Assessment of Add-On Therapy of N-Acetylcysteine in the Management of Acute Pancreatitis

Introduction

Acute pancreatitis (AP) is a common clinical condition ranging from mild self-limiting disease to severe necrotizing pancreatitis with high mortality. The global incidence of AP has increased over time, with an average annual percentage change from the 1960s to 2016 being 3.07%, and the number of incident cases was 2.8 million. The incidence has been varying considerably worldwide, with an increased incidence among the elderly.^1,2 The most commonly diagnosed types of AP include idiopathic, alcohol-related, and gallstone/bile-related.³ Unlike severe pancreatitis, early AP does not manifest organ failure and pancreatic necrosis but if persistent for >48 hours can increase severity. Therefore, precise prediction of the disease requires early addressing and severity detection.⁴ Initial evaluation of AP is performed by assessing serum lipase or amylase levels, along with liver biochemistry. Severity assessments have been done using different tools and scoring systems such as Ranson's criteria, revised Atlanta criteria for severity, BISAP (Bedside Index of Severity in AP), and APACHE II (Acute Physiology and Chronic Health Examination II), where the latter is said to be more accurate in predicting the outcome of the disease after 48 hours, in at least 88% of the cases.³ Guidelines for managing AP include fluid resuscitation using Ringer's lactate, normal saline, and other intravenous fluids along with analgesics and antiemetics, as the initial treatment.⁵ Antibiotics have been recommended for infected pancreatitis. Other interventional surgeries include endoscopy, cholecystectomy, etc., depending on the severity and etiology of AP.⁶ The pathophysiology of AP involves enzymatic activation in pancreatic acinar cells, leading to inflammation and infiltration of proinflammatory factors and leukocytes into the gland. This subsequently causes oxidative stress and cell damage. NAC works by preventing the increase in cytosolic Ca²⁺ concentration and reduce the accumulation of enzymes in acinar cells during AP. It is an antioxidant capable of restoring the levels of glutathione, the most important cellular antioxidant. It also prevents oxidative free radicals' production and therefore attenuates oxidative cell damage. A meta-analysis of antioxidant treatment for AP reported a reduction in patient complications.⁷ Since the therapeutic effect of NAC in the management of AP has been underexplored, this study observes the treatment outcome of NAC along with conventional therapy which is intravenous hydration–0.9% normal saline, pancreatin, and optional antibiotics.

Materials and Methods

This was a prospective observational study performed in the department of gastroenterology of a tertiary care hospital for a duration of 1 year from June 2020 to May 2021. The study was approved by the Institutional Human Ethical Committee. A count of 65 AP patients above 18 years of age was taken in to study. Patients with chronic pancreatitis, pregnant population, and pediatric population were excluded from the study. Written informed consent was obtained from all the patients. Demographic data, serum levels of amylase and lipase, and duration of hospital stay were collected. Patients were classified into two groups, those who received conventional therapy (0.9% normal saline, pancreatin, and optional antibiotics) and NAC with conventional therapy (NAC infusion: 1 g/5 mL + 25 mL normal saline followed by oral tablet of 600 mg twice a day). The effect of NAC with conventional therapy over conventional therapy was assessed in AP patients by comparing serum amylase (normal range: 40–140 U/L) and serum lipase (normal range: 10–140 U/L). Also, severity and mortality assessment were assessed using APACHE II score and Ranson's score, before and after therapy. APACHE II score, which proves to be the best in predicting the severity of the disease and prognosis, consists of 14 parameters and is used here in analyzing mortality score in the treatment groups. Ranson's score, a standard predictor of outcome in AP patients, is unique in assessing 11 parameters and is also used in the study for disease severity and mortality assessment. Both the scores are opted for their difference in their parameters assessed and for their speci-fi city and sensitivity.

Either minimization or prolongation in duration of hospital stay was assessed in both treatment groups. The significance of outcomes in the management of AP with NAC as an add-on was assessed by an independent t-test for the p-value of 0.05 and confidence interval at 95%, by using SPSS version 26 as a statistical tool.

Results

Of the total population, the majority of the patient were male (93%, n = 60) followed by female (7%, n = 5). A maximum number of patients were in the age group of 40 to 49 (27.6%). Among the participants 54% were diagnosed as an idiopathic AP, 25% were alcohol-related, and 15.50% were gallstone-induced (biliary pancreatitis). A count of 40 (62%) were receiving conventional therapy and 25 (38%) were receiving NAC along with conventional therapy.

Discussion

A randomized, double-blind, placebo-controlled trial by Siriwardena et al,⁸ revealed that there was no difference in APACHE II scores between active and placebo therapy during the first 7 days of treatment, indicating no variance in mortality rates. Similarly, the assessment of mortality rates in AP patients with APACHE II scores showed comparable outcomes after 24 and 48 hours of treatment with conventional therapy as well as NAC combined with conventional therapy.

In addition to the APACHE II score, we also evaluated serum amylase, serum lipase, and Ranson's criteria at admission and after 24 hours of treatment, revealing no significant differences between the two treatment groups. Furthermore, we separately examined the impact of NAC on patients with idiopathic and alcohol-induced AP. Our findings indicate that NAC combined with conventional therapy did not exhibit any significant effects compared with conventional therapy alone in our study. However, there is a lack of human studies supporting these findings, underscoring the necessity for further similar investigations to substantiate the effectiveness of NAC as an adjunct to conventional therapy in AP patients.

A study conducted by Sateesh et al⁹ demonstrated reduced oxidative stress and an enhanced antioxidant status in AP patients when clinically assessed. Antioxidant supplementation may potentially reduce hospital stay duration and complication rates in AP patients, but further validation through larger clinical trials is necessary to confirm this hypothesis. However, in our study, the duration of hospital stays did not exhibit any significant differences. It is noteworthy that most of the referenced studies are clinical trials, while our observational study also has a smaller sample size, indicating the need for a larger sample size to strengthen our findings and provide sufficient evidence to support our hypothesis.

Limitations

Our study has limited sample size, thereby posing challenges in assessing the efficacy of NAC when administered along with conventional therapy. Specifically, within the idiopathic and alcoholic subgroups, this combined treatment regimen showed no statistically significant outcomes compared with conventional therapy alone, attributable in part to the restricted number of participants (n = 25) who received NAC alongside conventional therapy. A more expansive sample size and an interventional study are imperative to support the hypothesis of this study. However, the absence of recent research that supports our hypothesis complicates the acquisition of relevant scholarly works.

Conclusion

In this study, both treatment options, conventional therapy and NAC with conventional therapy, demonstrated similar treatment outcomes for AP patients. This indicates that adding NAC to conventional therapy does not provide any additional benefits in treating AP. Additionally, in both idiopathic and alcohol-induced AP patients, NAC with conventional therapy showed treatment outcomes similar to conventional therapy alone. This suggests that the underlying cause of AP does not significantly influence treatment outcomes. Considering the potential benefits of NAC as an effective antioxidant supplement, we recommend conducting further studies with larger populations to confirm this hypothesis.