Long-term prognosis for transplant-free survivors of paracetamol-induced acute liver failure.

BACKGROUND: The prognosis for transplant-free survivors of paracetamol-induced acute liver failure remains unknown. AIM: To examine whether paracetamol-induced acute liver failure increases long-term mortality. METHODS: We followed up all transplant-free survivors of paracetamol-induced acute liver injury, hospitalized in a Danish national referral centre during 1984-2004. We compared age-specific mortality rates from 1 year post-discharge through 2008 between those in whom the liver injury led to an acute liver failure and those in whom it did not. RESULTS: We included 641 patients. On average, age-specific mortality rates were slightly higher for the 101 patients whose paracetamol-induced liver injury had caused an acute liver failure (adjusted mortality rate ratio = 1.70, 95% CI 1.02-2.85), but the association was age-dependent, and no survivors of acute liver failure died of liver disease, whereas suicides were frequent in both groups. These observations speak against long-term effects of acute liver failure. More likely, the elevated mortality rate ratio resulted from incomplete adjustment for the greater prevalence of substance abuse among survivors of acute liver failure. CONCLUSIONS: Paracetamol-induced acute liver failure did not affect long-term mortality. Clinical follow-up may be justified by the cause of the liver failure, but not by the liver failure itself.

Vasoconstrictor therapy for hepatorenal syndrome in liver cirrhosis.

Hepatorenal syndrome is a severe, but not uncommon complication of decompensated liver cirrhosis. In particular, the rapidly progressive form of hepatorenal syndrome (type 1) is associated with a dismal prognosis. Established hepatorenal syndrome has a spontaneous reversibility below 5%. Hepatorenal syndrome is involved in more than 50% of cirrhosis-related mortality. Thus, any treatment capable of reversing hepatorenal syndrome would be expected to reduce morbidity and mortality from liver cirrhosis. A pathophysiological hallmark of hepatorenal syndrome is arterial underfilling due to an extreme splanchnic vasodilatation. Consequently, potent vasoconstrictors capable of reversing this vasodilatation have been investigated in hepatorenal syndrome. Several vasoconstrictors including the alpha-adrenergic agonists, midodrine and noradrenalin, and the vasopressor analogues, ornipressin and terlipressin, have all been associated with a significant improvement in renal function in 57 to 100% of cases and even reversal of hepatorenal syndrome in 42 to 100% of cases. The majority of recent studies are on terlipressin. A randomized, controlled trial showed a significant effect of terlipressin on reversal of hepatorenal syndrome. The contribution of volume expansion to the beneficial effects of vasoconstrictors on hepatorenal syndrome remains to be determined. In general, reversal of hepatorenal syndrome was associated with an improved survival. However, it remains to be determined if vasoconstrictor therapy should be used in hepatorenal syndrome in general, or if it should be reserved for potential candidates for liver transplantation. In conclusion, evidence for a beneficial effect of vasoconstrictor therapy for the treatment of hepatorenal syndrome is steadily accumulating. Confirmation of the preliminary data in larger randomized, controlled trials looking at long-term survival is required.

Age and paracetamol self-poisoning.

BACKGROUND: Whereas paracetamol poisoning is predominantly seen in adolescents and young adults, the majority of paracetamol associated deaths occur in an older population. AIMS: The aim of the present study was to evaluate age as a risk factor for fulminant hepatic failure (FHF) and death in a large population of patients with paracetamol poisoning. PATIENTS: A total of 746 patients transferred to a specialised unit with severe paracetamol poisoning and 273 unselected patients admitted from the local region over a 10 year period. METHODS: A partly retrospective study based on hospital charts. The risk associated with age was evaluated by multivariate analysis. RESULTS: Paracetamol poisoning most frequently occurred in the age group 15-24 years. Transferred patients were significantly older than local patients (median age 37 years v 29 years; p = 0.0006). In contrast, FHF and death from paracetamol poisoning most frequently occurred in patients aged 40 years or above. In a logistic regression analysis, "age >/=40 years" was associated with an excess risk of FHF (odds ratio (OR) 2.33 (95% confidence interval (CI) 1.50-3.64)) and death or liver transplantation (OR 4.18 (95% CI 2.17-8.05)). In addition, older age was associated with other risk factors for paracetamol hepatotoxicity such as regular alcohol abuse and late presentation. CONCLUSIONS: Age 40 years or above was identified as a significant independent risk factor for FHF and mortality following paracetamol overdose. Patients aged 40 years or above should be considered as high risk patients, in particular when older age appears in combination with regular alcohol abuse or late presentation.

Effect of intravenous N-acetylcysteine infusion on haemostatic parameters in healthy subjects.

BACKGROUND AND AIMS: N-acetylcysteine is used to treat paracetamol overdose but depresses the activity of plasma coagulation factors II, VII, and X, which are often used to assess liver injury. The aim of this study was to investigate the effect of N-acetylcysteine on haemostasis in normal volunteers. METHODS: Haemostatic parameters in 10 healthy subjects were analysed before and following intravenous infusion of therapeutic doses of N-acetylcysteine, as well as in vitro. RESULTS: N-acetylcysteine induced significant decreases in plasma levels of vitamin K dependent haemostatic proteins in vivo, being maximal at one hour following the start of infusion, with maximal decreases from 1.00 to 0.73 (0.67-0.79) (mean (95% confidence interval)), 0.66 (0.58-0.73), 0.81 (0.73-0.90), 0.64 (0.57-0.70), 0.74 (0.65-0.82), and 0.61 (0.54-0.67) for factor II, VII, IX, and X activities, protein C activity, and free protein S reactivity, respectively. These data suggest that N-acetylcysteine induces protein modifications affecting activity. Five subjects developed an adverse reaction to infusion of N-acetylcysteine and these were associated with a rapid increase in levels of factor VIII and its carrier protein von Willebrand factor (vWf) from 1.0 to 1.85 (1.08-2.62) and 1.77 (0.83-2.71), respectively, which suggests that the allergic reaction induced release of vWf from endothelial cells. N-acetylcysteine did not affect factor VIII or vWf in subjects without adverse reactions, and nor did it affect factor V or antithrombin in any of the subjects. CONCLUSION: Therapeutic doses of N-acetylcysteine cause abnormal haemostatic activity, and this should be taken into account when using haemostatic function tests as an indicator of hepatic injury.

Effect of treatment with the Molecular Adsorbents Recirculating System on arterial amino acid levels and cerebral amino acid metabolism in patients with hepatic encephalopathy.

BACKGROUND: Liver failure is associated with low concentrations of branched-chain amino acids and high concentrations of most other amino acids. In this study the effect of treatment with the Molecular Adsorbents Recirculating System (MARS) on arterial amino acid levels and cerebral amino acid metabolism was examined in patients with severe hepatic encephalopathy. METHODS: The study included seven patients with hepatic encephalopathy from fulminant hepatic failure (FHF) and five patients with hepatic encephalopathy from acute-on-chronic liver failure (AoCLF). Cerebral blood flow and cerebral arteriovenous differences in amino acids were measured before and after 6 h of treatment with MARS. RESULTS: During MARS treatment, the total arterial amino acid concentration decreased by 20% from 8.92 +/- 7.79 mmol/L to 7.16 +/- 5.64 mmol/L (P < 0.05). The concentration decreased in all amino acids with the exception of the branched-chain amino acids. Fischer's ratio of branched-chain to aromatic amino acids increased from 0.73 +/- 0.47 to 0.91 +/- 0.54 (P < 0.05). A net cerebral efflux of amino acids in patients with FHF (8.94 +/- 8.34 micromol/100 g/min) as well as AoCLF (7.35 +/- 24.97 micromol/100 g/min) was not affected by the MARS treatment. MARS had no effect on the cerebral metabolic rate of any single amino acid in either group. CONCLUSIONS: MARS treatment tends to normalize the arterial amino acid concentrations in patients with hepatic encephalopathy. Even though the overall reduction in plasma amino acids and improvement in amino acid dysbalance may well be beneficial, it was not accompanied by any immediate improvement in cerebral amino acid metabolism in patients with FHF or AoCLF.

Hyperamylasaemia and acute pancreatitis in paracetamol poisoning.

BACKGROUND: Hyperamylasaemia and even acute pancreatitis have been reported in patients with paracetamol poisoning. AIMS: To describe the incidence, clinical characteristics, and prognostic implications of hyperamylasaemia in paracetamol poisoning. PATIENTS: Six hundred and two patients transferred to a specialized unit with severe paracetamol poisoning and 212 unselected patients admitted from the local region. METHODS: Retrospective study based on hospital charts. The optimum threshold of serum amylase to discriminate non-survivors was identified. RESULTS: An elevated serum amylase (>100 U/L) occurred in 28 of the unselected patients (13%), in 218 of the transferred patients (36%), and in 118 of 148 patients (80%) with fulminant hepatic failure. Only 33 cases of paracetamol-associated acute pancreatitis were diagnosed. A threshold serum amylase of 150 U/L to discriminate non-survivors had sensitivity 76%, specificity 85%, positive predictive value 33%, and negative predictive value 97%. In a logistic regression analysis, a serum amylase > 150 U/L was associated with an excess mortality (odds ratio 5.0, 2.6-9.7). CONCLUSIONS: Hyperamylasaemia is frequent in patients with paracetamol poisoning, whereas clinical acute pancreatitis occurs rarely. The incidence of hyperamylasaemia increases with the degree of hepatic dysfunction. A serum amylase exceeding 1.5 times the upper normal limit indicates a poor prognosis.

The impact of current tobacco use on the outcome of paracetamol poisoning.

BACKGROUND: Tobacco smoke contains a number of substances that are capable of inducing cytochrome P450. Consequently, current tobacco use may enhance the hepatotoxicity from a paracetamol overdose by increasing the oxidative metabolism of paracetamol. AIM: To evaluate, by multivariate analysis, the effect of current tobacco use on the morbidity and mortality from paracetamol-induced hepatotoxicity. METHODS: A retrospective study was carried out on the basis of the hospital charts of 602 patients admitted with single-dose paracetamol poisoning for whom information on current tobacco use was available. RESULTS: In patients admitted with paracetamol poisoning, the rate of current daily tobacco use of 70% (424 of 602 patients) was considerably higher than the rate of 31% in the background population (chi-squared test: P < 0.0001). Current tobacco use was an independent risk factor for the development of hepatic encephalopathy (odds ratio, 2.68; 95% confidence interval, 1.28-5.62) and mortality (odds ratio, 3.64; 95% confidence interval, 1.23-10.75). Current tobacco use was independently associated with high peak values of alanine transaminase and the international normalized ratio. CONCLUSIONS: Current tobacco use was very frequent in patients admitted with paracetamol poisoning. It was an independent risk factor of severe hepatotoxicity, acute liver failure and death following paracetamol overdose.

Highly urgent liver transplantation: possible impact of donor-recipient ABO matching on the outcome after transplantation.

BACKGROUND: Survival after liver transplantation for fulminant hepatic failure has been reported to be less favorable than survival for patients with chronic liver diseases. METHODS: We have studied all patients (n=229) undergoing highly urgent liver transplantation from 1990 to 2001 in the Nordic countries. The impact of patient and donor characteristics, with emphasis on donor-recipient ABO matching (identical, compatible, incompatible), has been studied. RESULTS: One-year and 3-year patient survival rates were 73% and 70% for the total period and 86% and 78% for the last 4-year period. Patients receiving an ABO-compatible liver allograft had significantly lower patient survival rates than those receiving an ABO-identical donor organ (1-year patient survival rates 66% of vs. 79%, P=0.03). Graft survival rates varied less (1-year graft survival rates of 64% vs. 74%, P=0.09). Patients receiving an ABO-incompatible liver allograft had patient survival rates of 70% at 1 year and 60% at 3 years but low graft survival rates (40% and 30% at 1 and 3 years). In a multiple regression analysis, significant independent predictors of poor patient survival were early year of transplantation, ABO-compatible donor, high donor age, and waiting time more than 3 days and less than 9 days. CONCLUSION: Survival after highly urgent liver transplantation has improved and is comparable to that observed in patients receiving a liver allograft because of chronic liver disease. Patients receiving an ABO-identical donor organ had significantly higher patient survival rates compared with those receiving an ABO-compatible donor liver.

The effect of regular medication on the outcome of paracetamol poisoning.

BACKGROUND: Patients admitted with paracetamol overdose frequently receive one or more types of regular medication that may affect the outcome of the paracetamol intoxication. AIM: To describe the use of regular medication in patients with paracetamol poisoning and to evaluate its effects on morbidity and mortality. METHODS: Seven hundred and thirty-seven consecutive patients admitted with paracetamol poisoning were studied and the use of regular medication was recorded. The relative risk of hepatic encephalopathy, death or liver transplantation, severe hepatic dysfunction and severe hepatocellular injury was evaluated by multivariate analysis. RESULTS: Regular medication was received by 332 patients (45%). Medication with benzodiazepines (105 cases), antidepressants (100 cases), neuroleptics (75 cases), paracetamol (58 cases), oral contraceptives (51 cases), beta-agonists (40 cases), opioid analgesics (32 cases) and anticonvulsants (27 cases) predominated. Regular medication with opioid analgesics was associated with a high incidence of hepatic dysfunction (odds ratio, 5.39; 95% confidence interval, 1.13-25.8). No significant findings were demonstrated for benzodiazepines, antidepressants, neuroleptics, paracetamol, oral contraceptives, beta-agonists or anticonvulsants in the multivariate analysis. CONCLUSIONS: Regular medication with psychotropic medication, analgesics, oral contraceptives, beta-agonists or anticonvulsants was frequent in patients admitted with paracetamol poisoning. Medication with opioid analgesics was associated with a significantly increased incidence of hepatic dysfunction, whereas the other medications did not appear to affect the outcome of the paracetamol intoxication.

Hemodynamic changes during a single treatment with the molecular adsorbents recirculating system in patients with acute-on-chronic liver failure.

The aim of this pilot study is to evaluate the circulatory safety of treatment with the molecular adsorbents recirculating system (MARS) by determining the effect on systemic hemodynamics of a single MARS treatment in patients with acute-on-chronic liver failure (AOCLF). In eight patients admitted with AOCLF, a single 10-hour MARS treatment was performed. Systemic hemodynamic variables were determined before and during treatment. Bilirubin and urea were monitored as measures of protein-bound and water-soluble toxins. During MARS treatment, mean arterial pressure increased from 67 +/- 9 to 76 +/- 6 mm Hg (P < .05). Systemic vascular resistance index increased from 757 +/- 134 to 884 +/- 183 dyne x s/cm(5)/m(2) (P < .05), whereas cardiac index remained constant (5.9 +/- 0.7 v 6.0 +/- 1.1 L/min/m(2)). No episode of dialysis-induced hypotension was observed. Systemic oxygen consumption remained constant (92 +/- 30 v 93 +/- 11 mL/min/m(2)). Bilirubin levels decreased from 537 +/- 192 to 351 +/- 106 micromol/L (P < .05), and urea levels, from 19.1 +/- 13.9 to 6.7 +/- 5.1 mmol/L (P < .05). In conclusion, MARS treatment proved safe in critically ill patients with no attributing side effects.

Early postoperative erythromycin breath test correlates with hepatic cytochrome P4503A activity in liver transplant recipients.

BACKGROUND: Interindividual variation in the pharmacokinetics of the immunosuppressive agents cyclosporine (INN, ciclosporin) and tacrolimus may result from differences in the activity of cytochrome P4503A (CYP3A). The erythromycin breath test is an in vivo assay of hepatic CYP3A activity, but the method has never been directly validated. The aim of the study was to investigate whether an early postoperative erythromycin breath test correlated with the hepatic CYP3A protein level and catalytic activity in liver transplant recipients. METHODS: In 18 liver transplant recipients, the erythromycin breath test was performed within 2 hours after transplantation. A graft biopsy was obtained during surgery and analyzed for the CYP3A protein level by Western blotting and for CYP3A activity with erythromycin demethylation and testosterone 6beta- hydroxylation assays. RESULTS: The erythromycin breath test values ranged from 0.14% to 1.65% of carbon 14 per hour, and the CYP3A protein level ranged from 732 to 7822 as measured by optical density. The in vitro catalytic activity determined by the erythromycin demethylation assay ranged from 94 to 902 disintegrations per minute per 5 minutes per milligram of protein, and the activity determined by testosterone 6beta-hydroxylation ranged from 0.030 to 0.627 nmol per minute per milligram of protein. Significant correlation was demonstrated between the erythromycin breath test and both the erythromycin demethylation (Spearman correlation coefficient: R = 0.76, R (2) = 0.57; P =.0004) and the testosterone 6beta-hydroxylation (Spearman correlation coefficient: R = 0.79, R (2) = 0.63; P =.0001) assays. The erythromycin breath test also correlated with the CYP3A protein level (Spearman correlation coefficient: R = 0.60, R (2) = 0.36; P =.01). CONCLUSION: Our data support the erythromycin breath test as a specific in vivo assay of CYP3A activity in humans. The test is applicable in liver transplant recipients in the early postoperative phase. Future studies should evaluate the clinical usefulness of an early postoperative erythromycin breath test as a predictor of cyclosporine-tacrolimus pharmacokinetics in liver transplantation.

Cerebral blood flow velocity increases during a single treatment with the molecular adsorbents recirculating system in patients with acute on chronic liver failure.

The aim of this uncontrolled pilot study is to determine the effect of treatment with the molecular adsorbents recirculating system (MARS) on cerebral perfusion in patients with acute on chronic liver failure (AOCLF). In 8 patients (median age, 44 years; range, 35 to 52 years) admitted with AOCLF, a single 10-hour MARS treatment was performed. Hepatic encephalopathy (HE) was graded according to the Fogarty criteria. Changes in cerebral perfusion were determined by transcranial Doppler as mean flow velocity (V(mean)) in the middle cerebral artery. Arterial ammonia and bilirubin levels were monitored as a measure of the capability of the MARS to remove water-soluble and protein-bound toxins. During MARS treatment, HE grade improved in 3 patients and remained unchanged in 5 patients (P =.11). V(mean) increased from 42 cm/sec (range, 26 to 59 cm/sec) to 72 cm/sec (range, 52 to 106 cm/sec; P <.05), whereas arterial ammonia level decreased from 88 micromol/L (range, 45 to 117 micromol/L) to 71 micromol/L (range, 26 to 98 micromol/L; P <.05) and bilirubin level from 537 micromol/L (range, 324 to 877 micromol/L) to 351 micromol/L (range, 228 to 512 micromol/L; P <.05). In conclusion, cerebral perfusion is increased and levels of ammonia and bilirubin are reduced during MARS treatment in patients with AOCLF.

The effect of selective bowel decontamination on the pharmacokinetics of mycophenolate mofetil in liver transplant recipients.

Mycophenolate mofetil (MMF) is a prodrug immunosuppressant with a high oral bioavailability. Enterohepatic cycling of a glucuronide derivative of MMF contributes substantially to the bioavailability, but is dependent on bacterial deglucuronidation by intestinal flora. This study aims to determine whether an antibiotic regimen with activity against such organisms reduces the bioavailability of MMF by impairing enterohepatic cycling. In a prospective trial, 6 liver transplant recipients were administered MMF and a 21-day antibiotic regimen for selective bowel decontamination (SBD). Time-concentration profiles of the pharmacologically active metabolite, mycophenolic acid (MPA), were obtained during and after the SBD regimen. The bioavailability of MPA was reduced during compared with after the regimen (14.5 +/- 3.5 v 21.1 +/- 9.8 mg. h/mL; P =.07). The most pronounced contribution to this reduction was observed from 6 hours onward (2.4 +/- 1.4 v 5.6 +/- 4.4 mg. h/mL; P <.05). The presence of secondary maxima in the time-concentration profiles of MPA after, but not during, SBD indicates that enterohepatic cycling may be inhibited during SBD and restored afterward. Enterohepatic cycling may contribute 7% to 54% (mean, 29%) of the bioavailability of MPA. We conclude that the bioavailability of MMF may be reduced when SBD is used, and the reduction is likely to result from the interruption of enterohepatic cycling. This mechanism should be taken into consideration not only during SBD, but in any clinical setting combining MMF and broad-spectrum antibiotics.

Paracetamol poisoning among immigrants in a department of hepatology.

INTRODUCTION: An increased incidence of suicides and suicidal behaviour among immigrants has been described in other countries. In Denmark, misuse of paracetamol is suspected in some foreign-born minority groups, although no data have been produced to substantiate this suspicion. METHODOLOGY: A retrospective study of the incidence of paracetamol poisoning in patients admitted to a specialised department of hepatology from 1994 to 1999 was carried out. RESULTS: Of a total of 580 patients, 56 (9.7%; 95%-confidence interval 7.2-12.1%) were immigrants, among whom a significant overrepresentation was found of immigrants from Turkey, Iran, Pakistan, and Lebanon (Observed/Expected-ratios of 1.95, 4.14, 2.67, and 2.45 respectively; p < 0.05). The immigrants differed from the Danish-born patients being younger (21 vs 35 years of age; p < 0.05), having a lower level of alcohol consumption (3% vs 30% with regular alcohol abuse; p < 0.05), and in general being less severely intoxicated (3% vs 22% developing hepatic encephalopathy; p < 0.05). Compared to the Danish-born patients, the immigrants more frequently stated socio-economic problems as the reason for their self-poisoning (29% vs 10%; p < 0.05). CONCLUSIONS: The study demonstrates an overrepresentation of immigrants among patients admitted with paracetamol poisoning in Denmark.

Risk factors in the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning.

AIMS: To identify risk factors in the development of side-effects to N-acetylcysteine (NAC) in patients with paracetamol poisoning. METHODS: A retrospective study was carried out based upon the hospital charts of 529 consecutive patients admitted with paracetamol poisoning, all treated with NAC, at the Department of Hepatology, Copenhagen University Hospital (the tertiary care centre of liver disease in Denmark). RESULTS: Forty-five patients (8.5%; 95% confidence intervals (CI) 6.4, 11%) developed side-effects to NAC and 18 patients (3.4%; 95% CI 2.1, 5.4%) developed systemic side-effects. Asthmatics were 2.9 times (95% CI 2.1, 4.7) more likely to develop side-effects (Chi-square: P = 0.004). Side-effects were of similar severity in asthmatics and nonasthmatics. A history of medical allergy was not a risk factor. Serum paracetamol was lower in patients with side-effects than in those without (Mann-Whitney: P = 0.00006). CONCLUSIONS: Asthma must be considered a risk factor in the development of side-effects to NAC. However, the side-effects are easily managed and there is no reason to withhold NAC from any patient with paracetamol poisoning. Paracetamol itself seems to offer some protection against the development of side-effects to NAC.

[Paracetamol poisoning among immigrants in a department of hepatology]. / Indvandrere med paracetamolforgiftning på en hepatologisk afdeling.

INTRODUCTION: An increased incidence of suicides and suicidal behaviour among immigrants has been described in other countries. In Denmark, misuse of paracetamol is suspected in some foreign-born minority groups, although no data have been produced to substantiate this suspicion. MATERIALS AND METHODS: A retrospective study of the incidence of paracetamol poisoning in patients admitted to a specialised department of hepatology from 1994 to 1999 was carried out. RESULTS: Of a total of 580 patients, 56 (9.7%) were immigrants, among whom a significant overrepresentation was found of immigrants from Turkey, Iran, Pakistan, and Lebanon (observed/expected ratios of 1.95, 4.14, 2.67, and 2.45 respectively). The immigrants differed from the Danish-born patients in that they were younger (21 vs 35 years of age), had a lower level of alcohol consumption (3% vs 30% with regular alcohol abuse), and were in general less severely intoxicated (3% vs 22% developing hepatic encephalopathy). Compared to the Danish-born patients, the immigrants more frequently stated socio-economic problems as the reason for their self-poisoning (29% vs 10%). DISCUSSION: The study demonstrates an overrepresentation of immigrants among patients admitted with paracetamol poisoning in Denmark.

[Side-effects of N-acetylcysteine treatment in patients with paracetamol poisoning]. / Bivirkninger ved N-acetylcystein-behandling af paracetamolforgiftede patienter.

Treatment of paracetamol intoxication with N-acetylcysteine (NAC) is standard in Denmark. NAC is considered safe with relatively few side effects. It is recommended that all patients be treated irrespective of paracetamol dose or time from intoxication to treatment start. Consequently a higher number of patients will be treated with NAC than with previous regimens based on plasma concentrations of paracetamol. In this retrospective study we evaluated the incidence of side effects of NAC in 310 patients admitted to the Department of Hepatology, Rigshospitalet, Copenhagen, over a four-year period (1.1.1994-31.12.1997). Twenty-six (8.4%) patients developed side effects. Side effects were anaphylactoid, mainly from skin (25 rash, pruritus or flushing), in rare cases more serious (four bronchospasm, three angioedema, one hypotension). None were life-threatening and all patients received the full course of NAC. In all cases the recommended treatment with antihistamine or steroids against adverse effects was administered. We conclude that treatment with NAC is safe. Accordingly we find no reason to change the recommendation for treatment of paracetamol intoxication in Denmark.

Major decrements in glycated hemoglobin levels between 1978 and 1989 in patients with insulin-dependent diabetes mellitus.

The Diabetes Control and Complications Trial has shown that intensive treatment can deter the development and progression of diabetic complications. Integral to intensive treatment is improved glycemic control. To describe the trend in glycemic control for subjects with insulin-dependent diabetes mellitus, we examined the medical records of 662 subjects seen between 1978 and 1989 at the Model Demonstration Unit of the Diabetes Research and Training Center (Washington University School of Medicine). Mean value of glycated hemoglobin showed steady decline from a peak of 11.5% in 1979 to 9.0% in 1989. This decline was observed both in subjects evaluated only once (annual rate of decline estimated from linear regression, -0.17 +/1 0.03; p = 0.0001) and in subjects evaluated more than once (annual rate of decline estimated from growth curves, -0.18 +/- 0.06; p = 0.0001). These results suggest that substantial lowering of glycated hemoglobin has occurred during the last decade. This reduction should result in a lowered risk of diabetic complications.

Reproducibility of a comprehensive diet history in the Diabetes Control and Complications Trial. The DCCT Research Group.

OBJECTIVE: To evaluate the reproducibility of a modified Burke-type diet history within the context of a long-term, randomized, 29-center clinical diabetes study. DESIGN: Diet histories were collected by trained interviewers at the end of years 1 and 2 after subjects were randomly assigned to the intensive treatment group or the conventional treatment group. Mean daily intakes of energy, protein, carbohydrate, total fat, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, cholesterol, and dietary fiber were calculated for each treatment group at each time period. SUBJECTS: The study population consisted of 139 subjects in the intensive treatment group and 128 subjects in the conventional treatment group. Ages ranged from 13 to 39 years; groups included men and women. Distribution by age, sex, race, proportion of smokers, weight reported as percent ideal body weight, and duration of IDDM were similar in both groups. STATISTICAL METHODS: Differences in nutrient intake between the conventional and intensive treatment groups at each time period were tested for significance using the Wilcoxon rank-sum test. The Wilcoxon paired differences test was used to assess changes between time periods within treatment groups. Linear agreement between repeated administrations of the diet history was evaluated using Pearson's correlation coefficient, and the extent of within-subject reproducibility was assessed by intraclass correlation. RESULTS: No statistically significant differences in energy and nutrient intakes were observed between the two groups at either year 1 or year 2. Within each treatment group, energy and nutrient intake differences between times were not statistically significant. Correlation coefficients between years 1 and 2 ranged from .51 for dietary fiber to .72 for dietary cholesterol; within-subject reproducibility was slightly higher. APPLICATIONS: These results demonstrate long-term reproducibility for the meal-based diet history in the DCCT population.