Pentazocine, a Kappa-Opioid Agonist, Is Better Than Diclofenac for Analgesia in Acute Pancreatitis: A Randomized Controlled Trial.

OBJECTIVES: The ideal analgesic is not known for patients with acute pancreatitis (AP). Concerns have been raised about serious adverse effects of opioid analgesics increasing the severity of AP. We hypothesized that nonsteroidal anti-inflammatory drugs might be better analgesics because of their anti-inflammatory effect. Our objective was to compare pentazocine, an opioid, and diclofenac, a nonsteroidal anti-inflammatory drug, for adequate analgesia in patients with AP. METHODS: In a double-blind randomized controlled trial, patients with AP were randomized to either intravenous diclofenac 75 mg or pentazocine 30 mg. Fentanyl was given as a rescue analgesic through a patient-controlled analgesia pump. Primary outcome was pain relief measured objectively by the dose of fentanyl required as the rescue analgesic, pain-free period, and numbers of effective and ineffective demands of fentanyl. Secondary outcome was adverse events. RESULTS: Fifty patients were randomized, 24 to the pentazocine group and 26 to the diclofenac group. Baseline characteristics were comparable between the groups. Pentazocine was found to be better than diclofenac in terms of significantly lower dose of the rescue analgesic (fentanyl) required (126 µg (interquartile range (IQR) 65-218 µg) vs 225.5 µg (IQR 133-427 µg); P = 0.028) and longer pain-free period (31.1 ± 8.2 vs 27.9 ± 6.6 hours, P = 0.047). The number of effective and ineffective demands was lower in the pentazocine group compared with the diclofenac group (11.5 (IQR 8-15) vs 16 (IQR 13-20), P = 0.098) although not statistically significant. Adverse events were similar between the groups. CONCLUSIONS: Pentazocine, a kappa-opioid receptor agonist, was significantly better than diclofenac for pain relief in AP (Trial registration number: CTRI/2016/09/007326).

Interleukin-6 significantly improves predictive value of systemic inflammatory response syndrome for predicting severe acute pancreatitis.

BACKGROUND: Predicting severe acute pancreatitis (AP) is important for triage, prognosis, and designing therapeutic trials. Persistent systemic inflammatory response syndrome (SIRS) predicts severe AP but its diagnostic accuracy is suboptimal. Our objective was to study if cytokine levels could improve the predictive value of clinical variables for the development of severe AP. METHODS: Consecutive patients with AP were included in a prospective cohort study at a tertiary care center. Serum levels of IL-6, TNF-α, IL-10, MCP-1, GM-CSF and IL-1ß were measured at day 3 of onset of AP. Variables such as age, co-morbidity, etiology, SIRS, and cytokines were modeled to predict severe AP by multivariable regression analysis. Genotyping was done to correlate IL-6, TNF-α and MCP-1 gene polymorphisms with cytokine levels. RESULTS: Of 236 patients with AP, 115 patients admitted within 7 days of onset formed the study group. 37 of the 115 (32%) patients developed organ failure. Independent predictors of organ failure were persistent SIRS (OR 34; 95% CI: 7.2-159) and day 3 serum IL-6 of >160 pg/ml (OR 16.1; 95% CI:1.8-142). IL-6 gene (-174 G/C) GG genotype was associated with significantly higher levels of IL-6 compared to CC/CG genotype. Serum IL-6 >160 pg/ml increased the positive predictive value of persistent SIRS from 56% to 85% and specificity from 64% to 95% for predicting OF without compromising its sensitivity and negative predictive value. CONCLUSION: Serum IL-6 of >160 ng/ml added significantly to the predictive value of SIRS for severe AP.

The application of six-minute walk test to identify 'pre-hypoxemia' phase in asymptomatic/mild disease COVID-19 patients managed in home isolation or primary health care setting.

The clinical spectrum of COVID-19 infection patients extends from being asymptomatic to mild, moderate and severe disease. This classification is largely based on oxygen saturation and respiratory rate. Asymptomatic/mild disease patients are managed in home isolation or COVID care centers. A subgroup of these patients will deteriorate and develop moderate to severe disease. Six-minute walk test is useful in identifying this group of patients by inducing hypoxia in normoxemia patients. This stage of the disease is labelled as 'pre-hypoxemia' phase in asymptomatic/mild disease. Identifying this stage in the course of illness of patients will help in intercepting further deterioration at the earliest by timely intervention.

Baveno criteria perform better than expanded Baveno and Rete Sicilia Selezione Terapia-Hepatitis C virus criteria for predicting varices needing treatment.

BACKGROUND AND AIMS: Endoscopy is the gold standard for the detection and staging of varices. Baveno, expanded Baveno, and Rete Sicilia Selezione Terapia-hepatitis C virus (RESIST-HCV) criteria predict varices non-invasively in patients with cirrhosis. We assessed the performance of these criteria for predicting varices needing treatment (VNT). METHODS: Consecutive patients with compensated cirrhosis due to viral etiologies evaluated between January 2014 and May 2017 were included in this retrospective analysis of a prospectively maintained database. VNTs were defined as either large varies or small varices with red color signs on endoscopy. Performance characteristics to predict VNTs were estimated for the three criteria and spared endoscopy rate (SER) and missed VNT rates were determined. RESULTS: Two hundred and ninety-five treatment-naïve cirrhosis patients, etiology hepatitis B (n = 154) or hepatitis C (n = 141), mean age 43.1 ± 13.2 years, 127 (43.1%) males were included. The median liver stiffness measurement (LSM) and platelet counts were 19.7 (interquartile range [IQR]: 14.8-28.8) kPa and 119 (IQR: 80-160) × 103/mm3, respectively. The SER and missed VNT rates were as follows-for Baveno criteria: 18.3% and 6.2%; expanded Baveno: 35.3% and 29.2%; and for RESIST-HCV criteria: 37.3% and 22.9%. The sensitivity, specificity, positive predictive value, and negative predictive value were 93.7%, 21.9%, 18.9%, and 94.7% for Baveno criteria; 70.8%, 42.3%, 19.3%, and 88.1% for expanded Baveno; and 77.1%, 44.5%, 21.3%, and 90.9% for RESIST-HCV criteria, respectively. CONCLUSION: Baveno criteria are useful to avoid screening endoscopies in patients with cirrhosis of viral etiologies. In contrast, although expanded Baveno criteria and RESIST-HCV criteria spare more endoscopies, a high missed VNT rate limits their applicability.

A randomized open-label trial to evaluate the efficacy and safety of triple therapy with aspirin, atorvastatin, and nicorandil in hospitalised patients with SARS Cov-2 infection: A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: The pathophysiology of SARS-Cov-2 is characterized by inflammation, immune dysregulation, coagulopathy, and endothelial dysfunction. No single therapeutic agent can target all these pathophysiologic substrates. Moreover, the current therapies are not fully effective in reducing mortality in moderate and severe disease. Hence, we aim to evaluate the combination of drugs (aspirin, atorvastatin, and nicorandil) with anti-inflammatory, antithrombotic, immunomodulatory, and vasodilator properties as adjuvant therapy in covid- 19. TRIAL DESIGN: Single-centre, prospective, two-arm parallel design, open-label randomized control superiority trial. PARTICIPANTS: The study will be conducted at the covid centre of Dr. Rajendra Prasad Government Medical College Tanda Kangra, Himachal Pradesh, India. All SARS-CoV-2 infected patients requiring admission to the study centre will be screened for the trial. All patients >18years who are RT-PCR/RAT positive for SARS-CoV-2 infection with pneumonia but without ARDS at presentation (presence of clinical features of dyspnoea hypoxia, fever, cough, spo2 <94% on room air and respiratory rate >24/minute) requiring hospital admission and consenting to participate in the trial will be included. Patients with documented significant liver disease/dysfunction (AST/ALT > 240), myopathy and rhabdomyolysis (CPK > 5x normal), allergy or intolerance to statins, allergy or intolerance to aspirin, patients taking medications with significant interaction with statins, prior statin use (within 30 days), prior aspirin use (within 30 days), history of active GI bleeding in past three months, coagulopathy, thrombocytopenia (platelet count < 100000/ dl), pregnancy, active breastfeeding, patient unable to take oral or nasogastric medications, patients in altered mental status, shock, acute renal failure, acute coronary syndrome, sepsis and ARDS at presentation will be excluded. INTERVENTION AND COMPARATOR: After randomization, participants in the intervention group will receive aspirin, atorvastatin, and nicorandil (Fig. 1). Atorvastatin will be prescribed as 40 mg starting dose followed by 40 mg oral tablets once daily for ten days or till hospital discharge whichever is later. Aspirin dose will be 325 starting dose followed by 75 mg once daily for ten days or till hospital discharge whichever is later. Nicorandil will be given as 10 mg starting dose followed by 5mg twice daily ten days or till hospital discharge whichever is later. All patients in the intervention and control group will receive a standard of care for covid management as per national guidelines. All patients will receive symptomatic treatment with antipyretics, adequate hydration, anticoagulation with low molecular weight heparin, intravenous remdesivir, corticosteroids (intravenous dexamethasone for 5 days or more duration if oxygen requirement increasing or inflammatory markers are raised), and oxygen support. Patients will receive treatment for comorbid conditions as per guidelines. Fig. 1 Schematic study design MAIN OUTCOMES: The patients will be followed up for outcomes during the hospital stay or for ten days whichever is longer. The primary outcome will be in-hospital mortality. Any progression to ARDS, shock, acute kidney injury, impaired consciousness, length of hospital stay, length of mechanical ventilation (invasive plus non-invasive) will be secondary outcomes. Changes in serum markers (CRP, D -dimer, S ferritin) will be other secondary outcomes. The safety endpoints will be hepatotoxicity (ALT/AST > 3x ULN; hyperbilirubinemia), myalgia-muscle ache, or weakness without creatine kinase (CK) elevation, myositis-muscle symptoms with increased CK levels (3-10) ULN, rhabdomyolysis-muscle symptoms with marked CK elevation (typically substantially greater than 10 times the upper limit of normal [ULN]) and with creatinine elevation (usually with brown urine and urinary myoglobin) observed during the hospital stay. RANDOMIZATION: Computer-generated block randomization will be used to randomize the participants in a 1:1 ratio to the active intervention group A (Aspirin, Atorvastatin, Nicorandil) plus conventional therapy and control group B conventional therapy only. BLINDING (MASKING): The study will be an open-label trial. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): A total of 396 patients will participate in this study, which is randomly divided with 198 participants in each group. TRIAL STATUS: The first version of the protocol was approved by the institutional ethical committee on 1st February 2021, IEC /006/2021. The recruitment started on 8/4/2021 and will continue until 08/07/2021. A total of 281 patients have been enrolled till 21/5/2021. TRIAL REGISTRATION: The trial has been prospectively registered in Clinical Trial Registry - India (ICMR- NIMS): CTRI/2021/04/032648 [Registered on: 8 April 2021]. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported under the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.

Controlled Attenuation Parameter for Assessment of Hepatic Steatosis in Indian Patients.

BACKGROUND/AIMS: The gold standard method for measurement of hepatic steatosis is liver histology. Controlled Attenuation Parameter (CAP) can measure hepatic steatosis non-invasively. We aimed to assess the accuracy of CAP for detection of hepatic steatosis. METHODS: A total of 462 patients (May 2012-January 2017)-89 non-alcoholic fatty liver disease, 182 chronic hepatitis B, 88 chronic hepatitis C and 103 patients with other etiologies who underwent simultaneous liver biopsy and CAP estimation using Transient Elastography (TE) were included. Steatosis was graded as S0: steatosis in 0-5% of hepatocytes, S1: 6-33%, S2: 34-66% and S3: 67-100%. Receiver Operating Characteristic (ROC) curves were plotted to evaluate the accuracy of CAP in detecting hepatic steatosis. Predictors of CAP were assessed by multivariate linear regression model. RESULTS: The mean age ± SD was 33.8 ± 11.6 years; 296 (64.1%) were males. On liver histology, steatosis grades S0, S1, S2 and S3 were seen in 331 (71.6%), 74 (16.0%), 39 (8.4%) and 18 (3.9%), respectively. The median CAP (IQR) values for S0, S1, S2, and S3 steatosis were 206 (176-252) dB/m, 295 (257-331) dB/m, 320 (296-356) dB/m, and 349 (306-363) dB/m, respectively. For estimation of ≥S1, ≥S2, and ≥S3 using CAP, AUROC were 0.879, 0.893, and 0.883, respectively. In multivariate analysis, only BMI (OR 1.18; CI, 1.11-1.26, P < 0.001) and grade of hepatic steatosis (grade 1, OR, 3.94; 95% CI, 1.58-9.84, P = 0.003; grade 2, OR 42.04; 95% CI, 4.97-355.31, P = 0.001 and grade 3, OR 35.83; 95% CI 4.31-297.61, P = 0.001) independently predicted CAP. CONCLUSIONS: CAP detects hepatic steatosis with good accuracy in Indian patients with various etiologies.

Infected Pancreatic Necrosis due to Multidrug-Resistant Organisms and Persistent Organ failure Predict Mortality in Acute Pancreatitis.

BACKGROUND: Organ failure determines outcome in acute pancreatitis (AP). It is controversial if infected pancreatic necrosis (IPN) is also an independent determinant of mortality. We hypothesized that the predictors of mortality in AP might have changed with advances in management and consequent decline in mortality over the past decades. Our objective was to study the predictors of mortality in patients with AP. METHODS: Consecutive patients with a first episode of AP hospitalized from January 2015 to December 2016 were included in an observational study. Patients with IPN were treated with a conservative first approach followed by intervention. Necrosectomy, if required, was delayed beyond 4 weeks and done primarily employing minimally invasive techniques. The primary outcome measure was independent predictors of in-hospital mortality. RESULTS: Of 209 patients with AP, 81 (39%) had persistent organ failure (OF) and 108 (52%) developed IPN. Overall, 46/209 (22%) patients died. Independent predictors of mortality were OF (odds ratio [OR]19; 95% CI: 6.1-58.8), and IPN due to infection with multidrug resistant (MDR) organisms (OR: 8.4; 95% CI:3.1-22.5). Infected pancreatic necrosis by itself was not found to be a significant predictor of mortality (OR 2; 95% CI: 0.4-9.5). CONCLUSION: Persistent OF and complicated IPN due to MDR infection were independent predictors of mortality in patients with AP. Renewed efforts to prevent MDR infection with antibiotic stewardship and strategies for early control of sepsis are urgently required.

High incidence of abnormal glucose metabolism in acute coronary syndrome patients at a moderate altitude: A sub-Himalayan study.

BACKGROUND: Abnormal glucose metabolic status at admission is an important marker of future cardiovascular events and long-term mortality after acute coronary syndrome (ACS), whether or not they are known diabetics. OBJECTIVE: The aims were to study the prevalence of abnormal glucose metabolism in ACS patients and to compare the different methods of diagnosing diabetes in ACS patients. METHODS: We did a prospective study. About 250 consecutive nondiabetic patients (200 men and 50 women) with ACS admitted to a tertiary care institute of Himachal Pradesh in 1 year were enrolled. Admission plasma glucose, next morning fasting plasma glucose (FPG), A1C, and a standardized 75-g oral glucose tolerance test (OGTT) 72 h after admission were done. Glucose metabolism was categorized as normal glucose metabolism, impaired glucose metabolism (impaired fasting glucose or impaired glucose tolerance [IGT]), and diabetes. Diabetes was arbitrarily classified further as undiagnosed (HBA1c ≥6.5%) or possibly stress diabetes (HBA1c <6.5%). A repeat OGTT after 3 months in objects with IGT and stress hyperglycemia at a time of admission was done. RESULTS: The mean age was 54 ± 12.46 years. The mean plasma glucose at admission was 124 ± 53.96 mg/dL, and the mean FPG was 102 ± 27.07 mg/dL. The mean 2-h postglucose load concentration was 159.5 ± 56.58 mg/dL. At baseline, 95 (38%) had normal glucose metabolism, 95 (38%) had impaired glucose metabolism (IGT and or IGT) and 60 (24%) had diabetes; 48 (19.2%) were undiagnosed diabetes and 12 (4.8%) had stress hyperglycemia. At follow up 58.66% and 55.55% of patients with impaired glucose tolerance and stress hyperglycemia continued to have impaired glucose tolerance respectively. About 75 gm OGTT has highest sensitivity and specificity to diagnose diabetes, whereas A1C most specific to rule out stress hyperglycemia. CONCLUSIONS: In this small hilly state of India, abnormal glucose metabolism (previously undiagnosed diabetes and IGT) is common in patients admitted with ACS. Abnormal glucometabolic status can be detected early in the postadmission period. Our results further suggest that 75-g OGTT remained the gold standard test to detect diabetes and could be used before discharge to diagnose diabetes.

Intracerebral delivery of small interfering RNAs (siRNAs) using adenoviral vector protects mice against lethal peripheral rabies challenge.

To investigate the potential of RNA interference (RNAi) as antiviral agent against rabies, two small interfering RNAs (siRNAs) targeting rabies virus (RABV) nucleoprotein (N) and polymerase (L) genes were designed and evaluated. Both siRNAs knockdown or silenced the target RABV genes as evaluated in a plasmid based transient expression model. For efficient delivery, adenoviruses expressing the siRNAs were constructed and antiviral potential of the delivered siRNAs was investigated in BHK-21 cells. When cells treated with adenoviruses expressing siRNAs were challenged with RABV, there was 88.35±2.4% and 41.52±9.3% reduction in RABV multiplication in infected cells with siRNAs targeting RABV-N and L genes, respectively. Relative quantification of RABV transcripts using real-time PCR revealed knockdown of both RABV-N and L gene transcripts, however, significant reduction was observed only with adenovirus expressing siRNA against RABV-N. When mice treated intracerebrally with adenoviruses expressing siRNAs were challenged peripherally with lethal RABV by the intramuscular route in masseter muscle, there was 66.6% and 33.3% protection with adenoviruses expressing siRNAs against RABV-N and L genes, respectively. These results demonstrated that adenovirus expressing siRNA against RABV-N efficiently inhibited the RABV multiplication both, in vitro and in vivo and conferred significant protection against lethal RABV challenge. This supported the hypothesis that RNAi, based on siRNA targeting RABV-N gene can prevent RABV infection and holds the potential of RNAi as an approach to prevent rabies infection.