Intravenous N-acetylcysteine Research Articles

A randomized controlled trial of intravenous N-acetylcysteine for the prevention of contrast-induced nephropathy after cardiac catheterization: Lack of effect

Background Contrast-induced nephropathy (CIN) after cardiac catheterization is common in patients with preexisting renal dysfunction. Studies of oral acetylcysteine to prevent CIN have produced conflicting results. Intravenous N-acetylcysteine (NAC) has logistic advantages in this setting. The objective of this study was to evaluate, in a blinded, randomized, placebo-controlled fashion, whether intravenous NAC reduced CIN in the setting of cardiac catheterization in patients with preexisting renal insufficiency. Methods Patients with renal dysfunction undergoing cardiac catheterization were randomly assigned to intravenous NAC 500 mg immediately before the procedure or placebo. All patients received isotonic saline (200 mL) beforehand, followed by 1.5 mL/kg per hour for 6 hours, unless contraindicated. Exclusion criteria included acute renal failure, creatinine >400 μmol/L, concurrent dialysis, unstable clinical status, and prior NAC use. Baseline creatinine was obtained immediately before the procedure and repeated 2 to 8 days later. The primary end point was the occurrence of CIN defined as a reduction in creatinine clearance from baseline of >5 mL/min (Cockcroft-Gault formula). Results The study was terminated early because of a determination of futility by the Data Safety Monitoring Committee after enrollment of 487 patients. The median baseline creatinine clearance was 44 mL/min (interquartile range, 33, 55). Median contrast received was 120 mL (interquartile range, 80, 175). Baseline characteristics were similar in the two groups. Altogether, 98 (22.0%) subjects had the primary end point: 23.3% in the NAC group and 20.7% in the placebo arm ( P = .57). Conclusions In this large, randomized trial, enrolling a high-risk group of patients with impaired renal function, intravenous NAC was ineffective in preventing CIN.

Answering Questions about Intravenous N-Acetylcysteine

Answering Questions about Intravenous N-Acetylcysteine

Status epilepticus after a massive intravenous N-acetylcysteine overdose leading to intracranial hypertension and death

Cases of N-acetylcysteine overdose have been reported before. In some cases, these overdoses have led to death if an anaphylactoid reaction was present. A healthy 30-month-old girl allegedly ingested acetaminophen at 418 mg/kg. Because the emergency physician feared the time of ingestion might not be accurate, he decided to start the 20.5-hour intravenous N-acetylcysteine protocol 8 hours after ingestion. He mistakenly prescribed the maximum milliliter-per-kilogram volume of the dextrose 5% diluent for the milliliter-per-kilogram volume of N-acetylcysteine 20% to be administered. Five hours after the error was detected (19.5 hours postingestion), the patient started developing myoclonus on the left side of her body, with left eye deviation. This condition persisted intermittently for 3 hours despite treatment with diazepam, lorazepam, and phenytoin. A first computed tomographic scan result was normal. A few hours later, she sustained shorter recurrences of the myoclonus. At 30 hours after ingestion, she started to have irregular breathing and became unresponsive to pain. A repeated computed tomographic scan showed diffuse cerebral edema. A postmortem examination showed the presence of acute anoxic encephalopathy with marked cerebral edema and the beginning of uncal herniation that confirmed the clinical diagnosis of intracranial hypertension and brain death. A cumulative intravenous dose of 2,450 mg/kg of N -acetylcysteine was associated with status epilepticus, intracranial hypertension, and death in a child.

Answering Questions about Intravenous N-Acetylcysteine

Answering Questions about Intravenous N-Acetylcysteine

Nevirapine-induced toxic epidermal necrolysis and toxic hepatitis treated successfully with a combination of intravenous immunoglobulins and N-acetylcysteine

We describe a case of an HIV-seropositive patient presenting with a severe stomatitis that initially improved with anti-infective agents. Only 13 days after the onset of the stomatitis, the patient developed rapidly progressive constitutional symptoms and a cutaneous eruption. He was diagnosed with a Stevens–Johnson syndrome (SJS) caused by the antiretroviral drug nevirapine (NVP). Despite meticulous supportive care and withdrawal of all drugs, his situation worsened and developed into a toxic epidermal necrolysis (TEN), or Lyell's syndrome, complicated by a toxic hepatitis. Treatment with a novel combination of intravenous immunoglobulins (IVIG) and N-acetylcysteine (NAC) resulted in an exceptionally fast recovery. A literature research revealed no other cases of patients treated with both NAC and IVIG for the combination of TEN and toxic hepatitis. Because of the rapid clinical recovery, this approach merits further investigation. This case report also illustrates the importance of early suspicion of SJS when an HIV-infected patient treated with nevirapine presents with stomatitis.

Bronchospasm Caused by N-Acetylcysteine Intratracheal Instillation in a Patient with Bronchial Asthma: A Case Report

We report of a successfully treated case of fatal bronchospasm, which developed after N-acetylcysteine bolus intratracheal instillation in a 49-year-old female patient with bronchial asthma undergoing laparoscopic cholecystectomy. N-acetylcysteine has been widely used as a potent mucolytic agent since 1963, with few reported adverse reactions. Its mucolytic action is due to the breakage of disulfide bonds in mucus mucoproteins. Most adverse reactions to N-acetylcysteine are usually mild and respond to the termination of the medication and symptomatic treatment with antihistamine. However, several cases of fatal bronchospasm have been reported in asthmatic patients after inhaled or intravenous N-acetylcysteine. N-acetylcysteine induced bronchospasm could be avoided in most asthmatic patients if its concentration is not allowed to exceed 10%, and concomitant -selective bronchodilators are utilized. Nevertheless, asthma is still a potent risk factor and requires special precautions, including careful risk-versus-benefit assessment, close observation and the immediate availability of resuscitation equipment and staff in the event of life-threatening bronchospasm.

EFFECTS OF N-ACETYLCYSTEINE ON OXIDANT-ANTIOXIDANT BALANCE IN OLEIC ACID–INDUCED LUNG INJURY

The antioxidant and anti-inflammatory properties of N-acetylcysteine has been documented in many experimental lung injury models. Because intravenous injection of oleic acid induces histopathologic changes similar to those seen in human acute lung injury or acute respiratory distress syndrome, the authors evaluated the effects of N-acetylcysteine (NAC) on oxidative stress and lung damage in an oleic acid (OA)-induced lung injury model. Thirty-five rats were divided into 5 groups as sham, NAC, OA, pre-OA-NAC, and post-OA-NAC. Lung damage was induced by intravenous administration of oleic acid. Pre-OA-NAC group received intravenous (IV) N-acetylcysteine 15 minutes before oleic acid infusion and post-OA-NAC group received IV N-acetylcysteine 2 hours after oleic acid infusion. In both of the N-acetylcysteine treatment groups, blood and tissue samples were collected 4 hours after oleic acid infusion, independent from the time of N-acetylcysteine infusion. In other groups, blood and tissue samples were collected 4 hours after ethanol, NAC, or OA infusions. Serum myeloperoxidase activity, total antioxidant capacity, malondialdehyde levels, and lung tissue Na+-K+ ATPase activity were measured and light microscopic analyses of lung specimens were performed. The administration of N-acetylcysteine significantly restored Na+-K+ ATPase activity and total antioxidant capacity levels and ameliorated lung architecture. N-acetylcysteine has been shown to have some attenuating effects in experimental animal studies. However, further investigations are necessary to suggest N-acetylcysteine as a treatment agent in critically ill patients with lung injury.

Intravenous N-acetylcysteine prevented contrast nephropathy

Source Citation Baker CS, Wragg A, Kumar S, et al. A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study. J Am Coll Cardiol. 2003;41:2114-8. 12821233

N-acetylcysteine does not prevent bronchopulmonary dysplasia in immature infants: a randomized controlled trial

Objective To evaluate whether N-acetylcysteine (NAC) infusion during the first week of life reduces the risk of death or bronchopulmonary dysplasia (BPD) in infants with extremely low birth weight. Study design In a Nordic multicenter, double-blind trial, infants (n = 391) weighing 500 to 999 g and on ventilator or nasal continuous positive airway pressure were randomized before the age of 36 hours to receive NAC 16 to 32 mg/kg/d (n = 194) or placebo (n = 197) intravenously for 6 days. Primary end points were death or BPD, defined as supplementary oxygen requirement at 36 weeks' gestational age. Results There was no difference in the combined incidence of the primary end points death or BPD, 51% vs. 49%, between the NAC group and control group. Also similar was the incidence of BPD in survivors at 36 weeks' gestational age, 40% vs. 40%, and the mean oxygen requirement at the age of 28 days, 31.2% vs. 30.7%, respectively. The severity of BPD was similar in both groups. Conclusions A 6-day course of intravenous N-acetylcysteine at the dosage used does not prevent BPD or death in infants with extremely low birth weight.

Anaphylactoid reactions to intravenous N-acetylcysteine: a prospective case controlled study

Introduction. Since its introduction in 1977, intravenous N-acetylcysteine has become the treatment of choice for paracetamol overdose. The aim of our study was to investigate the existence of predictive factors in the likelihood of developing anaphylactoid reactions to N-acetylcysteine. Methods. Prospective case-controlled study of all patients who presented to our emergency department (ED) between January 1997 and June 1999, and who were treated with intravenous N-acetylcysteine on the short stay observation ward. Results. Sixty-four patients received N-acetylcysteine infusions; thirty-one (48.4%) developed an anaphylactoid reaction. Nineteen patients who reacted were commenced on N-acetylcysteine prior to receipt of paracetamol concentrations and fifteen (48.4%) were categorised as high-risk. Seventy-one percent of reactions occurred within the first 15 min. Thirteen patients who developed a reaction, had levels which fell below the treatment lines. The levels of a further nine reactors lay above the high-risk but below the normal-risk lines. Only five patients who reacted had levels above the normal-risk line. Two of the patients who reacted to intravenous N-acetylcysteine presented at a later date with a further paracetamol overdose. Both required treatment with intravenous N-acetylcysteine, the first bag being infused over one hour. Neither developed a reaction. Conclusion. We report a substantially higher incidence of anaphylactoid reactions to intravenous N-acetylcysteine than has previously been documented. It appears that these reactions are more likely to occur in high-risk patients, when plasma paracetamol concentrations were found to be below the treatment lines and in late presenters. Perhaps, giving the loading dose of N-acetylcysteine over 60 min could reduce the incidence of adverse reactions.

258 Adverse effects of intravenous N-acetyl cysteine in acetaminophen poisoning treatment

258 Adverse effects of intravenous N-acetyl cysteine in acetaminophen poisoning treatment

Stability and microbiology of inhalant n-acetylcysteine used as an intravenous solution for the treatment of acetaminophen poisoning

Study objective: Intravenous N-acetylcysteine has been used as an antidote for acetaminophen poisoning for more than 25 years in Europe and Canada. In the United States, only the oral administration of N-acetylcysteine is approved by the US Food and Drug Administration. Many physicians routinely use the inhalant preparation as an intravenous formulation; however, no stability, microbiology, or pyrogen studies have been performed. In this study, we evaluate the stability and microbiology of inhalational N-acetylcysteine compounded as an intravenous formulation. Methods: A total of 8 N-acetylcysteine solutions (solution A through H) were prepared by injecting 150 mL of 20% solution through a 22-μm filter to 1 L of 5% dextrose (D5W; 2.6% solution). Solutions A through C were prepared at ambient conditions (25°C [77°F], 65% relative humidity), and solution D was prepared at accelerated conditions (40°C [104°F], 75% relative humidity) for stability testing. The assays were performed by means of high-performance liquid chromatography at 0, 4, 8, 12, 24, 36, 48, 60, and 72 hours according to US Pharmacopeia XXIV methodology. Solutions E through G were assessed for bacterial growth, and solution H underwent pyrogen testing by using a Limulus amebocyte lysate method. Results: Solutions A through C remained stable for at least 60 hours (<10% decomposition), but at 72 hours, there was a 10.3%, 14.9%, and 13.4% degradation, respectively. Under accelerated conditions (solution D), stability lasted for more than 72 hours. Solutions E through G remained free from bacterial growth at 72 hours, and solution H tested negative for endotoxins-pyrogens. Conclusion: Inhalational N-acetylcysteine prepared as an intravenous solution meets US Pharmacopeia standards for stability up to 60 hours and is free from bacteria and their byproducts, offering a viable alternative to the traditional use of oral N-acetylcysteine. [Ann Emerg Med. 2003;42:9-13.]

Adverse Effects of Intravenous N-Acetylcysteine

Various kinds of drugs have been evaluated as aparacetamol antidote; the most important of themis N-acetylcysteine (NAC), which serves as anavailable precursor for glutathione synthesis, thusreplenishing glutathione stores and preventingthe reaction of N-acetyl-p-benzoquinoneimine(NAPQI) with hepatocytes.

Case report and review of the role of late Nacetylcysteine administration in fulminant hepatic failure secondary to acetaminophen toxicity in infancy

Objective: To describe a rare case of fulminant hepatic failure in an infant secondary to acetaminophen toxicity reversed with the late administration of N-acetylcysteine (NAC). Design: Case report, clinical. Setting: Tertiary care pediatric intensive care unit (PICU). Patient: A 4 month-old female admitted to the PICU with metabolic acidosis, hepatomegaly and a decreased level of consciousness progressing to liver failure subsequently found to be caused by acetaminophen toxicity. Main results: This patient was admitted to the PICU with severe metabolic acidosis, hepatomegaly and a decreased level of consciousness, which progressed to fulminant hepatic failure with severe encephalopathy. The cause of the liver failure was later found to be caused by acetaminophen toxicity. According to a Arescue protocols used at our institution, intravenous NAC, consisting of a loading dose of 150 mg/kg followed by a doses of 50 mg/kg and 100 mg/kg infused over 4 and 16 hours, respectively, was administered at least 72 hours after the last possible oral dose of acetaminophen. Within 24 hours of initiating NAC therapy, the patient experienced a dramatic improvement in her liver function and encephalopathy, and was extubated and ultimately discharged from the PICU. Conclusion: NAC therapy remains the standard of care in known acetaminophen toxicity, particularly when the patient presents within 24 hours of the toxic ingestion. However, the late administration of NAC can both reverse liver failure and be lifesaving, and should be considered for children with liver failure regardless of the time of presentation or diagnosis. evidence to suggest that NAC may be useful for patients who present later than 24 hours after ingestion. We present the case of an infant who recovered from fulminant acute hepatic failure with severe encephalopathy, secondary to acetaminophen toxicity, after receiving intravenous N AC 72 hours after admission to hosp ital. This case highlights the potential ro le of late N AC administration in acetaminophen overdose.

Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity

The aim of this study was to determine by multivariate analysis how alcohol and other factors affect the clinical course and outcome in patients with acetaminophen (paracetamol) poisoning. A total of 645 consecutive patients admitted from 1994 to 2000 with single-dose acetaminophen poisoning were studied, giving special attention to alcohol history, time between overdose and intravenous N-acetylcysteine (NAC) treatment (“time to NAC”), and other data available at the time of admittance. Up until 72 hours after ingestion, time to NAC was the single most important independent risk factor. With a time to NAC less than 12 hours, the mortality rate was 0.42% (95% CI, 0.05-2.7). When time to NAC exceeded 12, 24, and 48 hours, the mortality rate increased to 6.1%, 13%, and 19%, respectively. Chronic alcohol abuse was an independent risk factor of mortality (odds ratio [OR], 3.52; 95% CI, 1.78-6.97). Acute alcohol ingestion was an independent protective factor regarding mortality in alcoholic patients (OR, 0.08; 95% CI, 0.01-0.66) but not in nonalcoholic patients (OR, 0.21; 95% CI, 0.03-1.67). Patient age and quantity of acetaminophen were independent risk factors. In conclusion, time to NAC was confirmed as the major risk factor in acetaminophen-induced hepatotoxicity and mortality. Chronic alcohol abuse was an independent risk factor that could be counteracted by concomitant acute alcohol ingestion. We suggest that patients with chronic alcoholism and suspected acetaminophen poisoning due to an increased risk of developing hepatotoxicity should be treated with NAC regardless of risk estimation. (HEPATOLOGY 2002;35:876-882.)

Acetaminophen poisoning and the use of intravenous N-acetylcysteine

Acetaminophen poisoning and the use of intravenous N-acetylcysteine

Acetaminophen poisoning and the use of intravenous N-acetylcysteine

Acetaminophen (N-acetyl-p-aminophenol) is the most widely used antipyretic and analgesic in the United States. Acetaminophen, a combination agent in approximately 125 medications, has been deemed safe and effective when used within the recommended dosage. In 1998 and 1999, however, 203,930 cases of acetaminophen overingestion were reported to U.S. poison centers, making it the leading pharmacologic agent associated with toxicity.

Managing acute liver failure

Acute liver failure in childhood is a rare but fatal disease with a mortality of 70% without transplantation. The aetiology depends on age. In neonates, sepsis or an inherited metabolic liver disease is most likely, whereas viral hepatitis or drug-induced liver failure, especially following paracetamol overdose, is common. The clinical presentation includes jaundice, coagulopathy and encephalopathy. Early diagnosis is essential in order to prevent complications such as cerebral oedema, gastrointestinal bleeding and renal failure. Poor prognostic features include a reduction in liver size, a rising bilirubin with fall in hepatic transaminases, and increasing coagulopathy. Early supportive management, particularly intravenous N-acetylcysteine, may be effective but, in most instances, liver transplantation will be the definitive treatment and thus early referral to a specialist unit for liver transplantation is mandatory.

Management of paracetamol overdose: current controversies.

Paracetamol (acetaminophen) is one of the most frequently used analgesics, and is the most commonly used substance in self-poisoning in the US and UK. Paracetamol toxicity is manifested primarily in the liver. Treatment with N-acetyl-cysteine (NAC), if started within 10 hours from ingestion, can prevent hepatic damage in most cases. Pharmacokinetic data relating plasma paracetamol concentration to time after ingestion have been used to generate a 'probable hepatoxicity line' to predict which cases of paracetamol overdose will result in hepatotoxicity and should be treated with NAC. However, later studies use a 25% lower line as their 'possible hepatotoxicity line'. Although adopting the original line may save considerable resources, further studies are needed to determine whether such an approach is safe. On the basis of the metabolism of paracetamol, several risk factors for paracetamol toxicity have been proposed. These risk factors include long term alcohol (ethanol) ingestion, fasting and treatment with drugs that induce the cytochrome P450 2E1 enzyme system. Although some studies have suggested that these risk factors may be associated with worse prognosis, the data are inconclusive. However, until further evidence is available, we suggest that the lower line should be used when risk factors are present. In Canada and the UK, the intravenous regimen for NAC is used almost exclusively; in the US, an oral regimen is used. Both regimens have been shown to be effective. There is no large scale study with direct comparison between these 2 therapeutic protocols and controversy still exists as to which regimen is superior. During the last few years there has been an increase in the number of reports of liver failure associated with prolonged paracetamol administration for therapeutic reasons. The true incidence of this phenomenon is not known. We suggest testing liver enzyme levels if a child has received more than 75 mg/kg/day of paracetamol for more than 24 hours during febrile illness, and to treat with NAC when transaminase levels are elevated. Paracetamol overdose during pregnancy should be treated with either oral or intravenous NAC according to the regular protocols in order to prevent maternal, and potentially fetal, toxicity. Unless severe maternal toxicity develops, paracetamol overdose does not appear to increase the risk for adverse pregnancy outcome.

Failure of intravenous N-Acetylcysteine to reduce methemoglobin produced by sodium nitrite in human volunteers: A randomized controlled trial

Study objective: To determine whether intravenous N -acetylcysteine (NAC) produces a clinically significant decline in sodium nitrite–induced methemoglobinemia in human volunteers. Methods: We conducted a randomized, control crossover trial with each subject serving as his own control. Methemoglob-inemia was induced with intravenous sodium nitrite (4 mg/kg) administered over 10 minutes starting at time 0. At time 30 minutes, subjects were randomly assigned to treatment with intravenous NAC for 100 minutes (150 mg/kg over 1 hour followed by 14 mg/kg per hour for 40 minutes) or administration of an equal volume of 5% dextrose in water. Each subject received the alternative treatment after an interval of at least 1 week. Blood methemoglobin concentrations were measured by multiwavelength co-oximetry at time 0, 15, 30, 50, 70, 90, 110, and 130 minutes. Area under the methemoglobin concentration-time curve (AUC) between 30 and 130 minutes was compared between groups using a 2-tailed, paired t test. Results: There were no statistically significant differences in the control and treatment groups with respect to baseline hemoglobin or methemoglobin concentrations, as well as nitrite-induced methemoglobin concentrations at the initiation of treatment (0.85±0.06 g/dL, 0.88±0.04 g/dL; mean±SEM; P =.31). Mean AUC for the control group (77.1±5.7 g·min/dL) was significantly lower than the mean AUC for the treatment group (84.5±4.7 g·min/dL); P = .01). Conclusion: Intravenous NAC failed to enhance methemoglobin reduction in this model. [Tanen DA, LoVecchio F, Curry SC. Failure of intravenous N -acetylcysteine to reduce methemoglobin produced by sodium nitrite in human volunteers: A randomized controlled trial. Ann Emerg Med. April 2000;35:369-373.]