Hepatotoxicity Despite Early Administration of Intravenous N-Acetylcysteine for Acute Acetaminophen Overdose

Objectives:  The objective was to evaluate the effectiveness of intravenous N -acetylcysteine (IV NAC; 300 mg/kg over 21 hours) in early acute acetaminophen (APAP) overdose patients.
Methods:  This observational case series included patients hospitalized between 2004 and 2007 for acute APAP overdoses and who were reported to a regional poison center. Inclusion criteria were plasma APAP concentrations on or above the treatment line on the Rumack-Matthew nomogram, administration of IV NAC within 8 hours of ingestion, and follow-up to known outcome. The hospital chart of each patient who received IV NAC for longer than the standard 21 hours was reviewed. Hepatotoxicity was defined as hepatic aminotransferase levels greater than 1,000 IU/L.
Results:  Seventy-seven patients met inclusion criteria and received at least 21 hours of IV NAC for an acute APAP overdose. Seven patients received antidotal therapy for greater than 21 hours. These patients tended to have ingested combination preparations, have very high initial plasma APAP concentrations, and had persistently elevated plasma concentrations during their hospital stay. Hepatotoxicity occurred in 4 patients (5.2%, 95% confidence interval [CI] = 0.2% to 10.1%), including 1 death and 1 liver transplantation.
Conclusions:  Hepatotoxicity developed in 5.2% of cases, suggesting that the 21-hour IV NAC regimen is suboptimal in some patients. In addition to high initial plasma APAP concentrations, APAP product formulation and persistently elevated plasma APAP concentrations were identified as factors possibly associated with developing hepatotoxicity. The authors propose a tailored approach to the discontinuation of IV NAC and point out the need for reevaluation of optimal doses and duration of therapy.     

Predicting acute acetaminophen hepatotoxicity with acetaminophen-aminotransferase multiplication product and the Psi parameter

Context. Prediction of potential hepatotoxicity is important for individualizing therapy with N-acetylcysteine (NAC) in patients with acute acetaminophen overdose. Acetaminophen-aminotransferase multiplication product (APAP × AT) and the Psi Parameter (Psi) have been reported to be the predictors of acetaminophen hepatotoxicity. Objective. To determine the validity of APAP × AT and Psi in predicting hepatotoxicity secondary to acute acetaminophen overdose. Materials and methods. We retrospectively reviewed acute acetaminophen overdose cases who were treated with NAC at Siriraj Hospital, Thailand during January 2004–June 2012. The patients’ ages were 12 years or more. Initial acetaminophen concentration (mg/L) and aminotransferase (IU/L) were multiplied to obtain APAP × AT. Psi were derived from initial acetaminophen concentrations (mg/L) and lag time (hours) to NAC therapy. The cut-off values for APAP × AT and Psi were 1500 mg?IU/L² and 5 mM?h, respectively. Hepatotoxicity (defined as aspartate or alanine aminotransferase (ALT) greater than 1000 IU/L) was the outcome of interest. Results. A total of 255 patients were included, 32 of whom developed hepatotoxicity. APAP × AT had sensitivity, specificity, and negative likelihood ratio of 90.6%, 62.8%, and 0.2, respectively. The sensitivity of Psi, specificity, and negative likelihood ratio were 96.9%, 91.5%, and 0.0, respectively. The areas under the curve of the receiver operating characteristic (ROC) curve for APAP × AT and Psi were 0.82 and 0.96, respectively, with a statistically significant difference between the two methods (p = 0.002). APAP × AT showed higher specificity (92.5%) in patients who presented 8–24 h after the overdose. Discussion and conclusion. Psi and APAP × AT are valid clinical tools in predicting hepatotoxicity secondary to acute acetaminophen overdose in adults. APAP × AT is useful in predicting a low likelihood of hepatotoxicity after standard NAC therapy among late-presenting patients.     

Refining the level for anticipated hepatotoxicity in acetaminophen poisoning

Treatment of an acetaminophen overdose with N-acetyl cysteine usually is based on the position of the 4-h acetaminophen (APAP) level on the Rumack-Matthew nomogram; however, there is disagreement on the level at which clinically relevant hepatotoxicity occurs. A retrospective review of all acute adult formulation APAP exposures reported to our poison center between 1986 and 1993 was performed and cases corresponding to the “possible risk or toxicity” range on the nomogram were identified. Our current poison center protocol for APAP poisoning does not recommend treatment with N-acetylcysteine (NAC) in low-risk patients if the 4-h serum APAP level or the extrapolated equivalent falls within the possible toxicity range on the nomogram. Seventeen cases met the inclusion criteria for the study and received no NAC; six additional patients met inclusion criteria but received one or two doses of NAC before therapy was discontinued. No patients in either group demonstrated clinical evidence of hepatotoxicity. This pilot study suggests that patients with no risk factors and APAP levels in the “possible risk” range may not require NAC therapy.     

A descriptive analysis of aspartate and alanine aminotransferase rise and fall following acetaminophen overdose

Context: Risk prediction following acetaminophen (paracetamol, APAP) overdose is based on serum APAP, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels. One recently proposed risk stratification tool, the APAPxAT multiplication product, uses either AST or ALT, whichever is higher, yet their interrelation is not well known following APAP-induced hepatic injury. Objective: To describe the kinetics of AST and ALT release into and disappearance from the circulation following APAP overdose. Materials and Methods: An observational case series of adult patients with peak AST or ALT > 100 IU/L attributable to APAP toxicity. Cases were identified by electronic search of hospital laboratory database and by discharge diagnosis corroborated by structured explicit medical record review. Results: Of 68 cases identified (mean age (SD): 39 (18) years, 63% female, and 21% ethanol co-ingested), 28 (41%) developed hepatotoxicity (peak AST or ALT > 1000 IU/L), 28 (41%) coagulopathy (international normalized ratio or INR > 2), and 21 (31%) both. Three patients (4%) were transferred for liver transplantation and ultimately six (8.8%) died. Serum AST and ALT activity rose in a closely aligned 1:1 AST:ALT ratio, but fell at distinctly different rates: AST activity fell with a half-life (interquartile range [IQR]) of 15.1 (12.2, 19.4) hours, and ALT 39.6 (32.9, 47.6) hours. Using an aminotransferase falling to below 50% of peak as the basis for discontinuing acetylcysteine would have resulted in antidotal treatment being stopped 24 (IQR: 9.6, 40) hours earlier (and in no cases later) using AST rather than ALT. Only six patients had an AST:ALT ratio greater than 2:1 at the time of acetylcysteine administration; of these six, four died and one survivor developed coagulopathy. Discussion: AST and ALT release into the circulation appears tightly linked and numerically similar, except in the sickest patients. Once the aminotransferases peak, AST returns to baseline more quickly. Conclusion: Either AST or ALT can be used for early risk stratification tools when only one is known. Any criterion for N-AC discontinuation should be based on the decline of AST rather than ALT, with a potential benefit measured in days.     

Comparison of S-Adenosyl-L-methionine and N-acetylcysteine protective effects on acetaminophen hepatic toxicity

Nutraceuticals are widely used by the general public, but very little information is available regarding the effects of nutritional agents on drug toxicity. Excessive doses of acetaminophen (APAP, 4-hydroxyacetanilide) induce hepatic centrilobular necrosis. The naturally occurring substance S-adenosyl-l-methionine (SAMe) has been reported to reduce the hepatic toxicity of APAP. The present study was designed to investigate the hepatoprotective effects of SAMe in comparison to the clinically used antidote N-acetylcysteine (NAC). Male C57BL/6 mice were injected intraperitoneally (i.p.) with an equimolar dose (1.25 mmol/kg) of either SAMe or NAC just before APAP, and the groups were denoted SAMe+APAP and NAC+APAP, respectively. Mice were immediately injected i.p. with 300 mg/kg APAP, and hepatotoxicity was evaluated after 4 h. SAMe was more hepatoprotective than NAC at a dose of 1.25 mmol/kg as liver weight was unchanged by APAP injection in the SAMe+APAP group, whereas liver weight was increased in the NAC+APAP group. SAMe was more hepatoprotective for APAP toxicity than NAC, because alanine aminotransferase levels were lower in the SAMe+APAP. Pretreatment with SAMe maintained total hepatic glutathione (GSH) levels higher than NAC pretreatment before APAP, although total hepatic GSH levels were lower in the SAMe+APAP and NAC+APAP groups than the vehicle control values. Oxidative stress was less extensive in the SAMe+APAP group compared with the APAP-treated mice as indicated by Western blots for protein carbonyls and 4-hydroxynonenal-adducted proteins. In summary, SAMe reduced APAP toxicity and was more potent than NAC in reducing APAP hepatotoxicity.     

Acetaminophen/diphenhydramine overdose in profound hypothermia

Background. There are few reports of acetaminophen overdose in hypothermic patients and even fewer reports describing profound hypothermia. The kinetics, risk of hepatotoxicity, and the possible dose adjustments to N-acetylcysteine (NAC) therapy are not known in this setting. Case report. A 37-year-old female was found unconscious outside in December and was brought by ambulance to a tertiary care Emergency Department (ED) following a presumed overdose of acetaminophen and diphenhydramine. She later confirmed the ingestion and reported the ingestion had occurred approximately 18 hours prior to being found. On arrival, she was profoundly hypothermic, with a core rectal temperature of 17°C. Her initial serum acetaminophen concentration was 232 mcg/mL 19 hours post ingestion of a reported dose of approximately 50 grams of acetaminophen and 2.5 grams of diphenhydramine. Active rewarming was started immediately and IV NAC was initiated using the standard treatment protocol. The patient did not develop serious signs of hepatic injury or NAC toxicity. The patient's AST and ALT peaked 12 hours after admission at 84 IU/L (ref 10–37 U/L) and 104 IU/L (ref 12–78 U/L), respectively. Her INR peaked 2 hours after admission at 1.46 (ref < 1.2). Discussion. Despite the significant ingestion of acetaminophen, delayed presentation, prolonged period of decreased responsiveness, and profound hypothermia, the patient did not develop any signs/symptoms of liver injury. NAC was administered in a standard dose during her rewarming period without apparent toxicity. The patient's absorption and/or metabolism of acetaminophen were likely slowed by her hypothermia and possibly by the anticholinergic coingestant. Initiation of IV NAC at a standard dose was apparently safe and effective in preventing hepatotoxicity as the patient was rewarmed. Conclusions. Profound hypothermia may be protective of hepatic injury in acetaminophen overdose. Delayed absorption from the coingestant, diphenhydramine, may also have played a role. IV NAC was given in a standard dose without apparent toxicity in the setting of profound hypothermia. Lastly, IV NAC, in standard dosing, appeared to be effective in preventing hepatotoxicity during rewarming in a patient with a potentially hepatotoxic concentration of acetaminophen with a coingestion of the anticholinergic agent, diphenhydramine.     

Acetaminophen psi parameter: A useful tool to quantify hepatotoxicity risk in acute acetaminophen overdose

Context. The risk of hepatotoxicity secondary to acute acetaminophen overdose is related to serum acetaminophen concentration and lag time from ingestion to N-acetylcysteine (NAC) therapy. Psi (Greek letter ψ) is a toxicokinetic parameter that takes the acetaminophen level at 4 h post-ingestion ([APAP]_{4 h}) and the time-to-initiation of NAC (tNAC) into account and was found to be significantly predictive of hepatotoxicity in Canadian patients with acetaminophen overdose treated with intravenous NAC. Objective. We report the relationship of psi and hepatotoxicity in a Thai population with acute acetaminophen overdose. Methods. This is a retrospective study of patients with acute paracetamol overdose during January 2004 to June 2009 at Siriraj Hospital. Patients were treated with the standard 21-h intravenous NAC regimen. Univariate analyses were performed with logistic regression to assess the relationships of psi, [APAP]_{4 h}, and tNAC, and hepatotoxicity. Results. A total of 127 patients were enrolled. The median (interquartile range; IQR) of [APAP]_{4 h} was 267.8 (196.0–380.0) mg/L. The median (IQR) of tNAC was 8.5 (6.2–12.0) h. Thirteen patients (10.2%) developed hepatotoxicity. Univariate analysis revealed [APAP]_{4 h}, tNAC, and psi as statistically significant predictors of hepatotoxicity. Discussion and conclusion. The psi parameter is a reliable prognostic tool to predict hepatotoxicity secondary to acute acetaminophen overdose treated with intravenous NAC. Our evidence shows that psi may be a more superior tool than either acetaminophen level or time-to-initiation of NAC at predicting hepatotoxicity.     

N‐acetylcysteine prevents glutathione decrease and does not interfere with paracetamol antinociceptive effect at therapeutic dosage: a randomized double‐blind controlled trial in healthy subjects

Paracetamol (APAP) may lead to hepatic changes even at therapeutic dosages. Glutathione (GSH) plays a pivotal role in APAP metabolism as it allows the detoxification of a toxic metabolite. N‐Acetylcysteine (NAC) is APAP antidote, is also largely used as a mucoactive drug and is often associated with APAP. This study aims at evaluating if 1‐ NAC modifies APAP pain efficacy and 2‐ NAC prevents glutathione depletion with APAP at therapeutic doses. This double‐blind randomized controlled study (NCT02206178) was carried out in 24 healthy volunteers. APAP was given for 4 days (1 g ×4 daily) with NAC or with placebo. Thermal pain tests, whole blood GSH, and hepatic enzymes (ASAT, ALAT) were measured before (D0) and after (D4) oral APAP‐NAC or APAP‐placebo intake. anova for repeated measures adapted to cross‐overdesign was performed and a two‐tailed type I error was fixed at 5%. The primary endpoint was the area under the curve (0–240 min) of pain intensity (Numerical Scale) after thermal pain stimulation using Pathway‐Medoc^®. APAP antinociceptive effect was similar in both groups. GSH was maintained to its baseline value in the APAP/NAC group but diminished in the APAP/placebo group (P = 0.033). This study shows for the first time that APAP antinociceptive effectiveness is not influenced by NAC. It also shows that the effect of APAP at therapeutic dosage on GSH may be counteracted by NAC. These issues are particularly important for patients as APAP is often prescribed for years as a first‐line pain treatment and further trials in patients are now warranted.     

Safety and Effectiveness of Acetadote for Acetaminophen Toxicity

Background: Acetaminophen (APAP) toxicity is commonly encountered in the Emergency Department. Until 2004, treatment consisted of either oral N-acetylcysteine (NAC) or filtered oral NAC administered intravenously (i.v.). Intravenous acetylcysteine (Acetadote) is a new Food and Drug Administration-approved i.v. formulation of acetylcysteine manufactured by Cumberland Pharmaceuticals in Nashville, Tennessee. Little post-marketing data exists on the effectiveness and safety of i.v. acetylcysteine. Objectives: We evaluated the clinical presentations and outcomes of patients treated with i.v. acetylcysteine for APAP toxicity. Methods: We performed a retrospective chart review of patients treated with i.v. acetylcysteine for APAP ingestion. The primary outcome measures were: adverse reactions to and effectiveness of i.v. acetylcysteine, as defined by elevation of transaminases, liver failure, renal failure, death, and hospital length of stay (LOS). Data collected included: comorbidities, allergies, intentionality, timing and dosing of i.v. acetylcysteine, hospital LOS, transaminases > 1000 IU/L, development of liver failure requiring transplant, development of renal failure requiring hemodialysis, death, and anaphylactoid reactions. Results: Sixty-four patients met our study criteria. Overall, 16 (25%) patients developed transaminases > 1000 IU/L, 4 (6%) of them died and 2 (3%) received liver transplants. Of the 15 patients (23%) treated within 8 h, none died or developed liver or renal failure, and only 1 developed transient transaminase elevation > 1000 IU/L. In the patients treated outside of 8 h, the median LOS was 3 days, whereas the group treated within 8 h had a median LOS of only 1 day. Six (9%) patients developed anaphylactoid reactions, 2 of whom received the i.v. acetylcysteine bolus over 15 min. Five of these patients were treated pharmacologically and completed treatment, and one had treatment discontinued for undocumented reasons. Conclusion: Intravenous acetylcysteine seemed to be a safe and effective formulation of N-acetylcysteine.     

Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose

Context: The paracetamol-aminotransferase multiplication product (APAP?×?ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses.

Objective: The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose.

Methods: We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase ≥1000?IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50?IU/L.

Results: Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product <10,000?mg/L?×?IU/L developed hepatotoxicity (sensitivity 100% [95%CI 48%, 100%], specificity 97% [90%, 100%]). Specificity fell to 54% (95%CI: 34, 59%) at a product cut-off point <1500?mg/L?×?IU/L. When calculated within eight hours of ingestion, mild elevations of the multiplication product fell quickly on repeat testing in patients without ALI or hepatotoxicity.

Conclusions: In modified-release paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000?mg/L?×?IU/L, it was very strongly associated with the development of acute liver injury and hepatotoxicity, especially when calculated more than eight hours post-ingestion. When below 1500?mg/L?×?IU/L the likelihood of developing hepatotoxicity was very low. Persistently high serial multiplication product calculations were associated with the greatest risk of hepatotoxicity.     

Analysis of an 8-hour acetylcysteine infusion protocol for repeated supratherapeutic ingestion (RSTI) of paracetamol

Objectives: In Australia, the treatment guideline for patients with repeated supratherapeutic ingestion (RSTI) of paracetamol recommends an abbreviated acetylcysteine regimen if the paracetamol concentration is low (<10?mg/L) and alanine aminotransferase (ALT) is normal or static after 8 hours of infusion. There are currently no studies of this recommendation.

Method: A retrospective review of paracetamol overdose presentations from October 2009 to August 2016 in two hospital toxicology networks was performed. All cases of RSTI treated with acetylcysteine were extracted.

Results: Of the 2249 paracetamol overdose presentations, 91 cases of RSTI were treated with acetylcysteine. Median time to initial blood tests was 6 hours post-last paracetamol dose (IQR 4–6). Sixty-three (69%) presentations had an initial detectable paracetamol concentration, median 30?mg/L (IQR 18–60). Median ALT on presentation was 48?IU/L (IQR 18–109). After 8 hours of acetylcysteine infusion, median ALT was 34?IU/L (IQR 16–71) in those receiving abbreviated treatment and 74?IU/L (IQR 40–231) in those continuing acetylcysteine. Thirty-nine presentations (43%) had an abbreviated regimen. Nine (10%) patients had an initial ALT ≥50?IU/L and subsequently developed hepatotoxicity (ALT >1000?IU/L). No patients with an initial ALT <50?IU/L developed hepatotoxicity. Median duration of acetylcysteine infusion for those receiving a non-abbreviated regimen was 20 hours (IQR 20–25) vs. 10.4 hours (IQR 4.8–12.0) who received an abbreviated regimen. There were no re-presentations with hepatotoxicity.

Conclusions: An 8-hour acetylcysteine infusion regimen for treatment of paracetamol RSTI may be safe and is likely to reduce length of stay for patients at low risk of hepatotoxicity. Larger prospective studies are needed to examine the efficacy of this abbreviated acetylcysteine protocol.     

Acetaminophen overdose in pregnancy

Acetaminophen (APAP) is the most common drug overdose in pregnancy. Available data regarding APAP overdose in pregnancy is limited to case reports and a small prospective case series. APAP has been demonstrated to cross the placenta and in toxic doses may harm the fetal and maternal hepatocytes. Fetal hepatocytes metabolize APAP into both active and toxic metabolites. These toxic metabolites may cause fetal hepatic necrosis. N-acetylcysteine (NAC) has also been demonstrated to cross the placenta and may bind toxic metabolites in both the mother and the fetus. Limited data suggest that the majority of morbidity and mortality from APAP overdose can be averted by initiation of NAC within the first 16 hours of ingestion and possibly even later. NAC may be safely administered during pregnancy and should be initiated early after APAP overdosage. The literature was reviewed through the use of OvidMEDLINE database, encompassing 1966 to the present. Searches were conducted using the key words acetaminophen, paracetamol, N-acetylcysteine, overdose, and hepatotoxicity. The search was further refined by selecting articles that contained these search words together with the key word pregnancy. Only English language papers were reviewed. Articles were selected on the basis of relevance to the topic. Pertinent citations found in the selected articles were also reviewed.     

Different effects of selective β1‐adrenoceptor antagonists,nebivolol or atenolol in acetaminophen‐induced hepatotoxicity of rats

Acetaminophen (APAP) overdose is a common cause of acute liver failure, and beta‐blockers are commonly used drugs in clinical practice. This study aimed to evaluate the effect of two different beta‐blocker agents as nebivolol and atenolol against APAP‐induced hepatotoxicity. Male Wistar rats were treated with APAP (2 g/kg/day, p.o.) to induce hepatotoxicity. Our results showed that nebivolol and atenolol reduced heart rate and blood pressure. Nebivolol (5 mg/kg/day, p.o.) for 14 days has a hepatoprotective effect shown by significant decrease in hepatic injury parameters (serum AST and ALT) with significant suppression of hepatic malondialdehyde (MDA) and nitric oxide (NO) which were elevated with APAP administration. Also, nebivolol increased reduced glutathione (GSH) which was reduced with APAP administration. Moreover, immunohistochemical examination revealed that nebivolol treatment markedly reduced inducible nitric oxide synthase (iNOS) expression, while expression of endothelial nitric oxide synthase (eNOS) was markedly enhanced, as compared to APAP group. The protective effects of nebivolol were also verified histopathologically. On the other hand, as compared to APAP group, oral administration of atenolol (50 mg/kg) increased hepatic injury parameters but did not change hepatic NO, MDA, and GSH. In conclusion, this study revealed that nebivolol not atenolol is protective against APAP‐induced hepatotoxicity possibly, in part, through its antioxidant activity, inhibition of iNOS expression, and induction of eNOS expression.     

Impact of activated charcoal after acute acetaminophen overdoses treated with N-acetylcysteine

Previous studies have suggested that patients receiving both activated charcoal (AC) and N-acetylcysteine (NAC) after acute acetaminophen (APAP) overdoses may have improved outcomes. We evaluated all acute acetaminophen overdoses that received NAC therapy reported to US poison centers for the years 1993 through 2004. Groups were separated based on therapy received: 1) both AC and NAC and 2) NAC alone. There were 97,960 acetaminophen overdoses reported, with 49,427 patients (50%) receiving NAC and AC. Reports of AST/ALT > 1000, a major effect, and death were 1301 (2.9%), 2957 (6.6%), and 232 (0.5%), respectively, for patients receiving NAC plus AC, vs. 5273 (12%), 4534 (10.3%), and 369 (0.8%), respectively, for patients receiving NAC alone (p < 0.01). Use of Toxic Exposure Surveillance System data in the present study has a number of limitations, including its retrospective nature and no documentation of when NAC therapy was initiated. It is possible that those patients who did not receive AC presented to the Emergency Department later in their overdose and had NAC therapy initiated later, and therefore they were predisposed to a greater risk of hepatic injury. Evaluation of 12 years of acute APAP overdoses suggests that the use of AC, in addition to NAC therapy, may provide improved patient outcomes.     

孟鲁司特治疗毛细支气管炎的多中心随机三盲对照研究

目的探讨孟鲁司特（白三烯受体拮抗剂）对毛细支气管炎继发的气道高反应性的改善作用。方法将2007年1月～2008年1月在乌鲁木齐市儿童医院儿科、新疆医科大学第一附属医院儿科、军区总医院儿科住院且符合纳入标准的400例毛细支气管炎患者完全随机分为4组。对照组（n=92）：给予常规治疗＋安慰剂口服;布地奈德组（n=91例）：对照组治疗＋布地奈德吸入7天,孟鲁司特短程组（n=88）：常规治疗＋孟鲁司特口服7天,孟鲁司特长程组（n=90）：常规治疗＋孟鲁司特口服28天。观察各组T-IgE水平、ECP水平变化,并对其进行为期1.5年的随访,统计毛细支气管炎后反复喘息次数及哮喘发生率,由两个试验助理分别负责统计受试者短期指标和长期指标的随访记录。直到试验完成揭盲时各参与人员均不知道受试对象的分组情况。揭盲后数据交由统计师统计分析。期间若患者出现药物副作用时中止试验并破盲。结果本研究共纳入400例患者,失访39例,最终纳入361例进行统计分析。结果显示,布地奈德组与对照组治疗前后在T-IgE（F=6.17,P=0.00）、ECP水平（F=8.13,P=0.00）、日后喘息反复发作次数（χ^2=49.46,P=0.00）、哮喘发生率（χ^2=27.21,P=0.00）方面的差异均有统计学意义;孟鲁司特短程组与对照组比较（F=12.56,P=0.00）、与布地奈德组比较（F=7.22,P=0.00）;孟鲁司特长程组与对照组比较（F=20.48,P=0.00）、与布地奈德组比较（F=13.56,P=0.00）,以及孟鲁司特短与长程组比较（F=1.04,P=0.00）,差异均有统计学意义。结论吸入布地奈德7天后尚不能改善毛细支气管炎后继发的气道高反应性,孟鲁司特可改善毛细支气管炎后继发的气道高反应性,即能减少毛细支气管炎患者日后喘息反复发作次数、降低毛细支气管炎后哮喘发生率,且孟鲁司特长程组优于短程组。     

Prolonged treatment with N-acetylcystine delays liver recovery from acetaminophen hepatotoxicity

Introduction  

Acetaminophen (APAP) toxicity is the most common cause of acute liver failure in the US and Europe. Massive hepatocyte necrosis is the predominant feature of APAP-induced acute liver injury (ALI). Liver regeneration is a vital process for survival after a toxic insult, it occurs at a relative late time point after the injurious phase. Currently, N-acetylcysteine (NAC), a glutathione precursor, is the antidote for acetaminophen overdose. However, NAC is effective only for patients who present within hours of an acute overdose, and is less effective for late-presenting patients. It is possible that in delayed patients, previously reduced endogenous glutathione (GSH) level has restored and prolonged treatment with NAC might be toxic and impair liver regeneration. Therefore, we hypothesize that prolonged treatment with NAC impairs liver regeneration in ALI induced by APAP.     

Acute Ethanol Coingestion Confers a Lower Risk of Hepatotoxicity after Deliberate Acetaminophen Overdose

Objectives:  Little is known about the clinical significance of acute ethanol coingestion around the time of acetaminophen (paracetamol) overdose. This study prospectively examined the effect of acute ethanol coingestion on risk of hepatotoxicity among patients admitted to hospital for N -acetylcysteine (NAC) therapy after deliberate acetaminophen overdose.
Methods:  This was a prospective observational study and included sequential patients who presented within 24 hours of acute acetaminophen ingestion and required NAC therapy. Significant hepatotoxicity was defined by alanine transaminase > 1,000 U/L or the international normalized ratio > 1.3 after a standardized intravenous administration of 300 mg/kg NAC.
Results:  There were 362 patients, including 178 (49.2%) who coingested ethanol acutely. The prevalence of hepatotoxicity was 5.1% (95% CI = 2.6% to 9.5%) in those who ingested ethanol, compared to 15.2% (95% CI = 10.7% to 21.2%) in those who did not (p = 0.0027 by chi-square proportional test). Acute ethanol intake conferred a lower risk of hepatotoxicity in patients who had acetaminophen concentrations above or below the "200-line" and was independent of the interval between ingestion and assessment.
Conclusions:  Acute ethanol intake is associated with a lower risk of hepatotoxicity after acetaminophen overdose. This apparent protective effect cannot be explained solely by lower exposure to acetaminophen in this group, nor differences in the interval between ingestion and initiation of treatment. Further work is required to establish mechanisms by which ethanol might confer protection against hepatotoxicity, so as to identify novel strategies for reducing risk after acute acetaminophen ingestion.