Early Acetaminophen Exposure Reduces Severe AKI After Cardiac Surgery

Patients undergoing cardiac surgery may experience postoperative acute kidney injury (AKI). The complication, known as cardiac surgery-associated AKI, is seen in 8% to 81% of cardiac surgery patients, and is associated with short- and long-term morbidity and mortality, prolonged stay in the intensive care unit (ICU) and hospital, and reduced quality of life. Patients who develop severe AKI face increased risk for worse outcomes, including an 8-fold increase in the odds of 30-day mortality.

According to Chao Xiong, MD, and colleagues, there is no specific pharmacologic prophylaxis for AKI subsequent to cardiac surgery. Acetaminophen is a commonly used postoperative analgesic, and evidence suggests that it protects against kidney damage mediated by free hemoglobin in both animals and humans. Because oxidative stress may be a contributing factor to the development of postoperative AKI, acetaminophen may be considered an antioxidant due to inhibition of hemoprotein-catalyzed lipid peroxidation.

The researchers conducted a retrospective, observational, cohort study to test the hypothesis that there is an association between perioperative administration of acetaminophen and reduced AKI after surgery.

The study utilized data from the Medical Information Mart for Intensive Care III (MIMIC-III) and the eICU Collaborative Research Database (eICU) on patients ≥18 years of age who had cardiac surgery. MIMIC-III (version 1.4) included deidentified clinical details from 46,476 patients who had 61,532 ICU admissions in 2001-2012 at Beth Israel Deaconess Medical Center in Boston, Massachusetts; eICU (version 2.0) included 139,367 patients who had 200,859 ICU admissions in 2014-2015 at 208 hospitals across the continental United States.

The study exposure was administration of acetaminophen in the first 48 hours following surgery. The primary outcome of interest was severe AKI in the first 7 days following surgery, defined as stage 2 or stage 3 AKI according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. Secondary outcomes included any stage AKI in the first 7 days after surgery, any new-onset postoperative kidney replacement therapy (KRT) during the index surgical admission, and in-hospital mortality. Multivariable cause-specific hazards regression analysis was used to characterize the association between early acetaminophen exposure and severe AKI.

Following application of inclusion criteria, the study cohort included 5791 cardiac surgical patients in the MIMIC-III database, and 3840 in the eICU database. In both cohorts, most patients were White and male. In MIMIC-III, 53% of the surgeries were nonelective versus only 7.5% of those in the eICU cohort.

Early postoperative acetaminophen was administered to 72% of patients in the MIMIC-III cohort and 71% of patients in the eICU cohort. Using both serum creatinine and urine output criteria, the incidence of severe postoperative AKI stages 2-3 using the KDIGO definition was 58.5% in the MIMIC-III cohort and 37.3% in the eICU cohort. The proportion of patients who developed any stage AKI was 86% in the MIMIC-III cohort and 50% in the eICU cohort. In a post hoc analysis using only serum creatinine criteria to diagnosis severe AKI, there was a significant decrease in incidence: 14.9% in the MIMIC-III cohort and 8.0% in the eICU cohort.

In general, patients who were given acetaminophen were more likely to be White, have a lower baseline hemoglobin concentration, need more postoperative vasopressor support and more mechanical ventilation, and were more often given high-risk nephrotoxins following surgery.

In the MIMIC-III cohort, the incidence of severe postoperative cardiac surgery-associated AKI was lower in patients given acetaminophen within 48 hours after surgery compared with those who were not given acetaminophen within 48 hours (52% vs 75%, respectively; P<.001). In the eICU cohort, the incidence of severe AKI was also lower in patients administered acetaminophen compared with those not exposed to acetaminophen (36.0% vs 40.3%, respectively; P=.01).

In both cohorts, the incidence of serve AKI defined only by serum creatinine was also significantly lower in the acetaminophen group compared with the group not exposed to acetaminophen: MIMIC-III, 11.9% vs 22.7%, respectively; P<.001); eICU, 7.3% vs 9.7%, respectively; P=.02).

Following adjustment for clinically relevant covariates, there was an association between early administration of acetaminophen and a lower hazard of postoperative severe AKI in both the MIMIC-III cohort (adjusted hazard ratio [aHR], 0.86; 95% CI, 0.79-0.94; P<.001) and the eICU cohort (aHR, 0.84; 95% CI, 0.72-0.97; P=.02). In the multivariable logistic regression model, there was an association between acetaminophen exposure as a dichotomous variable and a significant reduction in the risk of severe AKI in both cohorts: MIMIC-III, adjusted odds ratio (aOR), 0.48; 95% CI, 0.42-0.56; P<.001, and eICU, aOR, 0.80; 95% CI, 0.69-0.93; P=.004.

There was an independent association between use of acetaminophen and lower odds of any stage AKI in both cohorts. Following adjustment for covariates, there were no statistically significant associations in either cohort between acetaminophen exposure and the proportion of patients requiring postoperative KRT or in the rate of in-hospital mortality.

The inability to evaluate dosing of acetaminophen was cited by the authors as a limitation to the study findings.

In summary, the researchers said, “In two large registries, we found that acetaminophen use in the first 48 hours after cardiac surgery was associated with a lower incidence of postoperative severe AKI in adults recovering from cardiac surgery. Our results are largely consistent with the experimental results and the limited clinical data, and they suggest that a trial of acetaminophen for prevention of kidney injury is warranted.”

Takeaway Points

1. Researchers reported results of a study testing the hypothesis that administration of acetaminophen in the early postoperative period following cardiac surgery would be associated with reduced incidence of severe acute kidney injury (AKI).
2. In multivariable regression models, there was an association between early postoperative use of acetaminophen and a lower risk of severe AKI.
3. The benefit was consistent across sensitivity and subgroup analyses.

Source: American Journal of Kidney Diseases