of 0.25% bupivacaine. The Face, Legs, Activity, Cry, Consolability (FLACC) pain scale was applied 30 minutes after operation. Thereafter, the FLACC score was obtained every hour during the next 6 hours. If the FLACC score was 4 or over, we administered 0.5 mg/kg of intravenous meperidine. The data was transferred to SPSS-10 software and analyzed statistically with chi-square and analysis of variance tests. P < 0.05 was considered significant.
The mean analgesic duration in the acetaminophen, bupivacaine infiltration, and caudal block groups was 4.07, 5.40, and 5.37 hours, respectively. Significant differences were not observed between the bupivacaine infiltration and caudal block groups (P = 0.9), but the differences between the bupivacaine infiltration and acetaminophen groups (P = 0.034) and the caudal block and acetaminophen groups (P = 0.039) were significant. With regard to meperidine administration, significant differences were not observed between the bupivacaine infiltration and caudal block groups (P = 0.848), but significant differences were observed between these two groups and the acetaminophen group (P < 0.05).
Patients in the bupivacaine infiltration and caudal block groups had less postoperative pain than those in the acetaminophen group and received lower amount of meperidine. We concluded that in children, bupivacaine infiltration and caudal block with bupivacaine produce better analgesia than suppository acetaminophen. It seems that bupivacaine infiltration is better than caudal block because of its simplicity, lower incidence of complications, and failure rate.
PMCID: PMC4018710  PMID: 24904808
Bupivacaine; Anesthesia, Caudal; Pediatrics; Analgesia; Suppositories; Acetaminophen
18.  Paracetamol therapy and outcome of critically ill patients: a multicenter retrospective observational study 
Critical Care  2015;19(1):162.
In this study, we aimed to examine the association between paracetamol administration in the intensive care unit (ICU) and mortality in critically ill patients.
We conducted a multicenter retrospective observational study in four ICUs. We obtained information on paracetamol use, body temperature, demographic, clinical and outcome data from each hospital’s clinical information system and admissions and discharges database. We performed statistical analysis to assess the association between paracetamol administration and hospital mortality.
We studied 15,818 patients with 691,348 temperature measurements at 4 ICUs. Of these patients, 10,046 (64%) received at least 1 g of paracetamol. Patients who received paracetamol had lower in-hospital mortality (10% vs. 20%, P <0.001), and survivors were more likely to have received paracetamol (66% vs. 46%; P <0.001). However, patients treated with paracetamol were also more likely to be admitted to the ICU after surgery (70% vs. 51%; P <0.001) and/or after elective surgery (55% vs. 37%; P <0.001). In multivariate logistic regression analysis including a propensity score for paracetamol treatment, we found a significant and independent association between the use of paracetamol and reduced in-hospital mortality (adjusted odds ratio =0.60 (95% confidence interval (CI), 0.53 to 0.68), P <0.001). Cox proportional hazards analysis showed that patients who received paracetamol also had a significantly longer time to death (adjusted hazard ratio =0.51 (95% CI, 0.46 to 0.56), P <0.001). The association between paracetamol and decreased mortality and/or time to death was broadly consistent across surgical and medical patients. It remained present after adjusting for paracetamol administration as a time-dependent variable. However, when such time-dependent analysis was performed, the association of paracetamol with outcome lost statistical significance in the presence of fever and suspected infection and in patients in the lower tertiles of Acute Physiology and Chronic Health Evaluation II scores.
Paracetamol administration is common in the ICU and appears to be independently associated with reduced in-hospital mortality and time to death after adjustment for multiple potential confounders and propensity score. This association, however, was modified by the presence of fever, suspected infection and lesser illness severity and may represent the effect of indication bias.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-015-0865-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4411740  PMID: 25879463
19.  Acetaminophen-cysteine adducts during therapeutic dosing and following overdose 
BMC Gastroenterology  2011;11:20.
Acetaminophen-cysteine adducts (APAP-CYS) are a specific biomarker of acetaminophen exposure. APAP-CYS concentrations have been described in the setting of acute overdose, and a concentration >1.1 nmol/ml has been suggested as a marker of hepatic injury from acetaminophen overdose in patients with an ALT >1000 IU/L. However, the concentrations of APAP-CYS during therapeutic dosing, in cases of acetaminophen toxicity from repeated dosing and in cases of hepatic injury from non-acetaminophen hepatotoxins have not been well characterized. The objective of this study is to describe APAP-CYS concentrations in these clinical settings as well as to further characterize the concentrations observed following acetaminophen overdose.
Samples were collected during three clinical trials in which subjects received 4 g/day of acetaminophen and during an observational study of acetaminophen overdose patients. Trial 1 consisted of non-drinkers who received APAP for 10 days, Trial 2 consisted of moderate drinkers dosed for 10 days and Trial 3 included subjects who chronically abuse alcohol dosed for 5 days. Patients in the observational study were categorized by type of acetaminophen exposure (single or repeated). Serum APAP-CYS was measured using high pressure liquid chromatography with electrochemical detection.
Trial 1 included 144 samples from 24 subjects; Trial 2 included 182 samples from 91 subjects and Trial 3 included 200 samples from 40 subjects. In addition, we collected samples from 19 subjects with acute acetaminophen ingestion, 7 subjects with repeated acetaminophen exposure and 4 subjects who ingested another hepatotoxin. The mean (SD) peak APAP-CYS concentrations for the Trials were: Trial 1- 0.4 (0.20) nmol/ml, Trial 2- 0.1 (0.09) nmol/ml and Trial 3- 0.3 (0.12) nmol/ml. APAP-CYS concentrations varied substantially among the patients with acetaminophen toxicity (0.10 to 27.3 nmol/ml). No subject had detectable APAP-CYS following exposure to a non-acetaminophen hepatotoxin.
Lower concentrations of APAP-CYS are detectable after exposure to therapeutic doses of acetaminophen and higher concentrations are detected after acute acetaminophen overdose and in patients with acetaminophen toxicity following repeated exposure.
PMCID: PMC3066114  PMID: 21401949
20.  Pre emptive analgesia for reducing pain after cholecystectomy: Oral tramadol vs. acetaminophen codeine 
Considering that protocols of postoperative pain management would be planned regarding the facilities of each center or region and the importance of its proper management to reduce its related complication and improve patient's satisfaction, in this study we compared the effect of orally administrated tramadol and acetaminophen-codeine in this regard.
Materials and Methods:
In this prospective randomized double-blind clinical trial, 136 (68 in tramadol and 68 in acetaminophen codeine groups) ASA I and II patients scheduled for open cholecystectomy under general anaesthesia were enrolled. They randomly allocated to receive oral tramadol (50 mg capsule) or acetaminophen-codeine (325/10 mg) 1 hour before surgery. After surgery they evaluated for postoperative pain using VAS score, analgesic consumption and vomiting.
Mean of postoperative pain score during 24 hours after surgery was 2.1 ± 1.0 and 3.8 ± 2.0 in tramadol and acetaminophen-codeine groups, respectively (P < 0.05). Mean of analgesic consumption (morphine) during 24 hours after surgery was 6.2 ± 4.4 mg and 12.9 ± 5.7 mg in tramadol and acetaminophen-codeine groups, respectively (P < 0.05). Mean of vomiting during 24 hours after surgery was 1.2 ±0.9 and 0.4 ± 0.5 in tramadol and acetaminophen-codeine groups, respectively (P < 0.05).
The findings of current study indicated that in lower dose of tramadol (50 mg) and acetaminophen/codeine (325 mg/10 mg) the analgesic effect of tramadol is better and its side effects are higher than acetaminophen/codeine, which limit its use for mentioned purpose. It seems that administration of each of studied agents it depends on patients’ tolerance and decision of the physician.
PMCID: PMC3732874  PMID: 23930257
Acetaminophen codeine; postoperative pain; tramadol
21.  Comparing the Duration of the Analgesic Effects of Intravenous and Rectal Acetaminophen Following Tonsillectomy in Children 
Postoperative pain control (especially, after adenotonsillectomy) has a very important effect on recovery time, hospitalization duration, hemodynamic disorders, bleeding, nausea, vomiting and medical costs.
The aim of this study was to investigate and compare the effects of intravenous and rectal acetaminophen on controlling post-adenotonsillectomy pain in children, and duration of their analgesic effects.
Patients and Methods:
In this randomized double-blinded clinical trial, 96 children aged 4 - 10 years old with ASA physical status I or II who were candidates for adenotonsillectomy surgery in Amir-al-Momenin Hospital, Rasht, Iran were entered into the study and randomly divided into two equal groups. Anesthesia in both groups was induced injecting fentanyl-thiopental and at racurium; afterwards is of lurane was used to maintain anesthesia. After anesthesia induction, one group received intravenous and the other one, rectal acetaminophen, and were later compared based on CHIPPS criteria.
Data analysis indicated a significant relationship between reduction of postoperative pain and the use of intravenous or rectal acetaminophen (P = 0.0001); in group receiving IV acetaminophen, only 10.4% of patients had no pain whereas in group receiving rectal acetaminophen, this number reached 43.8%. Also, on 4 and 6 hour time intervals, pain in rectal acetaminophen receiving group was less than that in IV acetaminophen receiving group (P < 0.05). Demand for additional analgesic medication in rectal acetaminophen receiving group was less than that in IV group (P = 0.0001).
Post-operative pain in rectal acetaminophen group was less than that in intravenous acetaminophen group, and rectal acetaminophen group demanded their first additional analgesic medication later.
PMCID: PMC3961018  PMID: 24660154
Acetaminophen; Pain, Postoperative; Child, Hospitalized
22.  Comparison of Cold Water Sponging and Acetaminophen in Control of Fever Among Children Attending a Tertiary Hospital in South Nigeria 
A wide range of childhood illnesses are accompanied by fever, leading to varied attempts at treatment by caregivers at home before coming to a hospital. Common modalities of treatment include use of antipyretics and physical methods such as cold water sponging, fanning and removal of clothing. These treatment modalities have been received with varied attitudes among physicians and the scientific community. This study was to assess the efficacy of both modalities in first-line management of fever in our area.
The main aim of the study is to compare the effectiveness of cold water sponging with that of oral paracetamol in the treatment of fever in children attending the University of Calabar Teaching Hospital, Calabar.
Subjects and Methods:
This is a randomized clinical trial. Eighty-eight children aged 12-120 months who presented to the Children Outpatient Clinic (CHOP) and the Children Emergency Room (CHER) of University of Calabar Teaching Hospital, Calabar, with acute febrile illness and axillary temperatures spanning ≥ 38.0-40.0°C. All children within the age limit whose caregivers gave consent were recruited into the study and were randomized to receive either cold water sponging or oral paracetamol. Axillary temperature, pulse rate, respiratory rate and assessment of discomforts (crying, shivering, goose pimples and convulsions) were recorded every 30 min for 2 h. The results were analyzed using the SPSS statistical software and have been presented in the tables.
Cold water sponging was very effective in temperature reduction within the first 30 min, with 29 (70.73%) having their temperature reduced to within normal limits. This declined to 12 (29.26%) at 60 min and 4 (10.53%) at 120 min, with the mean temperature differences from the baseline value following the same trends (1.63°C by 30 min, 0.91°C by 60 min and 0.39°C by 120 min). When compared with paracetamol, cold water sponging was more effective in temperature reduction within the first 30 min (P = 0.000), with the difference in effect at 60 min less significant between these two groups (P = 0.229). Paracetamol demonstrated a gradual and sustained reduction in temperature with the proportions of afebrile children in this group increasing from 7 (16.27%) at 30 min to 33 (78.57%) at 120 min. The mean temperature differences from the baseline value also showed the same trend. Children who received cold water sponging had more discomforts compared with those who received only oral paracetamol.
It is concluded that cold water sponging, although producing rapid reduction in temperature compared with paracetamol, has effects that last only for a short time. Paracetamol on the other hand produces a gradual but sustained effect. The discomforts experienced should not be a limiting factor to the use of cold water sponging in reducing the body temperature of febrile children. Cold water sponging is safe and its use by mothers and primary caregivers should be encouraged while preparing to take the child to the nearest health facility for definitive treatment of the underlying cause of the fever.
PMCID: PMC3894045  PMID: 24479070
Children; cold water sponging; fever; paracetamol; temperature
23.  A systematic review of paracetamol for non-specific low back pain 
European Spine Journal  2008;17(11):1423-1430.
The objective of this study was to assess the efficacy of paracetamol (acetaminophen) in the treatment of pain and disability in patients with non-specific low back pain. We conducted a systematic review of randomized controlled trials to assess the efficacy of paracetamol in the treatment of pain and disability in patients with non-specific low back pain. A search for randomized controlled trials was conducted using the Medline, Embase and CINAHL databases. Trials were eligible if they were randomized controlled trials comparing paracetamol to no treatment, placebo or another treatment in patients with non-specific low back pain. Two of the authors independently assessed trials for methodological quality on the PEDro Scale and extracted data. Continuous pain and disability data were converted to a common 0–10 scale; ordinal data were dichotomized (e.g., no pain, pain). The data was analyzed using the MIX version 1.61 meta-analysis software. Out of 205 unique articles found in the searches, 7 eligible trials were identified. The trials enrolled a total of 676 participants with 5 investigating acute low back pain, 1 investigating chronic low back pain and 1 investigating both. No trial provided data comparing paracetamol to placebo and only one trial compared paracetamol to no treatment. In general the trials were small (only 1 trial had >25 subjects per group) and of low methodological quality (only 2 had a score above 6 on the quality scale). All but one of the trials provided imprecise estimates of the effects of treatment with confidence intervals spanning clinically important beneficial and also harmful effects of paracetamol. No trial reported a statistically significant difference in favor of paracetamol. There is insufficient evidence to assess the efficacy of paracetamol in patients with low back pain. There is a clear need for large, high quality randomized controlled trials evaluating paracetamol, to provide reliable evidence of paracetamol’s effectiveness in patients with low back pain and to establish the validity of the recommendations in clinical guidelines.
PMCID: PMC2583194  PMID: 18797937
Low back pain; Paracetamol; Acetaminophen; Review
24.  Alternating ibuprofen and acetaminophen in the treatment of febrile children: a pilot study [ISRCTN30487061] 
BMC Medicine  2006;4:4.
Alternating ibuprofen and acetaminophen for the treatment of febrile children is a prevalent practice among physicians and parents, despite the lack of evidence on effectiveness or safety. This randomized, double-blind and placebo-controlled clinical trial aims at comparing the antipyretic effectiveness and safety of a single administration of alternating ibuprofen and acetaminophen doses to that of ibuprofen mono-therapy in febrile children.
Seventy febrile children were randomly allocated to receive either a single oral dose of 10 mg/kg ibuprofen and 15 mg/kg oral acetaminophen after 4 hours, or a similar dose of ibuprofen and placebo at 4 hours. Rectal temperature was measured at baseline, 4, 5, 6, 7 and 8 hours later. Endpoints included proportions of afebrile children at 6, 7 and 8 hours, maximum decline in temperature, time to recurrence of fever, and change in temperature from baseline at each time point. Intent-to-treat analysis was planned with statistical significance set at P < 0.05.
A higher proportion of subjects in the intervention group (83.3%) became afebrile at 6 hours than in the control group (57.6%); P = 0.018. This difference was accentuated at 7 and 8 hours (P < 0.001) with a significantly longer time to recurrence of fever in the intervention group (mean ± SD of 7.4 ± 1.3 versus 5.7 ± 2.2 hours), P < 0.001. Odds ratios (95%CI) for defervescence were 5.6 (1.3; 23.8), 19.5 (3.5; 108.9) and 15.3 (3.4; 68.3) at 6, 7 and 8 hours respectively. Two-way ANOVA with repeated measures over time revealed a significantly larger decline in temperature in the intervention group at times 7 (P = 0.026) and 8 (P = 0.002) hours.
A single dose of alternating ibuprofen and acetaminophen appears to be a superior antipyretic regimen than ibuprofen mono-therapy. Further studies are needed to confirm these findings.
PMCID: PMC1421419  PMID: 16515705
25.  TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner 
Cell Death & Disease  2012;3(12):e447-.
Paracetamol (acetaminophen, APAP) is a universally used analgesic and antipyretic agent. Considered safe at therapeutic doses, overdoses cause acute liver damage characterized by centrilobular hepatic necrosis. One of the major clinical problems of paracetamol-induced liver disease is the development of hemorrhagic alterations. Although hepatocytes represent the main target of the cytotoxic effect of paracetamol overdose, perturbations within the endothelium involving morphological changes of liver sinusoidal endothelial cells (LSECs) have also been described in paracetamol-induced liver disease. Recently, we have shown that paracetamol-induced liver damage is synergistically enhanced by the TRAIL signaling pathway. As LSECs are constantly exposed to activated immune cells expressing death ligands, including TRAIL, we investigated the effect of TRAIL on paracetamol-induced LSEC death. We here demonstrate for the first time that TRAIL strongly enhances paracetamol-mediated LSEC death with typical features of apoptosis. Inhibition of caspases using specific inhibitors resulted in a strong reduction of cell death. TRAIL appears to enhance paracetamol-induced LSEC death via the activation of the pro-apoptotic BH3-only proteins Bid and Bim, which initiate the mitochondrial apoptotic pathway. Taken together this study shows that the liver endothelial layer, mainly LSECs, represent a direct target of the cytotoxic effect of paracetamol and that activation of TRAIL receptor synergistically enhances paracetamol-induced LSEC death via the mitochondrial apoptotic pathway. TRAIL-mediated acceleration of paracetamol-induced cell death may thus contribute to the pathogenesis of paracetamol-induced liver damage.
PMCID: PMC3542621  PMID: 23254290
liver sinusoidal endothelial cells (LSEC); paracetamol; TRAIL; Bcl-2 homologs; apoptosis

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