Intravenous N-acetylcysteine Research Articles

Clinical outcome of massive acetaminophen overdose treated with standard-dose N-acetylcysteine

Background Recent recognition of “massive” acetaminophen (APAP) overdoses has led to the question of whether standard dosing of N-acetylcysteine (NAC) is adequate to prevent hepatoxicity in these patients. The primary aim of this study was to evaluate the clinical outcome for patients with massive APAP overdose who received standard intravenous NAC dosing of 300 mg/kg over 21 h. Methods This was a single-center retrospective cohort study conducted by chart review of APAP overdoses reported to a regional poison center from 1 January 2010 to 31 December 2019. Massive APAP overdose was defined by single, acute overdose resulting in an APAP concentration exceeding 300 mcg/mL at 4 h post-ingestion. Standard univariate statistical analysis was conducted to describe the cohort, and a multivariate logistic model was utilized to calculate adjusted odds ratios for risk of hepatoxicity. Results 1425 cases of APAP overdose were reviewed. 104 cases met the inclusion criteria of massive APAP overdose. Overall, 79 cases (76%) had no acute liver injury or hepatotoxicity, and 25 (24%) developed hepatoxicity. Nine percent (n = 4) of cases receiving NAC within 8 h developed hepatotoxicity. Crude odds for hepatoxicity was 5.5-fold higher for cases who received NAC after 8 h. Conclusions Standard NAC dosing received within 8 h prevented hepatoxicity in 91% (n = 40) of cases in our series of massive APAP overdoses. Additional data is needed to determine the clinical outcomes of massive APAP overdose using current intravenous NAC dosing.

N-Acetyl-Cysteine Treatment after Lower Extremity Amputation Improves Areas of Perfusion Defect and Wound Healing Outcomes

Patients with critical limb-threatening ischemia (CLTI) and diabetes are at increased risk of poor major amputation site healing. Preclinical studies have demonstrated that the antioxidant N-acetyl-cysteine (NAC) can augment tissue perfusion and angiogenesis in mice. We hypothesize that perioperative administration of NAC in patients with CLTI improves amputation stump perfusion and healing. In a randomized prospective, double-blinded, placebo-controlled, pilot clinical trial, patients with CTLI were recruited at the time of major lower extremity amputation. Patients were randomized to a 5-day perioperative course of intravenous NAC or placebo treatment. Amputation stump perfusion was evaluated on postoperative days (POD) 0, 3, and 5 using noninvasive Laser-Assisted Fluorescent Angiography (LAFA; SPY Elite system). Rate of arterial inflow and peak perfusion were determined using dynamic intensity versus time analysis. Perfusion defects were determined at the time of peak perfusion as a percentage stump surface area (Fig). Amputation stump healing was also evaluated on POD 3, 5, and 30 using modified Bates-Jensen score. Continuous variables were analyzed using the Student t-test. Categorical variables were analyzed using Fisher’s exact test. A total of 33 patients were enrolled in the study. One patient withdrew consent and eight were excluded for missing or incomplete files. Four patients (three NAC, one placebo) had no perfusion defects. In the remaining 20 patients (7 NAC, 13 placebo) with baseline perfusion defects, NAC-treated patients had a more favorable recovery slope compared to control. From POD 3 to 5, NAC-treated patients had a greater relative reduction in defect size (–53% decrease vs +71%; P < .05), whereas perfusion defects increased in the placebo group. Patients that received NAC also had superior healing outcomes at POD30 (100% healing for NAC vs 46% for placebo; P < .01; Table). No differences in the LAFA-derived rate of arterial inflow or time to peak perfusion were observed between the study groups. In patients with CLTI and amputation stump perfusion defects at baseline, perioperative NAC administration may improve short-term perfusion and long-term tissue healing. Intraoperative LAFA may help identify patients with decreased stump perfusion who can benefit from early therapeutic intervention.

Role of N-acetyl Cysteine in Post-transarterial Chemoembolization Transaminitis in Hepatocellular Carcinoma: A Single-center Experience

Transarterial chemoembolization (TACE) is the most common locoregional therapy for hepatocellular carcinoma (HCC). Postembolization syndrome is not an uncommon complication. At present, there is no specific treatment for management of this complication. We aimed to study the role of N-acetyl cysteine (NAC), an antioxidant, in management of this complication. In a prospective observational study, consecutive patients with HCCundergoing TACE from January 2016 to January 2017 were included. Patients with postembolization syndrome, defined as an elevation of transaminase levels more than 3-4 times the upper limit of normal, were administered intravenous NAC for 72h (150mg/kg for 1h, then 12.5mg/kg/h for 4h, and continuous infusion 6.25mg/h for the remaining 67h). The other group received only supportive standard of care. The primary end point was reduction in post-TACE transaminitis. Of 112 patients with HCC, 53 (47.3%) received NAC. The majority were cirrhotics in both the groups. Both groups were well matched in demographic, laboratory, and tumor characteristics. In the NAC group, there was significant reduction in Aspartate transaminase (AST) and Alanine transaminase (ALT) levels from day 1 to day 3 (p= 0.000) compared with the non-NAC group, with no significant change in bilirubin or international normalized ratio levels. The duration of hospital stay was similar in both the groups. None had any major adverse events to NAC. This is a prospective, single-center experience, showing that early initiation of N-acetyl cysteine in those with post-TACE embolization syndromereduces the transaminase level significantly.

S2509 Aortic Dissection - A Rare Cause of Acute Liver Failure

INTRODUCTION: Acute liver failure (ALF) is a medical emergency which needs to be treated urgently. An atypical presentation might delay appropriate medical care. ALF as a result of aortic dissection presents atypically, and requires high clinical suspicion. CASE DESCRIPTION/METHODS: A 37-year-old female was admitted for deranged liver function test (LFT) associated with her first onset of complex generalized tonic clonic seizure. She had no past medical history. There were no family history of seizure or liver disease, in particular Wilson’s disease or hemochromatosis. There was no recent acetaminophen or excessive alcohol consumption. Upon admission, her blood pressure was 99/75 mmHg and there were no clinically detectable jaundice, hepatic flap, Kayser-Fleischer rings or chest pain. Her transaminases showed a hepatitic pattern of deranged LFT (ALT 388 U/L and AST 378 U/L with normal serum bilirubin, ALP and INR). Abdominal Ultrasound excluded the presence of liver cirrhosis or biliary obstruction. Serologies for viral hepatitis (A, B, C, E; EBV and CMV) and anti-liver panel were all negative. Computed Tomography (CT) of the brain excluded intracranial bleeding or mass. Chest radiography showed soft-tissue opacity over right upper mediastinum (Figure 1a). ECG showed sinus tachycardia. Urgent bedside echocardiography excluded acute myocardial infarction and valvular heart disease. Within 12 hours after admission, she started to developed features of ischemic hepatitis and acute liver failure (new asterixis, prolonged INR of 1.7, worsening LFT with ALT 3430 U/L, AST 3000 U/L, bilirubin 170umol/L). She also developed oliguric AKI. Intravenous N-acetylcysteine was given in view of early hepatic encephalopathy and rapidly progressing acute liver failure. While she had no chest pain, her rising serum troponin and widened mediastinum prompted an urgent CT Aortogram. The CT Aortogram showed a 4.3cm dilatation of the ascending thoracic aorta with acute hemopericardium and cardiac tamponade (Figure 1b). She underwent an emergent ascending aorta and aortic arch repair and temporary renal dialysis. Both her kidney, liver and neurological function recovered following surgical repair. DISCUSSION: This case highlighted the importance of prompt identification of acute aortic dissection as the etiology of fulminant acute liver failure. Delayed or missed diagnosis could have been catastrophic. The presence of neurological sequelae very early in the clinical presentation is a harbinger for an ischemic cause.Figure 1.: Chest X-ray showed a soft tissue opacity over the upper right mediastinum. This was further delineated on CT Aortogram to be an ulcerated ascending aorta dilatation.Figure 2.: Patchy diffuse hypoenhancement of the liver, gallbladder edema and ascites were seen on CT.

Is paracetamol responsible for fatal acute liver failure in pediatric patients after hip dysplasia surgery?

It is well known that local complications, such as avascular necrosis and arthrosis can develop after surgery for developmental dysplasia of the hip (DDH). Thus far, systemic complications that may develop in such cases have not been identified in the literature. This study is the first case series to evaluate acute liver failure (ALF) development after DDH surgery in pediatric patients. Six patients, five female and one male, who underwent DDH surgery were selected for this study. Perioperative fasting time, laboratory values, treatments, histopathological evaluations, and prognoses after ALF in these patients were evaluated retrospectively. All the patients were administered paracetamol and sevoflurane in therapeutic doses. The patients were referred postoperatively to our pediatric emergency department after 5 ± 1.67 days (range = 3-7 days) on average. The average perioperative fasting time was 9.3 ± 0.82 hours (range = 8-10 hours). Due to the very high aminotransferases and use of paracetamol, intravenous N-acetylcysteine was administered alongside supportive treatments to all the patients. After liver transplantation, two of three patients with grade 3 encephalopathy, died in the early postoperative period. Histopathological evaluations of the three patients' explants were compatible with toxic hepatitis due to paracetamol. Paracetamol is a commonly used analgesic after pediatric surgery. The therapeutic dose of paracetamol remains uncertain in children who have been fasting for a long time and have been exposed to hepatotoxic drugs due to previous surgery. In conclusion, caution should be exercised in the use of paracetamol in children with DDH who will undergo surgery, and careful perioperative clinical and laboratory monitoring for ALF is essential.

S2630 NAC Saved the Liver One More Time, Use of N-acetylcysteine in Amphetamine-Induced Acute Liver Failure

INTRODUCTION: Amphetamine is a popular recreational drug in the western world, it induces euphoria and boost self-confidence. Excessive dose causes agitation, hallucination, cardiovascular manifestation, and hyperthermia. Hepatotoxicity have been reported in the literature with no clear treatment recommendation. On the other hand, N-acetylcysteine (NAC) is a known medication used to treat acetaminophen induced hepatitis. NAC works as hepatoprotective agent via multiple mechanisms, including restoring hepatic glutathione, and serving as a glutathione substitute. We are presenting a case of ALF after sudden ingestion of amphetamine with rapid recovery after administration of intravenous NAC. CASE DESCRIPTION/METHODS: A 20-year-old male with no significant past medical history presented with palpitation after ingesting 2 grams of methamphetamine. he soon became obtunded and was intubated to protect his airway. He was also hypertensive, hyper thermic ∼108F and tachycardic. The rest of his physical exam was normal. Patient urine toxicology was positive for Amphetamine and stat to develop multi-organ failure including severe acute liver failure in less than 24h from admission. Patient PT/PTT/INR peaked around day 3, same wise, s. total bilirubin, AST, and ALT with the later peaked around 2,500 IU/L respectively. on the other hand, s. total protein and s. albumin reached a nadir around the same time period. N-acetylcysteine IV loading followed by maintenance does was started around 6 h after admission, with a significant recovery in liver enzymes started after only 3 days of therapy and normalization of AST, ALT and PT/INR/PTT observed by day 5. DISCUSSION: NAC, which is an established antidote in acetaminophen induce ALF, works via multiple mechanism mainly include supplying cysteine for glutathione synthesis and thus reduce oxidative stress. It was used successfully in treating our patient amphetamine induce acute hepatitis. Hence, we believe that more studies need to be conducted to investigate the extended role of NAC in treating cases of acute hepatitis.Figure 1.: Graph 1—AST, ALT peaked in the first few days then recovered with the use of NAC.Figure 2.: Graph 2—PT/PTT/ INR elevation and recovery over time with the use of NAC.Figure 3.: Graph 3—bilirubin continued to raise and peaked after AST/ALT then start to trend down while the total protein and Albumin showed the opposite curve.

A Randomized Controlled Trial of Intravenous N-Acetylcysteine in the Management of Anti-tuberculosis Drug-Induced Liver Injury.

Liver injury is a common complication of anti-tuberculosis therapy. N-acetylcysteine (NAC) used in patients with paracetamol toxicity with limited evidence of benefit in liver injury due to other causes. We conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy of intravenous NAC in hospitalized adult patients with anti-tuberculosis drug-induced liver injury (AT-DILI). The primary endpoint was time for serum alanine aminotransferase (ALT) to fall below 100 U/L. Secondary endpoints included length of hospital stay, in-hospital mortality, and adverse events. Fifty-three participants were randomized to NAC and 49 to placebo. Mean age was 38 (SD±10) years, 58 (57%) were female, 89 (87%) were HIV positive. Median (IQR) serum ALT and bilirubin at presentation were 462 (266-790) U/L and 56 (25-100) μmol/L, respectively. Median time to ALT <100 U/L was 7.5 (6-11) days in the NAC arm and 8 (5-13) days in the placebo arm. Median time to hospital discharge was shorter in the NAC arm (9 [6-15] days) than in the placebo arm (18 [10-25] days) (HR, 1.73; 95% CI, 1.13-2.65). Mortality was 14% overall and did not differ by study arm. The study infusion was stopped early due to an adverse reaction in 5 participants receiving NAC (nausea and vomiting [3], anaphylaxis [1], pain at drip site [1]). NAC did not shorten time to ALT <100 U/L in participants with AT-DILI, but significantly reduced length of hospital stay. NAC should be considered in management of AT-DILI. South African National Clinical Trials Registry (SANCTR: DOH-27-0414-4719).

Case Report: Use of hydroxychloroquine and N-acetylcysteine for treatment of a COVID-19 patient

There is worldwide concern for lack of specific therapy against the novel Betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This case report presents the results of a pharmacological intervention aimed at modulating the inflammatory effects of coronavirus disease 2019 (COVID-19), in an effort to avoid the use of mechanical ventilation. A COVID-19 positive patient was admitted with multisystem organ dysfunction, including acute respiratory insufficiency, and was treated with a combination of low oral doses of hydroxychloroquine and intravenous N-acetylcysteine (NAC). The combination therapy resulted in noticeable clinical improvement and a quantifiable decrease of several of the inflammatory markers measured, in particular ferritin levels, C-reactive protein (CRP) and lactic acid. He also developed pulmonary embolism (PE) and deep vein thrombosis (DVT), both known side effects of COVID-19 infection. Following thrombolysis and heparinization his clinical evolution continued a positive trend until discharge. The therapeutic approach utilized in this case suggests that early intervention not only decrease acute organ dysfunction but also may decrease the need for mechanical ventilation in COVID-19 positive patients.

Antenatal N-acetylcysteine to improve outcomes of premature infants with intra-amniotic infection and inflammation (Triple I): randomized clinical trial

BackgroundIntrauterine infection and/or inflammation (Triple I) is an important cause of preterm birth (PTB) and adverse newborn outcomes. N-acetylcysteine (NAC) is a Food and Drug Administration (FDA)-approved drug safely administered to pregnant women with acetaminophen toxicity.MethodsWe conducted a single-center, quadruple-blind, placebo-controlled trial of pregnant women with impending PTB due to confirmed Triple I. Participants (n = 67) were randomized to an intravenous infusion of NAC or placebo mimicking the FDA-approved regimen. Outcomes included clinical measures and mechanistic biomarkers.ResultsNewborns exposed to NAC (n = 33) had significantly improved status at birth and required less intensive resuscitation compared to placebo (n = 34). Fewer NAC-exposed newborns developed two or more prematurity-related severe morbidities [NAC: 21% vs. placebo: 47%, relative risk, 0.45; 95% confidence interval (CI) 0.21–0.95] with the strongest protection afforded against bronchopulmonary dysplasia (BPD, NAC: 3% vs. placebo: 32%, relative risk, 0.10; 95% CI: 0.01–0.73). These effects were independent of gestational age, birth weight, sex, or race. Umbilical cord plasma NAC concentration correlated directly with cysteine, but not with plasma or whole blood glutathione. NAC reduced the placental expression of histone deacetylase-2, suggesting that epigenetic mechanisms may be involved.ConclusionsThese data provide support for larger studies of intrapartum NAC to reduce prematurity-related morbidity.Impact In this randomized clinical trial of 65 women and their infants, maternal intravenous NAC employing the FDA-approved dosing protocol resulted in lower composite neonatal morbidity independent of gestational age, race, sex, and birthweight.Administration of NAC in amniocentesis-confirmed Triple I resulted in a remarkably lower incidence of BPD. As prior studies have not shown a benefit of postnatal NAC in ventilated infants, our trial highlights the critical antenatal timing of NAC administration.Repurposing of NAC for intrapartum administration should be explored in larger clinical trials as a strategy to improve prematurity-related outcomes and decrease the incidence of BPD.

Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine

Glucose 6-phosphate dehydrogenase (G6PD) deficiency facilitates human coronavirus infection due to glutathione depletion. G6PD deficiency may especially predispose to hemolysis upon coronavirus disease-2019 (COVID-19) infection when employing pro-oxidant therapy. However, glutathione depletion is reversible by N-acetylcysteine (NAC) administration. We describe a severe case of COVID-19 infection in a G6PD-deficient patient treated with hydroxychloroquine who benefited from intravenous (IV) NAC beyond reversal of hemolysis. NAC blocked hemolysis and elevation of liver enzymes, C-reactive protein (CRP), and ferritin and allowed removal from respirator and veno-venous extracorporeal membrane oxygenator and full recovery of the G6PD-deficient patient. NAC was also administered to 9 additional respirator-dependent COVID-19-infected patients without G6PD deficiency. NAC elicited clinical improvement and markedly reduced CRP in all patients and ferritin in 9/10 patients. NAC mechanism of action may involve the blockade of viral infection and the ensuing cytokine storm that warrant follow-up confirmatory studies in the setting of controlled clinical trials.

Case Report: Use of hydroxychloroquine and N-acetylcysteine for treatment of a COVID-19 positive patient

There is worldwide concern for lack of specific therapy against the novel Betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This case report presents the results of a pharmacological intervention aimed at modulating the inflammatory effects of coronavirus disease 2019 (COVID-19), in an effort to avoid the use of mechanical ventilation. A COVID-19 positive patient was admitted with multisystem organ dysfunction, including acute respiratory insufficiency, and was treated with a combination of low oral doses of hydroxychloroquine and intravenous N-acetylcysteine (NAC). The combination therapy resulted in noticeable clinical improvement and a quantifiable decrease of several of the inflammatory markers measured, in particular ferritin levels, C-reactive protein (CRP) and lactic acid. He also developed pulmonary embolism (PE) and deep vein thrombosis (DVT), both known side effects of COVID-19 infection. Following thrombolysis and heparinization his clinical evolution continued a positive trend until discharge. The therapeutic approach utilized in this case suggests that early intervention not only decrease acute organ dysfunction but also may decrease the need for mechanical ventilation in COVID-19 positive patients.

Increased Intravenous N-Acetylcysteine Dosing Following Massive Acetaminophen Ingestion: A Case Report

Kristen M. Audley, Postgraduate Year-2, Critical Care Pharmacy Resident, Christiana Care Health Services I Pharmacy Services Administration, Newark, DE. Jamie M. Rosini, Clinical Pharmacy Specialist, Emergency Medicine, Postgraduate Year-2 Critical Care Residency Program Director, Christiana Care Health Services I Pharmacy Services Administration, Newark, DE

A Combination of N-Acetylcysteine and Prednisone Has No Benefit Over Prednisone Alone in Severe Alcoholic Hepatitis: A Retrospective Analysis.

In this study, we assessed whether there were any survival advantages with a combination treatment of intravenous N-acetylcysteine (NAC) and prednisone over prednisone alone in those with severe alcoholic hepatitis [discriminant function (DF) ≥ 32]. Between January 1, 2013, and February 28, 2019, we identified 68 patients (mean age 47.2years ± 10.1, 57% women, 65% cirrhosis, MELD score 28.1 ± 6.6) with alcoholic hepatitis, and of those, 21 (31%) received prednisone and 47 (69%) received prednisone + NAC. Lille score ≥ 0.45 was considered a poor response. Renal insufficiency was defined as GFR < 60ml/min/1.73m2 calculated on two separate occasions. DF (74.2 ± 33.6 vs. 56.9 ± 15.9, p = 0.09) was similar, but MELD (29.2 ± 6.3 vs. 25.5 ± 6.4, p = 0.03) scores were higher in the combination group. The overall 30-day and 90-day mortality was 13.2% (9/68) and 20.6% (14/68), respectively. Women were more likely (OR 4.86, 95% CI 1.62-14.59) to respond to treatment based on Lille score compared to men, but the type of treatment regimen had no effect on Lille score (OR 0.84, 95% CI 0.25-2.78). Treatment regimen had no effect on both adjusted andunadjusted survivals. Multivariate analysis, after adjusting for confounding variables, confirmed these observations. DF + renal insufficiency had the highest AUROC (0.86) to predict mortality. The combination treatment of NAC + prednisone is not better than prednisone alone in patients with severe alcoholic hepatitis.

Comparison of Prophylactic Use of Intravenous N Acetylcysteine v/s Amiodarone in Preventing Post Operative Artrial Fibrillation after Coronary Artery Bypass Graft

Objective: compare the effectiveness of intravenous N-acetylcysteine and amiodarone in prevention of pos operative atrial fibrillation. Study Design: Randomized control trial Place and duration: study was conducted cardiac surgery department of Choudhary Pervaiz Elahi Institute of Cardiology, Multan from December 2017 to December 2018 in one year duration. Methodology: study was conducted on 130 patients. Patients were divided into two equal groups by lottery method. Study was started after permission from academic affairs committee written informed consent from the patients. Non probability consecutive sampling was used Study variables are age, gender, duration of ICU stay and mortality. An outcome variable was post operative atrial fibrillation. Data was computed on software SPSS version 23 and analyzed for all possible variables. P value ?0.05 was taken as significant. Results: POAF of amiodarone and NAC group was noted as 26.2% and 13.8%, respectively. The difference was statistically insignificant (0.079). Mortality of amiodarone and NAC groups was occurred as 7.7% and 4.6%, respectively. The difference was statistically insignificant (0.465). Conclusion: intravenous N-acetylcysteine is more effective in prevention of post operative atrial fibrillation as compared intravenous amiodarone but post operative stay is prolonged in patients of NAC.

Efficacy of Intravenous N-acetylcysteine As an Adjuvant Therapy in Acute Iron Toxicity in Rats

Iron is a one of the heavy metals that is necessary for cell function. Acute or chronic exposure to high dose lead to oxidative damage. In the liver, iron overload affect hepatic mitochondrial respiration. Deferoxamine is the established antidote of iron toxicity which act as a chelator. N-acetylcysteine is a safe over the counter mucolytic which is antioxidant and glutathione substitute properities. Its use as an antidote for some toxins is well established nowadays. The aim of this work is to study the efficacy of intravenous N-acetylcysteine as an adjuvant therapy with deferoxamine in acute iron intoxication in rats. This study was carried out on twenty male albino rats, weighted 200-250 gm and divided into group I: 10 rats received 400 mg/kg elemental iron orally followed by 25 mg/kg subcutaneous deferroxamine and group II: 10 rats received 400 mg/kg elemental iron followed by 150 mg/kg IV NAC and 25 mg/kg subcutaneous deferroxamine. The results revealed that N-acetylcysteine use lowered both oxidative stress markers malondialdehyde MDA and cyclic adenosine monophosphate cAMP. On the other hand, the reduction of serum and hepatic iron levels and the elevation of Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) were statistically insignificant. It was concluded that intravenous N-acetylcysteine helps in reduction of oxidative stress caused by acute iron toxicity.

Comparison of Oral and Intravenous N-acetyl Cysteine in Preventing Contrast Nephropathy.

Introduction:Despite high rates of morbidity and mortality in patients with contrast-induced nephropathy (CIN), there is no consensus regarding prevention of this well-known complication of contrast media use. One agent that has been widely used in this regard is N-acetyl cysteine (NAC). Nevertheless, its efficacy is still controversial. The aim of this study was to assess the efficacy of NAC, both in the oral and intravenous forms, for the prevention of CIN.Methods:This study is a double-blind randomized placebo controlled clinical trial. We randomized 434 adult patients with chronic kidney disease (constant serum creatinine ≥1.5 mg/dL) who were candidates for coronary angiography/plasty. The patients were categorized into three groups. One group received 1,200 mg NAC intravenously half an hour before the procedure and oral placebo starting 3 days before angiography. The second group received oral NAC 600 mg twice daily for 3 days, starting the day before the intervention and intravenous placebo half an hour before intervention. The third group received both oral and intravenous placebo. CIN was defined as a 25% relative increase in serum creatinine from baseline value, 48 h after use of contrast medium.Results:Of the 434 patients, 149 received intravenous NAC, 145 received oral NAC, and the remaining 140 received placebo. The incidence of CIN in the three groups was 6.1%, 7.6%, and 10.8%, respectively (p = 0.34).Conclusion:In patients with chronic kidney disease, neither intravenous nor oral NAC is superior to placebo for preventing CIN.

The N-AcetylCysteine and RAMipril in Takotsubo Syndrome Trial (NACRAM): Rationale and design of a randomised controlled trial of sequential N-Acetylcysteine and ramipril for the management of Takotsubo Syndrome

BackgroundTakotsubo Syndrome(TTS), contrary to historical reports, is now increasingly recognised to be associated with substantial mortality and morbidity, both in the short- and long-term. Although TTS is often precipitated by a catecholamine “pulse”, in-hospital hypotension is a common occurrence, increasing the risk of mortality. Furthermore, despite the transient catecholamine stimulus, there is increasing evidence that there are significant long term sequelae, including persistently impaired left ventricular(LV) systolic dysfunction, myocardial oedema with fibrosis, as well as persistent impairment of quality of life. A definitive therapeutic option to limit the extent of initial myocardial injury, and to accelerate recovery in TTS is therefore justified. However to date, there has been a lack of prospective studies in this area. Design and rationaleNACRAM is a multi-centre, randomised, placebo-controlled trial, sequentially testing early use of intravenous N-acetylcysteine(NAC), followed by/or oral ramipril for 12 weeks. The rationale for utilising these agents is related to their effects on limiting nitrosative stress and expression of the inflammasome activator thioredoxin interacting protein(TXNIP); both processes fundamental to the pathogenesis of TTS. End pointsNACRAM is assessing resolution of myocardial oedema on cardiac magnetic resonance imaging(CMR), improvements in LV systolic function as measured by global longitudinal strain(GLS) on echocardiography, quality of life, and inflammatory markers. DiscussionTo the best of our knowledge, NACRAM will be the first prospective study to help definitively evaluate a therapeutic option in acute attacks of TTS.

Two-bag intravenous N-acetylcysteine, antihistamine pretreatment and high plasma paracetamol levels are associated with a lower incidence of anaphylactoid reactions to N-acetylcysteine

Context: N-acetylcysteine (NAC) is used worldwide to prevent liver injury after paracetamol overdoses. Anaphylactoid reactions to NAC occur frequently and often lead to treatment interruptions or discontinuations. In Denmark in 2013, the NAC treatment regimen was simplified from a three-bag to a two-bag NAC regimen. Factors of importance for the development of anaphylactoid reaction to this new regimen are poorly explored. Previous studies have suggested a protective effect of high plasma levels of paracetamol on the development of anaphylactoid reactions. Likewise, exposure to antihistamines prior to NAC treatment may protect against these reactions.Methods: This is a retrospective cohort study of patients treated with NAC and with at least one plasma paracetamol sample performed in the Capital Region of Denmark from 2010 to 2017. The primary outcome was the incidence of anaphylactoid reactions to NAC requiring intravenous treatment with antihistamines and/or glucocorticoids. Logistic regression analyses were carried out to identify the risk of developing an anaphylactoid reaction to NAC affected by influencing factors.Results: Of 4315 admissions included in the study, 259 (6.0%) developed an anaphylactoid reaction to NAC. The two-bag regimen (adjusted OR 0.44 [95%CI: 0.32–0.60]), increasing age (adjusted OR 0.84 [95%CI: 0.78–0.90] per 10-year increase) or children <10 years (adjusted OR 0.14 [95%CI: 0.04–0.36]) and antihistamine co-ingestion in overdose (adjusted OR 0.17 [95%CI: 0.02–0.64]) were associated with significantly fewer anaphylactoid reactions. High plasma paracetamol concentrations protected against development of anaphylactoid reactions during the two-bag regimen (adjusted OR 0.59 [95%CI: 0.47–0.71] and three-bag regimen 0.82 [95%CI: 0.72–0.94] per doubling of paracetamol concentration). The effect differed between the two regimens (p = .004 for interaction).Conclusion: In this retrospective cohort, a high peak plasma paracetamol concentration, age, antihistamine co-ingestion and use of the two-bag NAC regimen were associated with fewer anaphylactoid reactions to NAC.

2488 Severe Dengue Fever With Impending Liver Failure in Thalassemic Patient With Pregnancy: A Diagnostic Challenge

INTRODUCTION: Dengue infection is a leading fatal arthropod-borne disease in the tropics. Gastrointestinal presentation of dengue fever (DF) includes abdominal pain, vomiting, jaundice, hepatomegaly and liver failure. The presentation in a patient with thalassemia, during pregnancy poses a clinical challenge in differential diagnosis between the severe form of dengue infection and a complication of pregnancy, HELLP syndrome. CASE DESCRIPTION/METHODS: A 36 years old female with thalassemia during 34 weeks of pregnancy was admitted due to fever with chills. She later developed dyspnea and uterine contraction on the third day of fever. The physical examination revealed body temperature of 39°C, marked pale conjunctiva, mild icteric sclera and mild hepatosplenomegaly. The initial investigation showed white blood cell count of 34020 × 106/L with lymphocytic predominance, hemoglobin of 9.8 g/dL, platelet count of 62000 × 106/L and INR 2.09. Liver function test revealed total bilirubin 4.4 mg/dL, direct bilirubin 3.4 mg/dL, aspartate aminotransferase (AST) 813 IU/L, alanine aminotransferase (ALT) 350 IU/L, and alkaline phosphatase (ALP) 180 IU/L. She underwent cesarean section due to fetal distress with the diagnosis of HELLP syndrome. After the operation, her fever persisted. The follow-up blood tests showed leukocytosis, worsening thrombocytopenia and high level of transaminase enzymes (AST 3285 IU/L and ALT 1279 IU/L). The following investigation showed hemolytic anemia and coagulopathy. No evidence of microangiopathic hemolysis was detected. The dengue NS1 antigen was positive. She was treated with intensive fluids replacement and intravenous N-acetyl cysteine. Her fever lasted for five days and abnormal blood tests become normal within 2 weeks. DISCUSSION: Concurrent DF in a pregnant woman with thalassemia poses difficulty in the diagnosis and might lead to a poor prognosis. Severe dengue infection can cause liver injury with severe thrombocytopenia and hemolytic crisis in thalassemic patients mimicking those occurs in HELLP syndrome. The clinical clues for diagnosis of DF in this situation include fever, thrombocytopenia and acute non-microangiopathic hemolytic anemia. However, awareness of the disease during an outbreak, especially in a rainy season, is probably the most important clue for an early diagnosis. Intensive fluids and hemodynamic management is the key for dengue treatment. Evidence of therapeutic role of N-acetyl cysteine or other liver support systems in DF with liver failure are limited.

2494 Rare Case of Concomitant Acute Hepatic Failure and Renal Failure Induced by Intravenous Amiodarone

INTRODUCTION: Hepatotoxicity caused by chronic oral amiodarone is well documented with around 15–20%. However, acute liver failure due to intravenous Amiodarone is rare clinical presentation with 3% incidence rate. Incidence of concomitant renal failure is even more rare. There is no full explanation for the underlying mechanism. CASE DESCRIPTION/METHODS: 67-year-old male with PMH of CAD s/p coronary artery bypass graft, CKD, presented with chest pain for one week. In the ED, he was found to have atrial flutter. Due to unresponsiveness to IV beta blocker and Diltiazem, patient was loaded with IV Amiodarone and continued IV Amiodarone drip. 16 hours later patient developed acute hepatic failure with AST 4250 (10-42 IU/L), ALT 2422 (10-60 IU/L), INR 2.28 (2-3 conventional anticoagulation), acute renal failure with creatinine of 3.2 mg/dl (0.44-1.0 mg/dl), BUN of 44 mg/d (5-25 mg/dl). Patient was intubated due to acute hepatic encephalopathy. IV Amiodarone was stopped immediately. All workup for other causes of acute hepatic failure came back negative. He was started on intravenous N-Acetyl cysteine and required hemodialysis for acute renal failure. LFTs peaked 72 hours after discontinuation of Amiodarone. Kidney functions improved 5 days after discontinuation of amiodarone and hemodialysis stopped. DISCUSSION: Acute hepatic failure due to intravenous amiodarone is extremely rare with incidence of 3%. The underlying mechanism is still not fully understood. However, a case–control retrospective study argues that hepatotoxicity due to intravenous amiodarone cannot be differentiated from ischemic hepatitis from concomitant hypotension. Intravenous amiodarone is formulated with polysorbate 80 as a solubilizer, which has been shown to induce hypotension. In this case, patient had a stable blood pressure when amiodarone was started. Intravenous (IV) amiodarone toxicity can raise AST/ALT up to 100–200-fold (AST of 21000 and ALT of 9020 in our case) within a day of infusion which then reverses quickly after discontinuation of amiodarone. In this case, liver function tests increased after 26 hours of starting intravenous amiodarone and peaked after 72 hours of stopping the infusion. All cases of acute liver failure due amiodarone didn't survive except for one case. The most common cause of death is encephalopathy. Administration of N-Acetylcysteine was administered is associated with good outcome. Incidence of concomitant renal failure is extremely rare. It is caused by concomitant acute tubular necrosis.