Serum Concentrations Of Acetaminophen Research Articles

Early biomarkers predicting outcome in a porcine model of acetaminophen intoxication: A pilot study.

Acetaminophen intoxication has become the leading cause of acute liver failure (ALF) in Europe and the USA. To identify early biomarkers in order to predict the development of ALF in a porcine model of acetaminophen intoxication. Six German Landrace pigs received a single acetaminophen bolus of 1 g/kg body weight via a jejunal catheter. Cytokines and laboratory parameters were analyzed at 8-hour intervals for a total of 40 h. Three of the 6 animals survived the intoxication. The nonsurviving animals had an increase in serum lactate and interleukin (IL)-6, with a simultaneous decrease in prothrombin time (PT) and albumin concentration 8 h after intoxication. In all nonsurviving animals, elevated levels of tumor necrosis factor alpha (TNF-α) at baseline before intoxication and during the course of ALF were observed. The acetaminophen serum concentrations and toxicokinetics did not differ between the nonsurviving and surviving animals. Methemoglobinemia was proportional to the administered doses and acetaminophen blood levels, but methemoglobinemia did not affect survival. Tumor necrosis factor alpha, IL-6, lactate, prothrombin time, and albumin blood concentration were identified as early predictors of outcome after acetaminophen intoxication. An elevated TNF-α level before acetaminophen exposure was the earliest prognostic marker for a lethal outcome. Therefore, it could serve as a very early indicator of prognosis.

Bioavailability of rectal acetaminophen in children following anorectal surgery

BackgroundAcetaminophen is widely used as an analgesic and antipyretic agent in pediatrics.Although bioavailability of rectal acetaminophen is unpredictable, rectal route is a usual and acceptable method of prescription. Major anorectal surgery may alter the normal structure of the surgical site, especially the vascular elements and the normal connections between port and systemic vessels. As a result the pharmacokinetics of rectal medications might also be altered.Based on this hypothesis, we decided to study acetaminophen plasma concentration among children who underwent these types of surgeries to determine the pharmacokinetic of absorption, plasma concentration, safety, and efficacy of rectal acetaminophen. Materials and methodsThe study included 20 cases with previous history of pull-through procedure owing to Hirschsprung's disease (HD), 20 cases with imperforate anus (IA) reconstructive surgeries who were admitted for colostomy closure, and 20 otherwise healthy cases of inguinal herniotomy. Venus blood sampling was done 4, 8 and 12 hrs after a single loading dose of rectal acetaminophen (40 mg/kg), and plasma acetaminophen concentration was compared between groups. ResultsMean serum acetaminophen levels of the HD group were significantly higher than those of the herniotomy group (36.3 ± 6.79, 27.4 ± 8.42, 16.8 ± 7.62 versus 25.9 ± 9.12, 16.7 ± 6.74, 8.1 ± 5.79 (μg/ml) at 4, 8 and 12 hrs after drug administration and P < 0.05). The IA group had higher concentrations of plasma acetaminophen compared to the herniotomy group; however, the p values were not statistically significant. (31.4 ± 10.39, 21.5 ± 9.12, 13.3 ± 6.79 versus 25.9 ± 9.12, 16.7 ± 6.74, 8.1 ± 5.79 (μg/ml) at 4, 8 and 12 hrs after drug administration). Serum concentrations of acetaminophen in IA and HD patients were above the therapeutic range four hours after administering the loading dose (31.4 ± 10.39 and 36.3 ± 6.79 versus 5–20 μg/ml). ConclusionBioavailability of rectal acetaminophen might get altered after major anorectal surgery in children. Rectal acetaminophen should be administered with special caution among infants with history of anorectal operations. Repeated dose of rectal acetaminophen may cause the drug blood concentration to reach toxic levels in these patients. Type of studyProspective comparative study. Level of evidenceLevel II.

Acetaminophen Serum Concentrations in Infants Treated Intravenously for Patent Ductus Arteriosus.

Although acetaminophen has emerged as a therapeutic option for treating hemodynamically significant patent ductus arteriosus (PDA) in preterm infants, limited data exist on pharmacodynamics. The objective of this research is to report serum acetaminophen concentrations at steady state in infants treated with intravenous acetaminophen for PDA and to examine associations with clinical outcomes. This retrospective study evaluated all infants admitted during the study period who received intravenous acetaminophen for the treatment of PDA. Acetaminophen dosing was 15 mg/kg every 6 hours. A serum acetaminophen concentration was obtained 4 hours after the eighth dose. Associations between serum concentrations and efficacy, assessed by ductal constriction on echocardiogram, and safety, assessed by serum creatinine and hepatic transaminases, were explored using simple linear regression. A total of 36 infants were included, with a median birth weight of 720 g (IQR 585-895 g) and a median gestational age of 25 weeks (IQR 24-26 weeks). The median acetaminophen concentration in the cohort was 12.3 mg/L (IQR 6.7-16.5 mg/L; range, 1.1-29.0 mg/L). Serum acetaminophen concentrations did not correlate with infant demographics, hepatic transaminases during treatment, or duct size at treatment completion. We observed ductal closure across a wide range of serum acetaminophen concentrations. We did not identify an association between acetaminophen serum concentrations following intravenous therapy and ductal response or hepatic toxicity.

Puzzling situation of acetaminophen toxicity in a referral hospital, Tehran, Iran

Puzzling situation of acetaminophen toxicity in a referral hospital, Tehran, Iran Acetaminophen carries a higher risk of overdose. A puzzling situation of acetaminophen toxicity was encouraging enough to explore the epidemiologic situation of acetaminophen toxicity and its outcomes among patients acquired poisoning. This cross-sectional study retrospectively reviewed the medical records of 185 patients with acetaminophen poisoning referred to Loghman Hakim Hospital. Toxicity determined by acetaminophen serum concentration and time elapsed after drug ingestion. Demographics, laboratory markers, toxic hepatitis, renal failures and liver enzyme elevations were compared between toxic and non-toxic patients. Twelve cases belonged to the former group and 173 patients fitted with the latter one. Having a mean age of 24.27±7.19 and 21.58±3.47 years, respectively; females were predominant. The average serum acetaminophen level was 70.37±61.92 and 24.90±26.36 within toxic and nontoxic patients respectively. Median of consumed tablets were estimated as 40 for non-toxic and 18 for toxic patients (p=0.017). Mean hospital stay was 1.75±1.05 days for toxic patients and 1.35±3.25 days for the non-toxic group (p-value<0.001), and of whom 92.4 % discharged within the first day. The laboratory assessments revealed no significant difference between groups. No death was recorded. Whereas hepatotoxicity was present in three toxic patients, renal failure was predominant in non-toxic patients. Rarely, a rise in liver enzyme noticed, however, 33.33 % of toxic and 2.31 % of the non-toxic group had elevated AST; and 33.33 % of toxic versus 1.73 % percent of non-toxic patients had increased ALT. Acetaminophen toxicity is a worldwide noteworthy cause of poisoning which has distinct mortality and morbidity rates and showed an amazing and undebatable poisoning effect in the present study. A comprehensive study is required to examine the possible reasons for the difference between Iranian acetaminophen products with other non-Iranian company products. Keywords: Acetaminophen; Hepatotoxicity; Poisoning; Renal failure; Toxicity; Iranian

Evaluation of Prothrombin Time in Acute Acetaminophen Overdose treated by N-acetylcysteine

Background: Acetaminophen (N-Acetyl-p aminophenol; APAP) is one of the most common types of analgesics. It is also the most common xneobitic reported to poison centers. This study investigates if therapeutic doses of NAC can falsely increase coagulation tests, prothrombin time (PT) and bleeding time (BT). ​​ Methods: Thirty-six APAP poisoned patients whose acetaminophen serum concentration were in toxic zone in the Rummak-Matheiw graph were treated by NAC according to standard intravenous 21 hours protocol. Prothrombin time (PT) and bleeding time (BT) in all cases were measured before the start of the NAC and at the 8th and 16th hour of the treatment. Results: The mean age of the cases was 21.5 ± 5.12 years old. Among them, 31 cases (86%) were female. The mean dose of ingested APAP was 9.6 ±2.0 grams (7.8 – 16.1 g). Mean of SLA was 196.0±37.7. The means of BT were nor significantly different at all evolution times (2.6±0.64, 2.6±0.62 and 2.6± 0.6. The means of PT rose at 16th hour of NAC treatment in as compared 8th hour (16.1± 1.1 s 12.3±0.6 s, respectively) (P <0.001). Conclusion: With specific reference to our study results, a low level of rising PT resulting from an NAC treatment is not a reliable indicator of liver damage. Further investigation on the effect of NAC on clotting factors is recommended.

Evaluating human liver reserve function by measuring serum concentrations of phenacetin and its metabolites

To evaluate human liver reserve function (LRF) by a simple and efficient method for measuring serum concentrations of phenacetin and its metabolites. Overall 20 patients with liver cirrhosis (Child-Pugh score ≥ 7, aged 48-79 years), 30 healthy young volunteers (aged 18-40 years), and 20 healthy elderly volunteers (aged 61-80 years) were enrolled. All participants received a single oral dose of 0.5 g phenacetin. Liquid chromatography tandem mass spectrometry was used to determine the serum concentrations of phenacetin and its metabolites, including acetaminophen, acetaminophen glucuronide and acetaminophen sulfate. The serum concentration of phenacetin was significantly higher in cirrhotic patients than those in either of the healthy volunteer groups (P < 0.001). It was higher in healthy elderly volunteers than that in healthy young ones but there was no statistically significant difference (P > 0.05) between them. The serum concentrations of acetaminophen, acetaminophen glucuronide and acetaminophen sulfate were significantly lower in cirrhotic patients than in the healthy controls (P < 0.001). The serum concentrations of these three metabolites in healthy elderly volunteers were lower than those in healthy younger volunteers but again, there was no statistical significant difference (P > 0.05). The serum concentration of acetaminophen in healthy male volunteers was significantly higher than that in the women (P < 0.05). Monitoring cytochrome P450 1A2 (CYP450 1A2)-mediated phenacetin metabolism is a simple and efficient method for evaluating human LRF. This method would warrant further validation in a large cohort clinical study.

Influence of acetaminophen at therapeutic doses on surrogate markers of severity of acute viral hepatitis

Data on the influence of acetaminophen intake on acute viral hepatitis is scarce, but it could play a role in the worsening of this disease. The aim of this study was to determine whether the intake of acetaminophen at therapeutic doses affects the severity of acute viral hepatitis. This was a prospective study concerning 37 consecutive patients hospitalized for acute viral hepatitis. Acetaminophen consumption and time since last intake were assessed by a questionnaire. Parameters of severity were studied in comparison to time related serum concentrations of acetaminophen. Patients hospitalized for acute viral hepatitis (18 male, 19 female patients) had a mean age of 29.2 +/- 11.5 years. The causal virus was HAV (n=23), HBV (n=7) and other viruses (n=8). The mean cumulated dose of acetaminophen was 7.7 +/- 5.65 g. The daily dose did not exceed the therapeutic dosage and the mean was 1.95 +/- 0.81 g (1-3 g). Patients who received 7.5 g of acetaminophen or more had a lower prothrombin index 52.4 +/- 30.3% vs 74.2 +/- 17.2% (P=0.039), and a lower factor V 54.7 +/- 33.2% vs 83.3 +/- 19.6% (P=0.033). Prothrombin index and bilirubinemia were negatively correlated with time related plasma acetaminophen concentrations. The use of acetaminophen at therapeutic doses was associated with greater alterations of surrogate markers of the severity of acute viral hepatitis especially hepatitis A. This was related to cumulated dosages and correlated to the time related acetaminophen plasma concentrations. Acetaminophen use should be interrupted when acute hepatitis is suspected.

High-dose rectal and oral acetaminophen in postoperative patients--serum and saliva concentrations.

The primary purpose of the study was to examine the absorption of acetaminophen by measuring serum and saliva concentrations produced by a standard postoperative acetaminophen dosing regimen and secondary to examine the correlation between saliva and serum concentrations of acetaminophen after rectal and oral dosing. Twenty-four women, aged 18-60 years, scheduled for minor gynaecological laparoscopic surgery were studied. Patients received acetaminophen 2000 mg suppositories after surgery and oral doses of 1000 mg at 4 and 8 h postoperatively. Alfentanil was available via patient-controlled analgesia. Saliva and blood samples were collected postoperatively. At 1, 2, 3, and 4 h after rectal dosing the saliva concentrations (mean+/-SD) were 15.2+/-5.9 micromol/l, 33.7+/-12.5 micromol/l, 45.5+/-19.1 micromol/l, and 55.4+/-23.1 micromol/l, respectively. The serum concentrations at 2 and 4 h were 31.0+/-11.2 micromol/l and 54.8+/-23.8 micromol/l, respectively. Additional oral dosing resulted in saliva concentrations at 5, 8, and 9 h of 99.7+/-49.5 micromol/l, 106.9+/-31.7 micromol/l, and 139.3+/-55.4 micromol/l, respectively, with coincident serum concentrations of 100.1 +/- 50.2 micromol/l, 105.6+/-29.0 micromol/l, and 141.2+/-52.1 micromol/l. After rectal dosing the linear regression resulted in r2=0.96, P<0.001 and saliva/ serum-ratio=0.99. After additional oral dosing the outcome of linear regression was: r2=0.90, P<0.001 and saliva/serum-ratio= 1.00. The slow and ongoing absorption process resulting in no maximum concentration within 4 h after administration of 2000 mg acetaminophen suppositories makes this rectal regimen therapeutically irrational for treatment of postoperative pain. The significant ratio and linear correlation between saliva and serum concentrations of acetaminophen suggests that saliva could be used instead of blood to monitor acetaminophen administration in patients.

Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose.

The evidence for efficacy of gastric lavage and activated charcoal for gastrointestinal decontamination in poisoning has relied entirely on volunteer studies and/or pharmacokinetic studies and evidence for any clinical benefits or resource savings is lacking. To investigate the value of gastrointestinal decontamination using gastric lavage and/or activated charcoal in acetaminophen (paracetamol) poisoning. We analyzed a series of 981 consecutive acetaminophen poisonings. These patients were treated with gastric lavage and activated charcoal, activated charcoal alone, or no gastrointestinal decontamination. The decision as to which treatment was received was determined by patient cooperation, the treating physician, coingested drugs, and time to presentation after the overdose. Of 981 patients admitted over 10 years, 10% (100) had serum concentrations of acetaminophen that indicated a probable or high risk of hepatotoxicity. The risk of toxic concentrations for patients ingesting less than 10 g of acetaminophen was very low. In patients presenting within 24 hours, who had ingested 10 g or more, those who had been given activated charcoal were significantly less likely to have probable or high risk concentrations (Odds ratio 0.36, 95% CI 0.23-0.58, p < 0.0001). Gastric lavage, in addition to activated charcoal, did not further decrease the risk (Odds ratio 1.12, 95% CI 0.57-2.20, p = 0.86). Toxic concentrations of serum acetaminophen (paracetamol) are uncommon in patients ingesting less than 10 g. In those ingesting more, activated charcoal appears to reduce the number of patients who achieve toxic acetaminophen concentrations and thus may reduce the need for treatment and hospital stay.

Acetaminophen as a marker of gastric emptying in ponies.

Gastric emptying was evaluated in ponies using the acetaminophen (AP) method. Fifteen minutes after i.v. administration of metoclopramide, erythromycin, yohimbine, atropine or saline, the ponies were given AP by stomach tube. Blood samples for AP analysis were collected at baseline and 15, 30, 45, 60, 75, 90, 105 and 120 min after AP administration. Time to reach peak serum concentration (Tmax), maximum serum concentration (Cmax) and area under the AP serum concentration vs. time curve (AUC) were determined for each treatment group. In the control group, Tmax was 31 min and this decreased significantly (P < 0.05) following the administration of metoclopramide. Atropine significantly increased Tmax and decreased Cmax and AUC. Yohimbine significantly increased AUC. Erythromycin did not significantly change any parameter. This study indicates that acetaminophen can be used to evaluate gastric emptying in ponies. The method is easy to perform and is minimally invasive. Metoclopramide stimulated gastric emptying of liquid in healthy, fasting ponies. Atropine significantly delayed, while erythromycin had little effect on, gastric emptying. Yohimbine increased the cumulative absorption of AP.

Acetaminophen in the management of background pain in children post-burn.

This retrospective review evaluated the pain management of 395 acutely burned pediatric patients who were treated by a pain management protocol emphasizing acetaminophen as the initial medication to control background pain. Pain was assessed by using standardized instruments based on observations by patients, nurses, and parents. Morphine was added when scheduled acetaminophen (10-15 mg/kg/4 hr) did not control background pain. Fifty percent of the children received only acetaminophen to control background pain. Younger children and children with the smallest burns, regardless of age, were likely to be managed with acetaminophen alone. Most peak serum concentrations of acetaminophen were less than 10 micrograms/mL. When needed, children also received medication for painful procedures, anxiety, and posttraumatic stress symptoms. These additional medications were not more frequently given to children receiving only acetaminophen for background pain. These data suggest that acetaminophen is a safe, useful medication for the control of post-burn background pain in some children.

Prediction of Acetaminophen Concentrations in Overdose Patients Using a Bayesian Pharmacokinetic Model

A pharmacokinetic program using population-based parameter estimates and a Bayesian forecasting model was retrospectively evaluated for predicting acetaminophen serum concentrations in overdose patients. Dynamic disposition factors known to affect acetaminophen disposition (emesis, activated charcoal, N-acetylcysteine, etc.) were included in the program. Twenty six patients who reported an acetaminophen ingestion of at least 70 mg/kg within 24 h of presentation to the hospital and had at least one measured acetaminophen concentration were included. Prediction of initial acetaminophen concentrations using only population-based parameter estimates resulted in a percent mean error (%ME) and percent mean absolute error (%MAE) of 9.3 and 42.2, respectively. Using only the initial concentration as feedback, the Bayesian forecasting model accurately predicted the second acetaminophen concentration (%ME = 4.0, %MAE = 23.6). The Bayesian model also accurately predicted all concentrations within 8 h of the ingestion (%ME = 10.6, %MAE = 24.0). The prediction of concentrations between 2 to 4 h and 4 to 4.5 h after ingestion with only population-based parameter estimates resulted in %ME of 17.0 and 13.2, respectively, and %MAE of 36.5 and 35.1, respectively. Our data suggests that acetaminophen serum concentrations occurring within the first 4.5 h after ingestion can be reliably predicted by the set of population-based parameter estimates evaluated. Once a single acetaminophen concentration is available, the Bayesian forecasting model can accurately predict subsequent concentrations within the first 8 h after an acetaminophen ingestion.

Acetaminophen pharmacokinetics: Comparison between pregnant and nonpregnant women

Acetaminophen is the most commonly taken drug during pregnancy, but knowledge about its absorption and disposition is lacking. Six healthy women volunteered to ingest a standard 1000 mg dose at 36 weeks' gestation and 6 weeks post partum. Mean maternal serum concentrations of acetaminophen were consistently less than but not significantly different from the postpartum values. The mean half-life of acetaminophen during pregnancy (3.7 hours) was not significantly different from the nonpregnant value (3.1 hours). The maximum plasma concentration occurred at 0.8 hours and was 20.8 ± 6.9 μg/ml during pregnancy and 23.7 ± 6.0 μg/ml in the nonpregnant state. The absorption, metabolism, and renal clearance of acetaminophen were unchanged. The decrease in the mean area under the curve during pregnancy may be explained by the increase in volume of distribution of acetaminophen. Potentially hepatotoxic metabolites were not measurable in the maternal serum. We conclude that the absorption and disposition of acetaminophen, when used in a standard oral dose, are not affected by pregnancy.

ACETAMINOPHEN ACCUMULATION IN PEDIATRIC PATIENTS AFTER REPEATED THERAPEUTIC DOSES

Acetaminophen is commonly used to control fever but little is known about its kinetics in infants and children after repeated doses. Twenty-one patients (age 0.5-6.4 yrs) with fever received acetaminophen elixir at a dose of 72-90 mg/kg/day given in divided doses as 12-15 mg/kg every 4 hr or 24-30 mg/kg every 8 hr. Multiple blood samples were collected and analyzed by HPLC after the first dose and/or at steady-state (1-3 days of therapy). Maximum acetaminophen serum concentration ranged from 10.2-19.6 μg/ml in patients on every 4 hr schedule and 13.9-40.1 μg/ml in those on every 8 hr schedule. Area under the serum concentration-time curve (AUC) normalized for dose/kg averaged 0.209 (ml/min/kg)−1 and elimination half-life averaged 2.3 hr. In 10 patients, total normalized AUC averaged 0.181 and 0.202 (ml/min/kg)−1 after the first dose and at steady-state, respectively (p<0.05). Five patients showed a 13.2-43 5% increase and one had a 10.4% decrease in AUC; four had <6% change in the AUC. There was no evidence of hepatotoxicity. These data suggest that acetaminophen may accumulate after repeated therapeutic doses in children with fever.

Acetaminophen accumulation in pediatric patients after repeated therapeutic doses

Acetaminophen serum concentrations were studied in 21 infants and children with fever. The maximum serum concentrations ranged from 9.96 to 19.6 micrograms/ml after a single dose of 12-14 mg/kg and 13.9 to 40.1 micrograms/ml after a single dose of 22-27 mg/kg. Ten patients were restudied at steady-state after repeat doses had been given every 4 or 8 h for 1 to 3 days. Total area under the acetaminophen serum concentration-time curve normalized for dose averaged 0.181 (ml/min/kg)-1 after the first dose and 0.202 (ml/min/kg)-1 at steady-state (p less than 0.05). Five patients showed a 13 to 44% increase in the AUC; one had a 10% decrease in the AUC; and four had less than 6% change in the AUC. There was no evidence of hepatotoxicity. These data suggest that acetaminophen may accumulate after repeated therapeutic doses in children with fever.

Colorimetric method for the quantitative determination of acetaminophen in serum.

A colorimetric method for quantitatively determining acetaminophen in serum is presented. The procedure involves preparing a protein-free filtrate by the addition of trichloroacetic acid, hydrolyzing the acetaminophen in the filtrate to p-aminophenol, and subsequent reaction of p-aminophenol with phenol and NH4OH to form an indophenol blue chromogen. The absorbance at 620 nm of this chromogen follows Beer's law up to acetaminophen concentrations of greater than 50 mg/1. The recovery of acetaminophen from serum is essentially 100% when compared with appropriately prepared standards. Serum acetaminophen concentrations as low as 1 mg/1 can be detected. Seventy drugs were tested for possible interference and none was found to interfere with the method. The coefficient of variation (day-to-day) is 4%. This new quantitative method provides the necessary sensitivity to quantitate therapeutic as well as toxic serum concentrations of acetaminophen.