Activated charcoal alone or after gastric lavage: a simulated large paracetamol intoxication. Early indicators of prognosis in fulminant hepatic failure: an assessment of the King's criteria. Efficacy of ipecac during the first hour after drug ingestion in human volunteers. Experiences in the treatment of fulminant hepatic failure by conservative therapy, charcoal haemoperfusion, and polyacrylonitrile haemodialysis. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Treatment of acetaminophen poisoning. The use of oral methionine. Cimetidine as adjunctive treatment for acetaminophen overdose. Effects of PEG-electrolyte (Colyte) lavage on serum acetaminophen concentrations. A model for treatment of acetaminophen overdose. Acute liver failure: clinical features, outcome analysis, and applicability of prognostic criteria. Effect of whole bowel irrigation on the pharmacokinetics of an acetaminophen formulation and progression of radiopaque markers through the gastrointestinal tract. Controlled trials of charcoal hemoperfusion and prognostic factors in fulminant hepatic failure. The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N-acetylcysteine. [Evaluation of the efficacy of N-acetylcysteine administered alone or in combination with activated charcoal in the treatment of acetaminophen overdoses]. Use and outcome of liver transplantation in acetaminophen-induced acute liver failure. Effect of anticholinergic drugs on the efficacy of activated charcoal. Treatment of acetaminophen ingestion with a superactivated charcoal-cola mixture. Evaluation of activated charcoal-sodium sulfate combination for inhibition of acetaminophen absorption and repletion of inorganic sulfate. Fulminant hepatic failure: outcome after listing for highly urgent liver transplantation-12 years experience in the nordic countries. Controlled trial of cysteamine in treatment of acute paracetamol (acetaminophen) poisoning. Efficacy of superactivated charcoal administered late (3 hours) after acetaminophen overdose. Comparison of activated charcoal and ipecac syrup in prevention of drug absorption. Charcoal haemoperfusion for paracetamol overdose. Serum phosphate as a predictor of outcome in acetaminophen-induced fulminant hepatic failure. Oral methionine in the treatment of severe paracetamol (Acetaminophen) overdose. Methionine and cysteamine in paracetamol (acetaminophen) overdose, prospective controlled trial of early therapy. A comparison of the efficacy of gastric lavage, ipecacuanha and activated charcoal in the emergency management of paracetamol overdose. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose. A prospective evaluation of the effect of activated charcoal before oral N-acetylcysteine in acetaminophen overdose. Cimetidine--acetaminophen interaction in humans. Gastric lavage for liquid poisons. Ipecac-induced emesis and reduction of plasma concentrations of drugs following accidental overdose in children. Shorter duration of oral N-acetylcysteine therapy for acute acetaminophen overdose. Serum phosphorus levels predict clinical outcome in fulminant hepatic failure. Treating paracetamol overdose by charcoal haemoperfusion and long-hours high-flux dialysis. Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine. Cysteamine, methionine, and penicillamine in the treatment of paracetamol poisoning. Early changes in coagulation following a paracetamol overdose and a controlled trial of fresh frozen plasma therapy. Paracetamol overdose and hepatotoxicity at a regional Australian hospital: a 4-year experience. Late treatment of paracetamol poisoning with mercaptamine. Comparative antidotal efficacy of activated charcoal tablets, capsules and suspension in healthy volunteers. Admission levels of serum Gc-globulin: predictive value in fulminant hepatic failure. Sorbitol catharsis does not enhance efficacy of charcoal in a simulated acetaminophen overdose. Efficacy of charcoal cathartic versus ipecac in reducing serum acetaminophen in a simulated overdose. Serious paracetamol poisoning and the results of liver transplantation. How long after drug ingestion is activated charcoal still effective? Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol. Effectiveness of delayed activated charcoal administration in simulated paracetamol (acetaminophen) overdose.
Activated charcoal is now being recommended for patients who have ingested potentially toxic amounts of a poison, where the ingested substance adsorbs to charcoal. Combination therapy with gastric lavage and activated charcoal is widely used, although clinical studies to date have not provided evidence of additional efficacy compared with the use of activated charcoal alone. There are also doubts regarding the efficacy of activated charcoal, when administered more than 1 h after the overdose. The aim of this study was to examine if there was a difference in the effect of the two interventions 1 h post ingestion, and to determine if activated charcoal was effective in reducing the systemic absorption of a drug, when administered 2 h post ingestion.
                We performed a four-limbed randomized cross-over study in 12 volunteers, who 1 h after a standard meal ingested paracetamol 50 mg kg(-1) in 125 mg tablets to mimic real-life, where several factors, such as food, interfere with gastric emptying and thus treatment. The interventions were activated charcoal after 1 h, combination therapy of gastric lavage followed by activated charcoal after 1 h, or activated charcoal after 2 h. Serum paracetamol concentrations were determined by h.p.l.c. Percentage reductions in the area under the curve (AUC) were used to estimate the efficacy of each intervention (paired observations).
                There was a significant (P<0.005) reduction in the paracetamol AUC with activated charcoal at 1 h (median reduction 66%, 95% confidence intervals 49, 76) compared with controls, and a significant (P<0.01) reduction for gastric lavage followed by activated charcoal at 1 h (median reduction 48.2%, 95% confidence interval 32.4, 63.7) compared with controls. There was no significant difference between the two interventions (95% confidence interval for the difference -3.8, 34.0). Furthermore, we found a significant (P<0.01) reduction in the paracetamol AUC when activated charcoal was administered 2 h after tablet ingestion when compared with controls (median 22.7%, 95% confidence intervals 13.6--34.4).
                These results suggest that combination treatment may be no better than activated charcoal alone in patients presenting early after large overdoses. The effect of activated charcoal given 2 h post ingestion is substantially less than at 1 h, emphasizing the importance of early intervention. An accurate and early assessment of the individual patient is critical in deciding whether liver transplantation is indicated in the treatment of fulminant hepatic failure. Based on analysis of patients treated between 1973 and 1985, the Liver Unit at King's College Hospital, London, developed a prognostic model to identify patients with a poor prognosis. The present study was done to determine the applicability of this model in fulminant hepatic failure patients seen at our center in the 1990s.
                The records of 145 patients with fulminant hepatic failure, treated conservatively at Queen Elizabeth Hospital, Birmingham between 1990 and 1994, were analyzed. An additional 81 patients, who were transplanted for fulminant hepatic failure during the same period were excluded from the study.
                Application of King's College Hospital criteria at the time of admission to this hospital in the acetaminophen group, had a positive predictive value of 88%, negative predictive value of 65% and predictive accuracy of 71%. The positive predictive value, negative predictive value and predictive accuracy of these criteria for non-acetaminophen-induced fulminant hepatic failure, were 79%, 50% and 68%. Multivariate analysis identified prothrombin time, serum creatinine, white cell count and abnormal potassium levels as independent predictors of mortality in acetaminophen-induced fulminant hepatic failure; and prothrombin time alone in fulminant hepatic failure induced by other etiologies.
                The King's College Hospital criteria for predicting outcome of fulminant hepatic failure were found to have a slightly lower predictive accuracy than shown in the original study. To determine the decrease of drug absorption when syrup of ipecac is administered at various times within one hour of drug ingestion.
                Ten healthy human volunteers were recruited for a four-limbed randomized crossover study. The three experimental limbs consisted of administration of 30 mL syrup of ipecac, at 5, 30, or 60 minutes after ingestion of 3900 mg acetaminophen as 12 x 325 mg tablets with 250 mL room temperature water. The fourth limb served as control. Blood samples were drawn at 0, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, and 8.0 hours after analgesic ingestion for serum acetaminophen concentration determination by high-performance liquid chromatography. Repeated measures ANOVA and Tukey's HSD tests were used for group comparisons.
                The area under the serum concentration vs time curve was (mean +/- SD) 206 +/- 48, 67 +/- 37, 183 +/- 78, and 162 +/- 47 mg/L for control, 5, 30, and 60 minutes, respectively. This corresponds to decreases in bioavailability of 67, 11, and 21%. Only the 5-minute group differed significantly from control (p < 0.05). Sedation was observed as a significant adverse effect of ipecac administration.
                Our data do not support benefit from ipecac administration at 30 minutes and beyond. Our data suggest that benefit is lost at some point between 5 and 30 minutes. The sedative effect of ipecac may confound the observation of patients who have ingested sedative hypnotic agents. nan Severe acetaminophen hepatotoxicity frequently leads to acute liver failure (ALF). We determined the incidence, risk factors, and outcomes of acetaminophen-induced ALF at 22 tertiary care centers in the United States. Detailed prospective data were gathered on 662 consecutive patients over a 6-year period fulfilling standard criteria for ALF (coagulopathy and encephalopathy), from which 275 (42%) were determined to result from acetaminophen liver injury. The annual percentage of acetaminophen-related ALF rose during the study from 28% in 1998 to 51% in 2003. Median dose ingested was 24 g (equivalent to 48 extra-strength tablets). Unintentional overdoses accounted for 131 (48%) cases, intentional (suicide attempts) 122 (44%), and 22 (8%) were of unknown intent. In the unintentional group, 38% took two or more acetaminophen preparations simultaneously, and 63% used narcotic-containing compounds. Eighty-one percent of unintentional patients reported taking acetaminophen and/or other analgesics for acute or chronic pain syndromes. Overall, 178 subjects (65%) survived, 74 (27%) died without transplantation, and 23 subjects (8%) underwent liver transplantation; 71% were alive at 3 weeks. Transplant-free survival rate and rate of liver transplantation were similar between intentional and unintentional groups. In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States. Susceptible patients have concomitant depression, chronic pain, alcohol or narcotic use, and/or take several preparations simultaneously. Education of patients, physicians, and pharmacies to limit high-risk use settings is recommended. One hundred thirty-two cases of severe acetaminophen (paracetamol) poisoning were treated with oral methionine. Seven of 96 patients who received the antidote within ten hours of ingestion of the overdose had severe liver damage (aspartate transaminase level, greater than 1,000 IU/L), but none of these patients died. Thirty-six patients received methionine between ten and 24 hours of ingestion; severe liver damage occurred in 47%, and two patients died. The treatment protocol for oral methionine is simple, and therapy is complete within 12 hours as compared with three days for oral acetylcysteine and 20 hours for intravenous acetylcysteine. Side effects from methionine were unimportant. Oral methionine is as effective as acetylcysteine in preventing severe liver damage and death after acetaminophen overdose. However, as with acetylcysteine, it must be given within ten hours of ingestion to be effective. The aim of this study was to determine if cimetidine in addition to N-acetylcysteine and standard supportive care provide additional hepatoprotection following acute acetaminophen poisoning. It was designed as a prospective study with alternate month treatment protocol, and the work was carried out at a regional certified poison information centre. For a 2-year period, consultations received by the Rocky Mountain Poison Center involving acute acetaminophen overdose patients with a serum level above the nomogram line, but who would not receive N-acetylcystine therapy until at least 8 h postingestion, were prospectively evaluated for adjunctive treatment with cimetidine. All patients received standard supportive therapy and N-acetylcysteine treatment. During odd numbered months, cimetidine 300 mg was administered intravenously every 6 h for the duration of N-acetylcysteine therapy. Forty-one cimetidine treated patients were compared to 66 patients in the control group. The peak measured AST levels (+/- s.e.) were 1259+/-330 and 1301+/-451 for the control and cimetidine treatment groups, respectively (P = 0.94). Fourteen of 64 patients (21%) in the control group and 8/41 patients (20%) in the cimetidine group developed an AST > 1000 IUL-1. There were no statistical differences between the cimetidine-treated and control groups when classified by AST < 100 IUL-1, 100-1000 IUL-1, or > 1000 IUL-1. The addition of cimetidine therapy to standard N-acetylcysteine treatment did not provide additional hepatoprotection in acutely acetaminophen poisoned patients when treatment was started later than 8 h post overdose.(ABSTRACT TRUNCATED AT 250 WORDS) The purpose of this study was to evaluate whole gut lavage with polyethylene glycol electrolyte solution (Colyte), as a potentially adjunctive measure in lowering serum acetaminophen levels. The effect of bowel lavage was evaluated on serial serum acetaminophen concentrations after 2-g and 4-g doses in 7 and 12 male patients, respectively. Mean peak level of serum acetaminophen after 2 g (60 min after intake) was not significantly lowered by bowel lavage. After 4 g, peak acetaminophen serum levels were significantly lower after bowel lavage (65.4% of controls, P < 0.001). Urinary concentrations of the mercapturic acid conjugate of the toxic metabolite were also significantly reduced by lavage (55% after 2 g and 45% after 4 g, P < 0.01). Activated charcoal given orally after administration of 4 g of acetaminophen had no significant effect on peak serum levels and had no additive effect on lavage. These studies suggest that rapid, complete bowel lavage with a polyethylene glycol electrolyte solution may be beneficial as an adjunct to the treatment of the acetaminophen intoxication. Acute liver failure (ALF) is an uncommon condition associated with high morbidity and mortality. We performed a retrospective analysis of patients evaluated for ALF. The aim of our study is to determine the clinical features and outcome of such patients and to assess the validity of King's College Hospital (KCH) prognostic criteria. One hundred seventy-seven patients were evaluated for ALF during a period of 13 years. Mean age was 39 years, and 63% were women. The causes included viral hepatitis (31%), acetaminophen toxicity (19%), idiosyncratic drug reactions (12%), miscellaneous causes (11%), and an indeterminate group (28%). Twenty-five patients (14%) recovered with medical therapy (group I), 65 patients (37%) died without orthotopic liver transplantation (OLT; group II), and 87 patients (49%) underwent OLT (group III). Patients in group II were older and often had advanced encephalopathy, whereas those in group I had less hyperbilirubinemia and often had hyperacute failure. KCH criteria had high specificity and positive predictive value but low negative predictive value for a poor outcome. We conclude that early prognostication is needed in patients with ALF to assist decision making regarding OLT. The fulfillment of KCH criteria usually predicts a poor outcome, but a lack of fulfillment does not predict survival. We describe the effects of whole bowel irrigation on a delayed-release acetaminophen preparation. We compare the mechanical effect of whole bowel irrigation on the progression of radiopaque markers through the gastrointestinal tract between an experimental and a control group.
                We performed a 2-armed, prospective, randomized, crossover volunteer study. In the experimental phase, subjects were administered a delayed-release acetaminophen preparation (75 mg/kg) along with a capsule containing radiopaque markers. We initiated whole bowel irrigation at 30 minutes after ingestion and continued until the rectal effluent was clear. Serum acetaminophen concentrations were measured at baseline and from 0.5 to 8 hours. Abdominal radiographs were obtained at the completion of whole bowel irrigation. In the control phase, whole bowel irrigation was not performed. The primary outcome measure was the effect on the area under the acetaminophen concentration versus time curve (AUC) between the 2 groups.
                Ten subjects participated in the study. We found an 11.5% reduction in the AUC, with the majority of the effect occurring in the delayed-release portion of the curve after the 2-hour mark. This reduction, however, was not statistically significant. Radiographs obtained at the end of whole bowel irrigation revealed radiopaque markers sequestered in the right hemicolon in 8 of 10 subjects. No discernible pattern was noted in the control arm.
                The effect of whole bowel irrigation on reduction of AUC for delayed-release acetaminophen preparation was not statistically significant. Whole bowel irrigation did appear to have a mechanical effect on the progression of radiopaque markers through the gastrointestinal tract, but the clinical significance of this finding is not clear. One hundred thirty-seven patients with fulminant hepatic failure were entered into two controlled trials of charcoal hemoperfusion carried out concurrently. In trial A, 75 patients with grade 3 encephalopathy were randomized to receive 5 or 10 h of hemoperfusion daily. Overall survival rates for the two groups were similar (51.3% vs. 50.0%) as was the frequency of major complications including cerebral edema and renal failure. In trial B, in which 62 patients with established grade 4 encephalopathy on admission were randomized to a no-perfusion group or to have 10 h of hemoperfusion daily, overall survival rates for the two groups were again similar (39.3% and 34.5%, respectively). There was in both trials a significant relationship between survival and etiology quite independent of the use or duration of hemoperfusion. Thus, percentage survival for the acetaminophen-overdose cases was 52.9%, for hepatitis A 66.7%, for hepatitis B 38.9%, for presumed non-A, non-B hepatitis 20%, and for halothane or drug reaction 12.5%. Within the etiologic subgroups survival was also influenced by the three major complications that developed, being inversely related to their frequency and combination, except in the non-A, non-B hepatitis and halothane or drug reaction subgroups, which had a high mortality throughout. In the latter cases particularly, orthotopic liver transplantation merits early consideration and in the group with better "intrinsic" survival (acetaminophen, hepatitis A and B) intensive management of complications (rather than charcoal hemoperfusion) would appear to be of major importance. We determine whether the incidence of adverse events caused by intravenous N -acetylcysteine is significantly less when the initial dose is infused over a 60-minute period compared with the standard infusion period of 15 minutes. A secondary objective is to assess the efficacy of the 2 treatment arms.
                This was a multicenter, randomized, prospective trial of patients who presented with acetaminophen poisoning and who were treated with N -acetylcysteine and had no history of hypersensitivity to N-acetylcysteine. Patients were randomly assigned to receive the initial dose of N-acetylcysteine over a 15-minute or 60-minute period. Baseline signs and symptoms and adverse events were serially evaluated before and during administration of N -acetylcysteine. Tests of liver injury and coagulation were collected at baseline and then at 12-hour intervals.
                The study was designed with an 80% power to detect a halving of the incidence of adverse events. Of 180 evaluable patients, 109 patients were randomized to the 15-minute group and 71 patients were randomized to the 60-minute group. The incidence of drug-related adverse events was 45% in the 15-minute group and 38% in the 60-minute group (95% confidence interval -8% to 22%). The study did not demonstrate a reduction of drug-related adverse outcomes with the 60-minute infusion. Incidence of maximum alanine aminotransferase levels indicating hepatotoxicity (serum level >1,000 IU/L) was 6.8% (5.6% for 15-minute, 8.7% for 60-minute). The difference did not attain statistical significance.
                This study did not demonstrate a reduction of drug-related adverse outcomes with the 60-minute infusion. The study also confirmed that early treatment with N -acetylcysteine (within 8 hours of ingestion) is more effective than later treatment. To evaluate the efficacy of N-acetylcysteine (N-AC) alone or combined with multiple-dose activated charcoal (AC) in the treatment of acetaminophen (ACT) overdose.
                Prospective observational case series of 14 consecutive pediatric patients. Group A (n = 7) were treated only with N-AC and group B (n = 7) with N-AC combined with AC. Plasma ACT concentrations were measured at 0.0, 24 and 48 h. As a measure of ACT disappearance, half-life of elimination (t1/2 beta) and exogenous body clearance (ClB) were calculated.
                Group A, Initial and final mean ACT plasmatic levels were 27 micrograms/mL and 4 micrograms/mL; t1/2 beta of 17 h and ClB 0.640 mL.kg.min. Group B, 27 micrograms/mL and 0.66 microgram/mL; t1/2 beta of 10 h and ClB 1.092 mL.kg.min. For both t1/2 beta and ClB differences, p < 0.05 (SS).
                N-AC significantly decreased the plasma ACT levels in both treatments; however, there were several advantages with the combined therapy: AC enhanced the efficacy of N-AC according with the higher eliminatión of the overdosed drug (97.6% vs. 85.2%), the t1/2 beta decreased 42%, and the ClB increased 70% in relation to the group A. Data of this study suggested that N-AC plus AC is more effective than N-AC alone in enhancing ACT elimination in overdosed patients and that it provided additional hepatoprotective benefit. Once defined clinical criteria are fulfilled in acetaminophen-induced hepatotoxicity, prognosis without orthotopic liver transplantation (OLT) may be very poor. In the present study, we examined the application and outcome of OLT in 548 patients admitted to a single center between 1990 and 1996. Four hundred twenty-four (77%) of the patients studied did not fulfill transplantation criteria, and 396 of these (93%) survived. The majority of the 28 nonsurvivors (7%) in this group fulfilled two of three combined criteria, and the finding of a high APACHE III score could be used as an indicator for the need for OLT. Of the 56 patients (45%) not listed, in only a small proportion was this caused by psychiatric reasons, and in the majority, it was a consequence of the rapid development of multiple organ failure and cerebral edema. This also applied to 24 (35%) of the 68 listed patients in whom the rapidity of clinical deterioration, reflected in increasing APACHE III scores, was such that even with the prompt availability of donor organs, OLT was not possible. In the final event, only 44 (35%) of those who fulfilled criteria underwent OLT, of whom 33 (75%) survived to leave the hospital. Survival was greatest in those receiving unreduced grafts, and markers of early graft function differed significantly between survivors and nonsurvivors. Liver transplantation is an effective treatment in a relatively small number of patients with acetaminophen-induced hepatotoxicity, and for a substantial proportion, transplantation was never an option because of the rapidity of clinical deterioration. APACHE III scoring may be of value in decision making and in better defining patients in clinical trials. Although it is a commonly held belief that the ingestion of drugs with an anticholinergic action would prolong the duration of time after drug ingestion for effective gastrointestinal decontamination, data are lacking to support this belief. The purpose of this study is to determine whether activated charcoal is more effective in the presence of concurrent anticholinergic activity.
                A three-limbed randomized crossover study in 10 healthy volunteers was completed to determine the ability of a 50 g dose of activated charcoal to reduce the bioavailability of a simulated overdose of acetaminophen (12 x 325 mg tablets) in the presence and absence of a concurrently present anticholinergic drug, atropine (0.01 mg/kg I. M. administered 15 min prior to the acetaminophen ingestion).
                After the acetaminophen ingestion, median Cmax occurred at 1 h for all three exposures but was lower in the atropine-treated study arm (31+/-19 mg/L) than in the control or charcoal alone intervention arms (49+/-13 and 51+/-16 mg/L, respectively) (P<0.05). Compared to the control area under the serum concentration vs. time curve, a single dose of activated charcoal 1 h after drug ingestion reduced acetaminophen bioavailability by 20% (95% CI 4-36%) and by 47% (95% CI 35-59%) in the presence of atropine (P<0.05 atropine plus charcoal vs. charcoal alone).
                Our data support the belief that activated charcoal is more effective in the presence of anticholinergic activity. Additional study is required to determine whether in patients with anticholinergic drug overdose, activated charcoal is effective at times beyond the recommendation for overdoses of drugs without this pharmacodynamic effect. We evaluate the adsorptive capacity of a superactivated charcoal-cola mixture to acetaminophen compared with superactivated charcoal alone.
                This was a triple-arm, prospective, unblinded study of 8 healthy adult human volunteers who ingested 80 mg/kg of acetaminophen. In the control arm of the study, participants ingested acetaminophen alone. In the next arm, acetaminophen was followed by 1 g/kg of superactivated charcoal mixed with water. In the final arm, acetaminophen was followed by 1 g/kg of superactivated charcoal mixed with caffeine-free diet cola. Serum acetaminophen concentrations over 6 hours for each arm were analyzed for area under the time-concentration curve (AUC), peak concentrations, and time to peak concentrations.
                AUCs were 298.5+/-82.5 mg-h/L (control), 77.1+/-85.2 mg-h/L (superactivated charcoal), and 81.3 +/- 71.8 mg-h/L (superactivated charcoal-cola). Comparison of AUCs by analysis of variance revealed mean square of 128,315.1 between treatments, and residual mean square of 6,405.0, yielding an F ratio of 20.03 (P <.0001). Student-Newman-Keuls pairwise multiple comparison procedure revealed a statistically significant difference in AUC for control versus superactivated charcoal (P <.05) and for control versus superactivated charcoal-cola (P <.05), but not for superactivated charcoal versus superactivated charcoal-cola (P >.05). Time-concentration curves for the 3 study arms were illustrated graphically.
                Combining superactivated charcoal with cola does not limit the adsorptive capacity of superactivated charcoal. Activated charcoal is an effective inhibitor of acetaminophen absorption while sodium sulfate can prevent the depletion of endogenous inorganic sulfate associated with the formation of acetaminophen sulfate. Administration of activated charcoal plus sodium sulfate soon after acetaminophen overdose may reduce acetaminophen absorption and facilitate the elimination of absorbed acetaminophen by providing sufficient sulfate ion for rapid sulfation of the drug. This investigation was designed to determine if sodium sulfate modifies the inhibitory effect of activated charcoal on acetaminophen absorption or if activated charcoal affects the absorption of sodium sulfate. Eight normal adults received, on separate occasions, 1 g acetaminophen, 1 g acetaminophen and 18 g sodium sulfate (decahydrate), 1 g acetaminophen with 10 g activated charcoal and 1 g acetaminophen, with 10 g activated charcoal and 18 g sodium sulfate, in random order. Urine was collected for 48 hours and assayed for acetaminophen and its major metabolites and for inorganic sulfate. The results confirm that activated charcoal can reduce acetaminophen absorption and show that oral administration of activated charcoal with sodium sulfate does not alter the inhibitory effect of activated charcoal on acetaminophen absorption or the bioavailability of the sulfate. A combination of activated charcoal and sodium sulfate may therefore be useful for the initial management of acetaminophen overdose. Fulminant hepatic failure is a common indication for liver transplantation. Outcomes of patients listed for a highly urgent liver transplantation have been studied, with special emphasis on etiology of the liver disease, clinical condition, and ABO blood type. Data have been collected from the Nordic Liver Transplantation Registry. All Nordic patients listed for a highly urgent primary liver transplantation during a 12-year period have been included. Of the 315 patients listed for a highly urgent liver transplantation, 229 (73%) received a first liver allograft, 50 patients (16%) died without transplantation, and 36 patients (11%) were permanently withdrawn and survived. In 43% of the patients, no definite etiology of the liver failure could be established. Paracetamol intoxication was the most frequent specific indication for listing. Patients with blood type A had no significant shorter waiting time (3.8 v 6.6 days; P =.1) but a higher rate of transplantation (82% v 66%, P =.006) as compared with blood type O patients. In a multivariate analysis, paracetamol intoxication remained the single independent predictor of an outcome without transplantation. In conclusion, a high transplantation rate was observed among patients listed for a highly urgent liver transplantation because of fulminant hepatic failure. Blood type O patients had a lower chance of receiving a liver allograft. Patients with paracetamol intoxication had both a higher mortality without transplantation and a higher withdrawal rate attributable to improved condition. A randomised controlled trial of the use of intravenous cysteamine in the treatment of severe paracetamol poisoning has been performed. Thirty-eight patients presenting 3-17 h after ingestion were admitted to the trial; of these eighteen received cysteamine. Two patients died from hepatic failure, one in each treatment group. Analysis of the series as a whole showed no advantage of cysteamine in preventing biochemical abnormalities of liver function except for aspartate aminotranferase and serum ferritin levels, which were significantly less after cysteamine therapy. Separate analysis of the patients treated within 9 h of paractamol ingestion and of those treated 9-17 h after paracetamol ingesion similarly showed no definite advantage of cysteamine. Histological evidence of liver damage showed a possible beneficial effect of cysteamine. Cysteamine therapy did not prevent renal or pancreatic damage. The purpose of this study was to investigate the effect of superactivated charcoal (SAC) given late after a drug overdose. Acetaminophen was chosen as our overdose drug because it has relatively few side effects, serum levels are easily attainable and measurable, and it is generally a common drug overdose. Forty-six healthy adult volunteers participated in this randomized, controlled study. Acetaminophen was administered the morning after an overnight fast. Thirteen participants received 2000 mg acetaminophen and the remaining 33 received 3000 mg. After 3 hours, half of the participants (22 of 46) received 75 g of SAC (Requa, Greenwich, CT) orally as a slurry in 8 oz of apple juice. Serum acetaminophen levels were measured at 4 and 7 hours after the initial acetaminophen administration. There were significantly lower uncorrected and corrected acetaminophen levels in the SAC group compared with the control group at both 4 and 7 hours after ingesting acetaminophen. This randomized human experimental design trial demonstrates some detoxification benefit in administering superactivated charcoal 3 hours after an overdose. The efficacy of activated charcoal and ipecac syrup in the prevention of drug absorption was studied in 6 healthy adult volunteers, using a randomized, cross-over design. Paracetamol 1000 mg, tetracycline 500 mg and aminophylline 350 mg were ingested on an empty stomach with 100 ml water. Then, after 5 or 30 min, the subjects ingested, either activated charcoal suspension (50 g charcoal), syrup of ipecac, or, only after 5 min, water 300 ml. Activated charcoal, given either after 5 or 30 min, significantly (p less than 0.01 or less 0.05) reduced the absorption of these 3 drugs measured, for example as AUC0-24 h. Syrup of ipecac caused emesis on each occasion, with a mean delay of 15 min. When ipecac was given 5 min after the drugs, its effect on absorption was significant, but when it was given after 30 min only the absorption of tetracycline was reduced. Activated charcoal was significantly (p less than 0.05) more effective than ipecac in reducing drug absorption when given at the same time points. In cases of acute intoxication, depending on the quality and quantity of the drugs ingested, the relative efficacy of charcoal and ipecac may be somewhat different from that observed in the present study. Despite its emetic action, however, ipecac syrup is not very effective in preventing drug absorption and, in general, activated charcoal should also be given after induced emesis or gastric lavage. 1 A controlled trial of charcoal haemoperfusion as an early treatment for paracetamol overdose showed no benefit. 2 The plasma clearances of paracetamol by the charcoal column were variable and disappointingly small (range 4-119 ml/minute). The cumulative amounts removed were also low, mean 1.4 g (range 0.2-5.2 g). 3 No clinical problems were encountered with the technique of haemoperfusion and in particular the drop in blood platelet counts was small (mean fall 16%). nan 30 patients at risk of hepatic damage from paracetamol (acetaminophen) ingestion were given 2-5 g oral methionine every four hours up to a total dose of 10 g. The first dose was given within ten hours of the overdose. There were no deaths and no reports of hepatic encephalopathy or other complications. In 21 patients plasma aspartate-aminotransferase remained within normal limits. These results suggest that methionine may be effective in reducing the frequency and severity of paracetamol-induced liver damage and may provide an effective non-toxic alternative to cysteamine. nan The aim of this prospective trial was to compare the efficacy of gastric lavage, activated charcoal and ipecacuanha at limiting the absorption of paracetamol in overdose and to assess the significance of the continued absorption of paracetamol following treatment. Patients aged 16 and over who had ingested 5 gms or more of paracetamol within 4h of admission were entered into the trial. The percentage fall in plasma paracetamol level was used as the measure of the success of a treatment at limiting absorption. The mean percentage fall was 39.3 for gastric lavage, 52.2 for activated charcoal and 40.7 for ipecacuanha, with a significant difference between the treatment methods (p = 0.03). Activated charcoal was more effective at limiting the absorption of paracetamol following overdose than either gastric lavage or ipecacuanha induced emesis. In treated patients continuing paracetamol absorption is not significant if more than 2h have elapsed since ingestion. Six hundred sixty-two consecutive patients with acetaminophen overdoses were evaluated. Those at risk on the basis of their acetaminophen blood levels, as plotted on the study nomogram, were treated with oral acetylcysteine. Statistically significant differences in severity of hepatic toxicity were observed between patients treated within 16 hours after ingestion and those treated between 16 and 24 hours after ingestion. No deaths occurred among patients treated within 24 hours of ingestion, except for one patient who was an alleged gunshot homicide. Seven percent of patients with plasma acetaminophen levels in the potentially toxic range and treated with acetylcysteine within ten hours of ingestion showed transient SGOT level elevations, whereas 29% of those treated between ten and 16 hours after ingestion and 62% of those treated between 16 and 24 hours after ingestion showed such transient toxicity. No consistent difference in hepatotoxicity could be demonstrated between those patients with a history of chronic alcohol use and those patients with no history of chronic alcohol use. Acute alcohol use resulted in less severe toxic reactions than in those patients without acute alcohol use. 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. To evaluate whether activated charcoal (AC) reduces the efficacy of subsequent oral N-acetylcysteine therapy during acute acetaminophen overdose.
                Prospective observational case series of all acute acetaminophen overdoses reported to three certified regional poison centers. TYPES OF PATIENTS: All patients with acute acetaminophen overdose in whom N-acetylcysteine therapy was initiated within 16 hours after ingestion.
                All patients were treated with oral N-acetylcysteine therapy for 72 hours. The decision to use AC was left to the treating physician without input from the investigator.
                One hundred twenty-two patients were evaluated. Maximum recorded SGOT levels of more than 125 U/mL were defined as evidence of hepatotoxicity. AC was used in addition to N-acetylcysteine in 82 of 122 patients. Hepatotoxicity developed in four of 82 patients who received AC versus ten of 40 patients who did not receive AC (P < .005). An increasing dose of N-acetylcysteine provided no additional benefit (P > .05). Spacing the administration of AC and oral N-acetylcysteine less than or more than two hours apart did not affect outcome (P > .05).
                Administration of AC before the administration of oral N-acetylcysteine in acetaminophen overdose does not reduce the efficacy of N-acetylcysteine therapy and may provide some additional hepatoprotective benefit. The practice of increasing the dose of oral N-acetylcysteine therapy after the administration of AC appears unwarranted. The effect of single-dose and multiple-dose cimetidine administration on acetaminophen pharmacokinetics was investigated in a three-phase, randomized, crossover study using four normal subjects. In each phase of the study, subjects ingested 750 mg of acetaminophen as a single dose alone (A), or in combination with 200 mg of cimetidine (A + C), or following a one-week pretreatment with daily cimetidine, 200 mg every six hours and 400 mg before retiring (A + C*). Statistical analysis using two-way analysis of variance indicated no significant difference in peak concentration and peak time of acetaminophen between treatments. Cimetidine did not significantly affect acetaminophen half-life, 2.38 hours (A), 2.65 hours (A + C), and 2.50 hours (A + C*). Acetaminophen clearance was minimally affected by cimetidine; the mean clearance of acetaminophen ranged from 4.16 (A + C*) to 5.57 mL/min/kg (A). Area under the acetaminophen plasma concentration-time curve was slightly increased by cimetidine, 35.4 (A), 41.6 (A + C), and 47.6 micrograms/mL/h (A + C*). Since cimetidine did not affect acetaminophen pharmacokinetics to any significant extent, clinical combination of both medications at therapeutic dosage presumably would not produce adverse interactions. This study was conducted to determine whether gastric lavage reduces the absorption of ingested liquids.
                The study design was a randomized controlled human volunteer crossover study in 10 subjects. On 2 separate occasions 2 weeks apart, the volunteers ingested a solution of 4.0 g of acetaminophen in 60 mL of water. Eight blood specimens were obtained over the initial 8 hours for determination of serum acetaminophen concentrations, which were used to calculate routine pharmacokinetic parameters. One hour after 1 drug ingestion, gastric lavage was performed through a 34-F orogastric tube. Serum acetaminophen concentrations were measured by high-performance liquid chromatography and a 2-tailed t test was used for statistical analysis.
                The mean values for area under the concentration curve (+/-SD) for the control and gastric lavage groups were 195+/-31 and 154+/-52 mg/L.hour, respectively (P <.05). The mean reduction in acetaminophen bioavailability because of gastric lavage was 20%+/-28% (95% confidence interval 3 to 37).
                In this experimental model for the ingestion of liquids, gastric lavage at 1 hour resulted in a significant decrease in the mean serum bioavailability of acetaminophen. Nonetheless, this treatment effect is unlikely to be of clinical value because of its modest extent, unreliable performance, and the availability of a more effective, less risky alternative, activated charcoal. Syrup of ipecac is widely used following accidental drug overdosage in children. Proof of its efficacy, however, in reducing the risk of poisoning is limited. We prospectively studied the effect of early v late induction of emesis by ipecac in 50 children younger than 5 years of age with accidental acetaminophen poisoning. The mean estimated ingested dose was 165 mg/kg, and all patients vomited within 15 to 255 (mean 78) minutes postingestion. Although the predicted four-hour plasma acetaminophen concentration was 97 +/- 4 micrograms/mL (mean +/- SEM, calculated on the basis of the estimated ingested dose), the measured four-hour plasma acetaminophen concentration was 34 +/- 5 micrograms/mL (P less than .01). To assess the efficacy of early v late ipecac-induced emesis, we used the ratio of measured to predicted four-hour acetaminophen plasma concentration. The ratio of the measured to predicted four-hour level increased as the delay in time to vomiting increased (r = .60, P less than .001). Ipecac syrup was administered more promptly when available in the home than when obtained from a pharmacy or a medical facility (26 +/- 8 v 83 +/- 13 minutes postingestion, respectively; P less than .001) and vomiting occurred earlier (49 +/- 9 v 103 +/- 12 minutes postingestion; P less than .01). Although the mean estimated doses ingested were greater in patients who received ipecac syrup at home, their four-hour plasma acetaminophen concentrations were lower. These data suggest that prompt administration of ipecac syrup results in a greater reduction in plasma acetaminophen concentrations in potentially toxic overdosages in children.(ABSTRACT TRUNCATED AT 250 WORDS) We sought to evaluate the safety and efficacy of a shorter N-acetylcysteine (NAC) regimen in the treatment of acute acetaminophen overdose.
                We performed a retrospective case series in a large urban county hospital. Of 305 patients identified through the emergency department, 75 patients met the criteria inclusion: an acute overdose ingestion, serum acetaminophen concentration in toxic range according to the Rumack-Matthew nomogram, and oral NAC treatment initiated within 24 hours of the ingestion. The regional poison control center recommended oral treatment with NAC 140 mg/kg, followed by maintenance doses of 70 mg/kg every 4 hours until the serum acetaminophen level was no longer detectable, rather than the standard 72-hour treatment regimen.
                The primary outcome measure was the development of hepatotoxicity. Twenty-five (33.3%) patients were treated for a period of less than 24 hours, 25 (33.3%) were treated for 24 to 36 hours, and 25 (33.3%) were treated for 37 to 64 hours; the mean and median duration of treatment was 31 hours. None of the patients treated for less than 24 hours had evidence of hepatotoxicity (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] level >1,000 IU/L); hepatotoxicity developed in 2 (8%) patients treated for 24 to 36 hours and 4 (16%) patients treated for 37 to 64 hours. There were no deaths or patients who received liver transplantation. The overall incidence of hepatotoxicity in our patients was similar to that found in other protocols with administration of oral NAC for 72 hours or intravenous NAC for 20 or 48 hours.
                This observational study suggests that a shorter course of oral NAC therapy in patients who do not show evidence of hepatotoxicity within 36 hours of an acute acetaminophen overdose is safe and effective. The aim of this pilot study was to evaluate the incidence of hypophosphatemia and its association with clinical outcome in fulminant hepatic failure (FHF). Patients with FHF referred for orthotopic liver transplantation (OLT) between January, 1991 and May, 2002 were identified. FHF was defined as the development of coagulopathy and encephalopathy within 8 weeks of onset of jaundice. Demographic and laboratory data, including serum phosphate, calcium, magnesium, creatinine, and PT/INR were obtained from medical records. Clinical outcomes (death, OLT, or hepatic recovery) and associated morbidities (renal failure, bleeding, and sepsis) also were noted. Thirty-eight patients, 8 men and 30 women, aged 34 +/- 4 years, were included in the study. Hypophosphatemia (< 2.5 mg/dL) developed in 33 of 38 (87%) patients within 10 days of referral. Twelve patients (32%) died, 14 patients (37%) underwent OLT, and 12 patients (32%) recovered. The mean nadir serum phosphorus level was significantly lower in those who recovered compared with those who either died or required OLT (1.18 +/- 0.54 versus 1.79 +/- 1.00 mg/dL; P =.02). A trend toward lower mean serum phosphorus level also was noted in those who recovered compared with those who died (1.18 +/- 0.54 versus 1.96 +/- 1.35 mg/dL; P =.09). Serum phosphorus levels > 2.5 mg/dL was a predictor of mortality, and when used alone, was equivalent to the King's College Criteria. In conclusion, hypophosphatemia occurred frequently in patients with FHF. Lower serum phosphorus levels were observed in patients who recovered as compared with those who died or required OLT, and may be associated with recovery of hepatic function. The greater decline in serum phosphorus level in those who recover hepatic function may represent cellular use of phosphorus during hepatocyte regeneration. After serious paracetamol overdose, charcoal haemoperfusion was used to remove paracetamol from the circulation, aiming to reduce the severity of subsequent hepatic damage. Daily long-hours high-flux dialysis was given to patients with grade III-IV hepatic encephalopathy, and also to those at risk of developing encephalopathy. We reviewed patients treated in this manner who had not received N-acetylcysteine within the first 15 h after overdose. From January 1983 to January 1993, 73 patients with serious paracetamol overdose were seen, of whom 51 received charcoal haemoperfusion and/or high-flux dialysis. Patients who were admitted within the first 42 h after overdose and who received haemoperfusion and/or dialysis had significantly lower peak levels of prothrombin time, bilirubin and creatinine than those who were admitted after 42 h. Mortality was also lower amongst patients admitted before 42 h, at 2/18 (11%) vs. 15/33 (45%), p < 0.05. The influence of acetylcysteine, administered at presentation to hospital, on the subsequent clinical course of 100 patients who developed paracetamol-induced fulminant hepatic failure was analysed retrospectively. Mortality was 37% in patients who received acetylcysteine 10-36 h after the overdose, compared with 58% in patients not given the antidote. In patients given acetylcysteine, progression to grade III/IV coma was significantly less common than in those who did not receive the antidote (51% vs 75%), although the median peak prothrombin time was similar for both groups. Whether the beneficial effect is related to replenishment of glutathione stores or a consequence of another hepatic protective mechanism of acetylcysteine requires further study. 60 patients with paracetamol poisoning have been treated with intravenous cysteamine, L-methionine, or D-penicillamine and the incidence and severity of hepatic necrosis compared with those observed in 70 patients receiving supportive therapy only. Of 31 patients with 4-hour plasma-paracetamol concentrations greater than 250 mug/ml given supportive therapy 22 sustained severe liver damage, 3 died in hepatic failure, and 4 developed acute renal failure. None of 23 similarly poisoned patients given cysteamine within 10 hours of ingestion suffered severe liver damage or renal failure and none died. Cysteamine was partially effective at 10-12 hours, but ineffective 12 hours or more after ingestion. Liver damage was absent or mild in 17 patients given L-methionine within 10-12 hours of ingestion but severe in 3 treated within 10 hours. Of 5 patients treated with D-penicillamine, 1 developed severe liver damage with acute renal failure. It is concluded that cysteamine prevents severe liver damage after paracetamol poisoning if given within 10 hours in adequate dosage. Early changes in coagulation were found in patients following a paracetamol overdose. Low levels of clotting factors II, V and VII were present within 24 hours of the overdose. As the levels of factor II correlated with plasma fibrinogen values at this time, it is possible that they were consumed in the process of intravascular coagulation, although this was not supported by the presence of raised titres of fibrin degradation products. The prothrombin time ratio was greater than 2-2 within 30 hours of ingestion of the overdose in all patients who eventually died, whereas it was less than this in those developing only moderate liver damage. The administration of fresh frozen plasma to patients did appear to reduce the maximum abnormality of the prothrombin time ratio, which was significantly less three days after the overdose in the group receiving fresh frozen plasma. However, the coagulation disturbance was of short duration, and the prothrombin time ratio had also returned to normal within one week of the overdose in the control patients, and the administration of fresh frozen plasma did not appear to reduce the morbidity or mortality in the treated patients. Paracetamol is a component of a number of drugs taken in overdose (OD). The influence of alcohol use (acute or chronic) on the presentation and clinical course of paracetamol OD is contentious. This study explores the relationship between paracetamol OD, alcohol consumption and clinical outcomes at a regional Australian hospital.
                To determine the frequency, circumstances and outcomes of paracetamol OD presentations to a regional Australian general hospital over a 4-year period.
                Medical records of patients admitted to the Ballarat Health Services (BHS) as a result of paracetamol OD between January 2000 and December 2003 were reviewed. Patient demographics, amount of paracetamol ingested, other drug coingestions, alcohol history, previous medication OD, clinical course and outcomes were recorded.
                Annual admissions resulting from paracetamol OD almost doubled during the 4 years studied. The risk of a repeat paracetamol OD was highest within 4 weeks of the initial OD. Alcohol, benzodiazepines and antidepressants were commonly coingested. The strongest predictor of severe hepatotoxicity was delayed or no N-acetyl cysteine treatment in patients consuming greater than 10 g of paracetamol or with toxic serum paracetamol levels. A history of alcohol consumption did not appear to worsen outcomes. Forty patients who had taken overdoses of paracetamol were treated with mercaptamine. Twenty-three patients given mercaptamine within 10 hours of poisoning had normal liver function tests at follow-up, and one could not be traced. In 16 patients mecraptamine was begun more than 10 hours after ingestion of paracetamol ("late" mercaptamine). Eight of these patients developed severe liver damage, which in six was moderate or severe before mercaptamine administration. Acute renal failure occurred in two patients; in one other renal function was temporarily severely impaired. At follow-up two patients were not available, and one admitted moribund had died soon after admission. The remaining 13 all had normal liver function tests. It is concluded that late mercaptamine is not dangerous and may prevent further liver damage. The efficacy of several formulations of activated charcoal (AC) was compared by measuring the intestinal absorption of a solution of 1 g paracetamol administered 2 min before administration of 5 g AC as suspension (200 ml), tablets (40 of 125 mg) or capsules (25 of 200 mg). The suspension medium without AC was used as the control treatment. Based on the results of a pilot experiment, an 8 subject panel was used in a two 4 x 4 Latin square design. All treatments with AC resulted in a statistically significant decrease in paracetamol absorption compared to the control treatment. The suspension was considerably and significantly more effective than the tablets or capsules. Treatment with tablets was slightly but significantly more effective than capsules. The intake of large numbers of tablets and capsules was difficult. In the hospital AC suspensions are available. For first aid elsewhere, at home, at the working place or in the general practitioner's surgery a preservable and easily redispersible AC formulation would be preferable to the present solid forms. Gc-globulin scavenges actin released from necrotic hepatocytes to the extracellular space. In 77 patients with fulminant hepatic failure (FHF) (excluding patients treated with liver transplantation), admission levels of serum Gc-globulin and degree of complexing with monomeric actin (complex ratio) were determined to evaluate their predictive values in relation to survival/nonsurvival. Gc-globulin levels were significantly reduced in 47 nonsurvivors, compared with 30 survivors (96 +/- 71 mg/L vs. 169 +/- 101 mg/L, P < .001), whereas the complex ratio in nonsurvivors did not differ significantly from that of survivors. Gc-globulin levels were significantly lower in 59 patients with non-acetaminophen-induced FHF, compared with 18 patients with acetaminophen-induced FHF (P < .01). Using a cutoff level of serum Gc-globulin of 100 mg/L, a lesser value correctly predicted nonsurvival in 79 percent of patients with non-acetaminophen-induced FHF, whereas a higher value predicted survival in 60 percent. In patients with acetaminophen-induced FHF, nonsurvival was correctly predicted in 100 percent of patients and survival in 53 percent. In comparison, the King's College Hospital (KCH) criteria correctly predicted nonsurvival and survival in 69 percent and 57 percent, respectively, of the same non-acetaminophen-induced FHF patients and in 60 percent and 38 percent, respectively, of the acetaminophen-induced FHF patients. Thus, in our study population, the predictive properties of Gc-globulin were in the same range as the KCH criteria. An advantage of Gc-globulin is that it gives an estimate of the outcome already on admission. Acute liver transplantation should be considered in FHF patients with Gc-globulin less than 100 mg/L. The use of a 70% sorbitol solution has recently been advocated as an adjunct to activated charcoal. This results in rapid and profuse catharsis that could possibly cause fluid and electrolyte imbalance. An investigation was undertaken to determine if sorbitol catharsis enhanced the antidotal efficacy of activated charcoal. Eight healthy volunteers participated in a randomized, crossover trial. Subjects ingested 3 g of acetaminophen followed by either no intervention, 50 g of plain activated charcoal at one hour, or 50 g activated charcoal-sorbitol solution at one hour. Serial acetaminophen levels were determined at intervals over eight hours and side effects noted. Both interventions significantly reduced the area under the curve versus control (P less than .05). The addition of sorbitol did not enhance the efficacy of activated charcoal but did increase the side effects noted. Sorbitol has not been proven effective in enhancing drug removal and has side effects that can be significant in a poisoned patient. Current data do not warrant its use, and further investigations should be carried out with other ingested drugs. The traditional role of gastric emptying as the initial step in the management of the poisoned patient has recently been questioned; immediate activated charcoal administration has been recommended by some. In the setting of acetaminophen overdose, ipecac-induced emesis may interfere with subsequent oral antidotal therapy. Therefore, we conducted a study to compare the efficacy of initial therapy with ipecac with therapy with activated charcoal-cathartic in a simulated acetaminophen overdosage. Ten healthy volunteers participated in a randomized, crossover trial. Subjects ingested 3.0 g acetaminophen, followed by either no intervention, 30 mL syrup of ipecac, or 50 g activated charcoal-sorbitol solution at one hour. Serial acetaminophen levels were determined at intervals over eight hours. Both interventions significantly reduced the area under the curve compared with control (P less than .05). When comparing ipecac with activated charcoal-cathartic, no significant difference was noted among these groups. Paracetamol poisoning is the most common cause of fulminant liver failure in the United Kingdom. An accurate assessment of prognosis at the time of referral will allow the appropriate application of liver transplantation in this setting. The outcome of 92 patients consecutively admitted to a specialist liver unit with severe poisoning has been examined. In patients who did not have a transplant, a fatal outcome was seen for 26/82 (32%), and was associated with late presentation, coma grade, prothrombin time prolongation, metabolic acidosis, and renal dysfunction. Cerebral oedema, and sepsis were responsible for most deaths. Prognostic criteria defined at King's College Hospital seemed to predict the outcome of patients who did not have a transplant managed on the Birmingham liver unit. Seventeen patients were listed for transplantation, 10 had liver transplantation, and seven of 10 survived. Seven were listed but not transplanted, and one of seven survived. Psychological rehabilitation of patients who had a transplant has not proved difficult. These results suggest a role for liver transplantation in the management of selected patients with paracetamol poisoning. The recent American Academy of Clinical Toxicology/European Association of Poisons Centres and Clinical Toxicologists position statement on activated charcoal stated "there are insufficient data to support or exclude its use after 1 hour of ingestion.'' The purpose of this study was to determine the effectiveness of activated charcoal administered 1, 2, and 3 hours after drug ingestion.
                This was a human volunteer, randomized crossover study. Ten volunteers ingested 4 g of acetaminophen on four occasions at least 1 week apart. One ingestion served as a control and the other three as experimental ingestions with charcoal being administered at 1, 2, and 3 hours after acetaminophen dosing. Eight blood specimens were obtained over the initial 8 hours for serum acetaminophen concentrations that were used for calculation of routine pharmacokinetic parameters. Repeated measures of ANOVA and Tukey's HSD test were used for statistical analysis.
                Pharmacokinetic parameters for acetaminophen in our volunteers were consistent with literature values. The mean area under the curve (AUC+/-SD) for the control and the 1-, 2-, and 3-hour groups were 221 +/- 54, 154 +/- 71, 206 +/- 67 and 204 +/- 58 mg/L/h, respectively. The 1-hour group was the only one differing from control (p < 0.01). The decrease of bioavailability at 1 hour was 30.3%, which is similar to previous studies.
                Our data do not support the administration of activated charcoal as a gastrointestinal decontamination strategy beyond 1 hour after drug overdose. To determine the safety and efficacy of a 48-hour IV N-acetylcysteine (IV NAC) treatment protocol for acute acetaminophen overdose.
                Nonrandomized trial open to all eligible patients.
                Multicenter; hospitals included moderate- and high-volume private, university, and municipal hospitals in urban and suburban settings.
                Two hundred twenty-three patients were entered. Of these, 179 met inclusion criteria: acute acetaminophen overdose, plasma acetaminophen concentration above the treatment nomogram line, treatment with IV NAC according to the protocol, and sufficient data to determine outcome.
                IV NAC treatment consisted of a loading dose of 140 mg/kg followed by 12 doses of 70 mg/kg every four hours.
                Patients were grouped for analysis according to risk group based on the initial plasma acetaminophen concentration. Hepatotoxicity (aspartate aminotransferase or alanine aminotransferase of more than 1,000 IU/L) developed in 10% (five of 50) of patients at "probable risk" when IV NAC was started within ten hours of acetaminophen ingestion and in 27.1% (23 of 85) when therapy was begun after ten to 24 hours. Among "high-risk" patients first treated 16 to 24 hours after overdose, hepatotoxicity occurred in 57.9% (11 of 19). There were two deaths (two of 179, 1.1%). Adverse reactions resulting from NAC occurred in 32 of 223 cases (14.3%), consisting in 29 of 32 patients (91% of reactions) of transient, patchy, skin erythema or mild urticaria during the loading dose that did not require discontinuation of therapy.
                This 48-hour IV NAC protocol is safe and effective antidotal therapy for acetaminophen overdose. Based on available data, it is equal to 72-hour oral and 20-hour IV treatment protocols when started early and superior to the 20-hour IV regimen when treatment is delayed. Further study will be required to determine its relative efficacy in the high-risk patient treated very late. Oral activated charcoal is used to treat drug overdose and is effective at reducing drug absorption when administered within 1 h of drug ingestion. There are fewer data on efficacy when the delay is longer, as is the case in most drug overdoses. This study investigated the efficacy of activated charcoal at preventing paracetamol (acetaminophen) absorption after simulated overdose when administration was delayed between 1 and 4 h.
                An open randomized-order four-way crossover study was performed in healthy volunteers comparing the effect of activated charcoal 50 g on the absorption of 3 g paracetamol tablets when administered after an interval of 1, 2 or 4 h or not at all. Plasma paracetamol concentrations were measured over 9 h after paracetamol ingestion using h.p.l.c. and areas under the curve between 4 and 9 h (AUC(4,9 h)) calculated as a measure of paracetamol absorption.
                Activated charcoal significantly reduced paracetamol AUC(4,9 h) when administered after 1 h (mean reduction 56%; 95% Confidence intervals 34, 78; P<0.002) or 2 h (22%; 6, 39; P<0.03) but not after 4 h (8%; -8, 24). When administered after 1 h activated charcoal reduced individual plasma paracetamol concentrations significantly at all times between 4 and 9 h after paracetamol administration. Administration at 2 or 4 h had no significant effect.
                These results in healthy volunteers cannot be extrapolated directly to poisoned patients. However, they provide no evidence of efficacy for activated charcoal when administered after an interval of more than 2 h.
Our results highlight a paucity of randomised trials on interventions for paracetamol overdose. Activated charcoal seems the best choice to reduce absorption. N-acetylcysteine should be given to patients with overdose but the selection criteria are not clear. No N-acetylcysteine regime has been shown to be more effective than any other. It is a delicate balance when to proceed to liver transplantation, which may be life-saving for patients with poor prognosis.