Impact of Hypoalbuminemia on Cefoperazone/Sulbactam Induced Coagulopathy in Post-Operative Surgical Patients

This study will be conducted in the Department of Pharmacology in collaboration with the General Surgery Department of Shaikh Zayed Medical Complex, Lahore. The study population will include adult post-operative surgical patients who are on cefoperazone-sulbactam therapy for at least 72 hours and who are willing to give informed consent. Sample size was estimated using the WHO sample size calculator to compare two proportions in a prospective cohort study. It was based using incidence in a recent relevant study. The minimum sample size was determined to be 49 patients in each group i.e. hypoalbuminemic (serum albumin \< 3.5 g/dl) and normoalbuminemic ( serum albumin >= 3.5 g/dl) groups (98 patients total) based on an assumed incidence of coagulopathy of 40% in hypoalbuminemic patients and 15% in normoalbuminemic patients, a 95% confidence level, a study power of 80%, and a ratio of 1:1 for exposed to unexposed patients. Including 10% for possible dropouts and incomplete follow-up increased the final sample size to 54 patients per group for a total sample size of 108 post operative patients.

Data Collection Procedure: Non-probability consecutive sampling technique will be used for data collection procedure; all eligible post-operative surgical patients admitted to the General Surgery Department and prescribed cefoperazone/sulbactam for at least 72 hours will be recruited for the study with approval from the Institutional Review Board (IRB) and informed written consent from the patients. Demographic and clinical data, such as gender, age, type of surgery, co-morbidities and indication for antibiotic therapy will be collected on a structured proforma. Laboratory studies will be performed within 24 hours of surgery and before or within 24 hours of starting cefoperazone/sulbactam and will include serum albumin, complete blood count (CBC), serum creatinine, estimated glomerular filtration rate (eGFR), prothrombin time (PT), and international normalized ratio (INR). Patients will then be divided into two groups: patients with hypoalbuminemia (serum albumin \<3.5 g/dL) and patients with normal albumin levels (serum albumin ≥3.5 g/dL).

Details of nutritional status (BMI and Nutritional Risk Screening-2002 score), dosage of cefoperazone/sulbactam, duration of therapy, cumulative dose and other co-administered drugs will also be recorded. Patients will be followed up prospectively during the treatment period with cefoperazone/sulbactam. Monitoring of PT and INR will be done on Day 0 (baseline), Day 3, Day 5 and Day 7 of treatment or until the end of the treatment. Any coagulopathy (PT > 25% seconds from baseline, INR>1.5 or clinically significant bleeding due to coagulation abnormality) associated with cefoperazone/sulbactam will be recorded. All the data collected will be entered into a pre-designed data collection form and patient information will be kept confidential throughout the study process.

Statistical Analysis: Quantitative variable will be reported in the form of mean ± standard deviation for data that is normally distributed or median and interquartile range (IQR) for data that is not normally distributed. Qualitative variables will be presented as frequencies and percentages. Independent Sample t-test will be used to compare baseline characteristics of the hypoalbuminemic and normoalbuminemic patients for continuous variables with normal distribution, while Mann-Whitney U test will be used for continuous variables not normally distributed. Categorical variables will be compared between the two groups using the Chi-square test or Fisher's Exact test, as appropriate. The primary outcome, coagulopathy due to administration of cefoperazone/sulbactam will be compared between the hypoalbuminemic and normoalbuminemic cohorts by the Chi-square test. Relative Risk (RR) with 95% Confidence interval (CI) will be calculated to assess the association between hypoalbuminemia and coagulopathy. Variables that had a p value \<0.20 on univariate analysis and clinically relevant covariates such as age, gender, renal dysfunction, nutritional status, duration of therapy, cumulative antibiotic dose and comorbidities will be entered into a multivariable logistic regression model to identify independent predictors of coagulopathy induced by cefoperazone/sulbactam. Adjusted Odds Ratios (AOR) will be reported with their 95% confidence intervals (CIs). All statistical analyses will use a 2-tailed p-value cut off of ≤ 0.05.