Association Between Early Postoperative Acetaminophen Exposure and Acute Kidney Injury in Pediatric Patients Undergoing Cardiac Surgery

Abstract

Importance:

Acute kidney injury (AKI) is a common and serious complication for pediatric cardiac surgery patients associated with increased morbidity, mortality, and length of stay. Current strategies focus on risk reduction and early identification, as there are no known preventive or therapeutic agents. Cardiac surgery and cardiopulmonary bypass lyse erythrocytes, releasing free hemoglobin and contributing to oxidative injury. Acetaminophen may prevent AKI by reducing the oxidation state of free hemoglobin.

Objective:

To test the hypothesis that early postoperative acetaminophen exposure is associated with reduced risk of AKI in pediatric cardiac surgery patients

Design, Setting, and Participants:

In this retrospective observational study, the setting was 2 tertiary referral children’s hospitals. The primary and validation cohorts included children older than 28 days admitted for cardiac surgery between July 1, 2008 and June 1, 2016. Exclusion criteria were postoperative extracorporeal membrane oxygenation and inadequate serum creatinine measurements to determine AKI status.

Exposure:

Acetaminophen exposure in the first 48 postoperative hours

Main Outcome Measure:

AKI, based on Kidney Disease Improving Global Outcomes creatinine criteria (increase by 1.5-fold or 0.3 mg/dL), in the first postoperative week

Results:

The primary cohort (N=666) had a median age of 6.5 months [interquartile range 3.9–44.7 months], and 341 (51%) had AKI. In unadjusted analyses, those with AKI had lower acetaminophen doses than those without AKI [47 (16–88) vs. 78 (43–104) mg/kg, P<0.001]. In logistic regression analysis adjusting for age, cardiopulmonary bypass time, red cell distribution width, nephrotoxin exposures, hypotension, and Risk Adjustment for Congenital Heart Surgery score, acetaminophen exposure was protective for postoperative AKI [odds ratio 0.86 per 10 mg/kg, 95% confidence interval (0.82–0.90)]. Findings were replicated in the validation cohort [N=333; age 14.1 (3.9–158.2) months; 162 (48.6%) with AKI; acetaminophen dose 60 (40–87) vs. 70 (45–94) mg/kg in AKI vs. no AKI, P=0.033; adjusted odds ratio 0.91 (95% confidence interval 0.84–0.99) for each additional 10 mg/kg].

Conclusions and Relevance:

The results indicate that early postoperative acetaminophen exposure may be associated with lower rate of AKI in pediatric patients who undergo cardiac surgery. Further analysis to validate these findings, potentially through a prospective, randomized trial, may establish acetaminophen as a preventive agent for AKI.

Introduction

Acute kidney injury (AKI) occurs in approximately 25% of children admitted to intensive care units (ICUs).^1–9 Among pediatric ICU patients, AKI is associated with increased length of stay and consistently demonstrates odds ratios >3 for mortality.^1,2,8–12 Rates of AKI among children who have cardiac surgery are even higher, with similar associations to increased morbidity, mortality, and length of stay.^13–26 Currently, efforts to reduce the impact of AKI in pediatric patients are focused on early detection and risk reduction, as there are no proven therapeutics to prevent or treat AKI.

For children who undergo cardiac surgery, the necessary cardiopulmonary bypass (CPB) causes hemolysis; which together with the tissue damage from surgery and administration of packed red blood cells leads to relatively high circulating levels of free hemoglobin in these patients.^27,28 Cell-free plasma hemoglobin has been associated with AKI after cardiac bypass in children.²⁹ Based on data from animal models and adults, it is hypothesized that free hemoglobin contributes to AKI through oxidation of the central iron of the heme moiety to the highly reactive and nephrotoxic ferryl (Fe⁴⁺) form.^30–32 This pathogenic mechanism for AKI illuminates a potential therapeutic agent. Acetaminophen, a well-established drug used for analgesia and fever reduction, is known to reduce oxidation of free hemoglobin by preventing the oxidation of iron from Fe³⁺ to Fe⁴⁺.^32,33 The hemoreductant activity of acetaminophen derives from the structural similarity between the heme moiety of hemoglobin and the peroxidase moiety of cyclooxygenase. In recent years, acetaminophen has been increasingly used postoperatively in children in order to reduce opioid exposure.

The primary goal of this study was to test the hypothesis that acetaminophen use in the first 48 hours after cardiac surgery is associated with reduced risk of AKI in children. To test this hypothesis, we performed a retrospective observational study of children who had cardiac surgery in a primary cohort from the Monroe Carell Jr. Children’s Hospital at Vanderbilt, and we validated our findings in a second independent cohort from Duke Children’s Hospital.

Methods

Population and Electronic Health Record Data Extraction

This study was reviewed and approved by the institutional review boards of both Vanderbilt University Medical Center and Duke University. Inclusion criteria for the primary cohort were cardiac surgery at the children’s hospital between the dates of 3/1/2008 and 6/1/2016, and age over 28 days. Exclusion criteria were postoperative extracorporeal membrane oxygenation (as this may include renal replacement therapy and thus affect serum creatinine values) and absence of either the baseline or postoperative serum creatinine measurements to determine AKI status. If subjects had multiple cardiac surgeries, data from only the first surgery were included. After the primary cohort was analyzed, a second cohort was assembled to determine if the findings were unique to the institution, or if they could be replicated in an independent validation cohort. Inclusion criteria for the validation cohort were the same as for the primary cohort, with the exception that the study inclusion dates were 6/25/2013 to 3/29/2016. All study data, including demographic, laboratory, medication administration, and administrative data, were extracted from electronic health records data sources. Medications administered in the first 48 postoperative hours were categorized as high risk nephrotoxins (e.g. aminoglycosides, ketorolac, tacrolimus), moderate risk nephrotoxins, (e.g. loop diuretics, enalapril, trimethoprim/sulfamethoxazole, eTable1), or non-nephrotoxins. Postoperative hypotension was defined using the systolic blood pressure measurements documented in the first 48 postoperative hours, irrespective of any vasopressor support; hypotension was defined as one or more systolic blood pressure < [70mmHg + (2 x age in years)] if ≤10 years of age, and <90 mmHg if >10 years of age.³⁴

Exposure and Outcome Definitions

Exposure was defined as dichotomous exposure to acetaminophen for the initial analysis, and then the cumulative weight-adjusted intravenous, enteral, and/or rectal acetaminophen dose (mg/kg), alone or in combination with other medications, received in the first 48 hours after surgery. Subjects were also categorized into those receiving no acetaminophen, or lowest (≤40 mg/kg), middle (40–80 mg/kg), or highest (>80 mg/kg) doses of acetaminophen. The AKI outcome was defined by change in creatinine. Baseline creatinine measurements were defined as the lowest obtained in the 28 days before surgery. Postoperative creatinine measurements were defined as those obtained in the 7 days after surgery. AKI was defined solely using the creatinine criteria, as reliable urine output data are not available for all pediatric inpatients,³⁵ and accurate height measurements were not consistently available for pediatric inpatients for estimated glomerular filtration rate. Subjects were classified as having AKI using Kidney Disease Improving Global Outcomes (KDIGO) serum creatinine criteria if any postoperative creatinine measurement increased by ≥0.3 mg/dL from baseline (to convert to micromoles per liter, multiply by 88.4) or was ≥1.5-fold more than the baseline.⁷ Those not meeting these criteria were classified as no-AKI. AKI stage was determined for each AKI case, using serum creatinine based KDIGO definitions for Stage 1 (1.5-fold or 0.3 mg/dL increase), Stage 2 (2-fold increase), and Stage 3 (3-fold increase or creatinine ≥ 4 mg/dL) based on the highest creatinine measurement in the 7 days after surgery.

Statistical Analysis

Descriptive statistics were presented as median [interquartile range (IQR)] or frequency (%) as appropriate. Continuous variables were compared using the Wilcoxon rank-sum test and categorical variables using the Pearson chi-square test. The Kruskal-Wallis test was used to test weight-adjusted acetaminophen dose across AKI stage. We analyzed the association between AKI and dichotomous acetaminophen exposure using Pearson chi-square test. We also investigated the effect of acetaminophen dose (continuous variable, mg/kg) using logistic regression, after adjusting for pre-specified risk factors such as age, CPB time, red cell distribution width (RDW, given prior associations with AKI),^36,37 nephrotoxin exposure, postoperative hypotension, and risk adjustment for congenital heart surgery (RACHS) score.³⁸ The nonlinear effect of age was modeled using the restricted cubic spline with 3 knots chosen at the 10^th, 50^th, and 90^th percentile. The same logistic regression model was used for both the primary and validation cohort. Subgroup analyses were also performed. First, logistic regression was performed as above for each cohort, excluding those individuals who had no acetaminophen exposure. In addition, a subgroup analysis was done by pooling individuals from both cohorts with RACHS score ≥3 as an alternative method to account for variability in clinical status after surgery and likely degree of cell-free hemoglobin. For this analysis, the same logistic regression was performed as above, with the inclusion of clinical site as an additional covariate. Sensitivity analyses of unmeasured confounding effects were also performed (see eAppendix). Multiple imputation was performed based on 10 completed datasets by applying predictive mean matching to handle missing data for the variables of RACHS score, RDW, and CPB time.³⁹ All analyses were performed with the statistical programming language R, version 3.3.0 (R Development Core Team, Vienna, Austria). The statistical significance was determined at the level of 0.05, and all p-values were based on 2-sided tests.

Results

Study cohorts

The primary cohort included 666 subjects with baseline and postoperative serum creatinine measurements. Half were male, and half met criteria for AKI (Table 1). Of the 341 with AKI, 159 (47%) had Stage 1, 131 (38%) had Stage 2, and 51 (15%) had Stage 3 AKI. Those with AKI had more postoperative serum creatinine measurements than those without (8 [interquartile range (IQR) 4–7] vs. 5 [IQR 5–10]). Primary cardiac diagnoses are listed in eTable 2. The validation cohort comprised 333 individuals, with similar incidence of AKI (Table 1). Of the 162 with AKI, 51 (31%) had Stage 1, 91 (56%) had Stage 2, and 20 (12%) had Stage 3 AKI. Primary cardiac diagnoses for the validation cohort are listed in eTable 3.

Table 1.

Characteristics of the Primary and Validation Cohorts

	Primary Cohort (n=666)	Validation Cohort (n=333)
Age (months)	6.5 [3.9–44.7]	14.1 [3.9–158.2]
Female Sex	328 (49)	172 (52)
Weight (kg)	7.1 [5.0–14.6]	9.2 [4.7–49.0]
Pre-Operative Baseline Serum Creatinine (mg/dL)	0.35 [0.25–0.45]	0.30 [0.20–0.60]
Post-Operative Peak Serum Creatinine (mg/dL)	0.53 [0.45–0.66]	0.50 [0.40–0.90]
RACHS Score*
1	143 (22)	88 (32)
2	256 (40)	112 (41)
≥3	237 (37)	73 (27)
CPB Time (min)**	87 [59–122]	95 [39–149]
AKI Outcome
No AKI	325 (49)	171 (51)
Stage 1	159 (24)	51 (15)
Stage 2	131 (20)	91 (27)
Stage 3	51 (8)	20 (6)

Median [Interquartile Range] for continuous variables; Frequency (%) for categorical variables

^*RACHS - Risk Adjustment for Congenital Heart Surgery, with scores available for n=636 in the primary cohort and n=273 in the validation cohort

^**CPB - Cardiopulmonary Bypass, with time available for n=665 in the primary cohort and all 333 of the validation cohort; AKI – Acute Kidney Injury. SI conversion factor: To convert creatinine to μmol/L, multiply by 88.4.

AKI and Acetaminophen

In the primary cohort, 72 (11%) of the cohort had no acetaminophen exposure in the first 48 hours after surgery. The incidence of AKI was higher among those with no acetaminophen exposure than among those who received acetaminophen (Figure 1A). Comparing those with and without AKI, those without AKI had significantly higher weight-adjusted acetaminophen dose in the first 48 hours after surgery compared to those with AKI (Table 2). Other variables significantly associated with AKI included younger age, longer CPB time, higher RDW, presence of hypotension, fewer high risk nephrotoxins, and higher RACHS score (Table 2). When stratified by AKI stage, those with no AKI had the highest median acetaminophen dose (78 [IQR 43–104] mg/kg), followed by those with stage 1 AKI (57 [IQR 17–100] mg/kg), stage 2 AKI (48 [IQR 28–78] mg/kg), and stage 3 AKI (31 [IQR 0–70] mg/kg, p<0.001 for difference in distribution across groups). Those with no acetaminophen exposure had the highest rates of AKI, with decreasing incidence in the lowest, middle, and highest acetaminophen dose groups (Figure 1B). In the logistic regression analysis adjusting for age, CPB time, RDW, hypotension, nephrotoxin exposure, and RACHS score, acetaminophen exposure was protective for postoperative AKI, with odds ratio 0.86 per 10 mg/kg (95% confidence interval (CI) 0.82–0.90, Figure 2). The relationship of continuous acetaminophen dose to adjusted odds for AKI is shown in Figure 3. The patients who did not receive acetaminophen were younger and had longer CPB times, higher RDW, and more hypotension than those who had acetaminophen exposure (eTable 4). When subset analysis of the primary cohort was performed excluding those with no acetaminophen exposure, acetaminophen remained protective against AKI (OR 0.85 per 10 mg/kg, 95% CI 0.80–0.90, p<0.001). Analysis of the sensitivity of our main findings to unmeasured confounding identified the joint minimum strength of association that an unmeasured confounder must have with acetaminophen exposure and AKI is >3.07 to make these findings statistically insignificant (eTable 5).

Figure 1. Incidence of AKI by Acetaminophen Exposure and Dose.

A) The incidence (%) of early postoperative AKI is shown for those administered no acetaminophen (white bars) or at least one dose of acetaminophen (black bars) in the first 48 hours after surgery. The primary cohort is shown on the left, and the validation cohort on the right. The number in each subset are indicated below each bar. P-values from Pearson chi-square test. B) The incidence (%) of early postoperative AKI is shown for those with no acetaminophen administered in the first 48 hours after surgery (white bars) and for lowest (Lo, ≤40 mg/kg, light gray), middle (Mid, 40–80 mg/kg, dark gray), and highest (Hi, >80 mg/kg, black) cumulative dose of acetaminophen in the first 48 hours after surgery. The number in each subset are indicated below each bar, and the percentage of those with AKI above each bar. P-values from Pearson chi-square test. AKI – Acute kidney injury. Acet – Acetaminophen.

Table 2.

Risk Factors for Acute Kidney Injury (AKI) in the Primary and Validation Cohorts

	Primary Cohort (n=666)			Validation Cohort (n=333)
	No AKI (n=325)	AKI (n=341)	Unadjusted P-value	No AKI (n=171)	AKI (n=162)	Unadjusted P-value
Acetaminophen Dose (mg/kg)	78 [43–104]	47 [16–88]	<0.001	70 [45–94]	60 [40–87]	0.031
Age (months)	15.2  [4.5–70.9]	5.5 [3.3–16.6]	<0.001	39.8 [5.3– 203.9]	6.7 [2.9–46.9]	<0.001
Female Sex	171 (53)	157 (46)	0.09	95 (56)	77 (48)	0.14
Weight (kg)	9.2 [5.6–20.2]	6.1 [4.7–9.3]	<0.001	13.7 [5.3–62.0]	6.5 [4.4–16.9]	<0.001
Baseline Serum Creatinine (mg/dL)	0.43 [0.36– 0.52]	0.26 [0.21– 0.34]	<0.001	0.40 [0.30– 0.80]	0.30 [0.20– 0.50]	<0.001
Peak Serum Creatinine (mg/dL)	0.52 [0.44– 0.62]	0.54 [0.45– 0.71]	0.005	0.50 [0.40– 0.80]	0.60 [0.50– 1.00]	0.004
CPB Time (min)*	80 [51–111]	99 [68–132]	<0.001	85 [32–123]	110 [41–170]	0.011
RDW (%)**	13.2 [12.7– 14.4]	14 [13.2– 15.3]	<0.001	13.9 [13.2– 15.3]	15.4 [14.2– 16.8]	<0.001
Hypotension	238 (73)	280 (82)	0.006	74 (43)	85 (52)	0.093
High Risk Nephrotoxins			0.018			0.002
0	158 (49)	192 (56)		52 (30)	72 (44)
1	148 (46)	117 (34)		77 (45)	73 (45)
2	18 (6)	29 (9)		35 (20)	12 (7)
≥3	1 (0)	3 (1)		7 (4)	5 (3)
Moderate Risk Nephrotoxins			0.2			0.36
0	17 (5)	13 (4)		6 (4)	2 (1)
1	151 (46)	147 (43)		21 (12)	14 (9)
2	128 (39)	134 (39)		54 (32)	54 (33)
≥3	29 (9)	47 (14)		90 (53)	92 (57)
RACHS Score#			<0.001			0.018
1	93 (29)	50 (16)		57 (40)	31 (24)
2	123 (38)	133 (42)		52 (36)	60 (46)
≥3	104 (32)	133 (42)		34 (24)	39 (30)

Median [Interquartile Range], p-value from the univariate Wilcoxon rank-sum test for continuous variables; Number (%), p-value from the univariate Pearson chi-square test for categorical variables

^*CPB - Cardiopulmonary Bypass, with time available for n=665 in the primary cohort and all 333 of the validation cohort

^**RDW – Red Cell Distribution Width, with values available for n=613 in the primary cohort and n=329 in the validation cohort

^#RACHS - Risk Adjustment for Congenital Heart Surgery, with scores available for n=636 in the primary cohort and n=273 in the validation cohort; SI conversion factor: To convert creatinine to μmol/L, multiply by 88.4.

Figure 2. Multivariable Analyses of the Primary and Validation Cohorts.

Shown are the ORs and the 95% CI for each of the clinical variables in the multiple logistic model for association to AKI in the primary cohort (left, N=666) and validation cohort (right, N=333). ORs are for weight-adjusted acetaminophen dose (per additional 10 mg/kg); Age (75th vs. 25th percentile for each cohort); CPB time (per additional 50 minutes); RDW (per additional 1%); Hypotension (present vs. absent); High risk nephrotoxins (one or more vs. none); Moderate risk nephrotoxins (one, two, and three or more vs. none); and RACHS score (two and three or more vs. one). Point estimates and 95% CI are listed to the right of each plot. AKI – Acute kidney injury. OR – Odds ratio. CI – Confidence interval. CPB – Cardiopulmonary bypass. RDW – Red cell distribution width. RACHS – Risk Adjustment for Congenital Heart Surgery.

Figure 3. Adjusted Odds Ratios for AKI by Acetaminophen Dose.

The odds of AKI are shown on the Y-axes, with weight-adjusted acetaminophen dose (mg/kg) on the X-axes, based on multivariable analyses adjusting for age, cardiopulmonary bypass time, red cell distribution width, hypotension, nephrotoxin exposure, and Risk Adjustment for Congenital Heart Surgery (RACHS) score, which were set to their median values. Shaded areas indicate 95% confidence intervals. Left panel – Primary cohort (N=666). Right Panel – Validation cohort (N=333). AKI – Acute kidney injury.

For the validation cohort, 18 (6%) had no acetaminophen exposure, and there was no significant difference in AKI incidence between those with no acetaminophen and those who received acetaminophen (Figure 1A). Comparing those with and without AKI, the median early postoperative acetaminophen dose was again higher among those without AKI than those with AKI (Table 2). Younger age, longer CPB time, higher RDW, fewer high risk nephrotoxins, and higher RACHS score were also associated with postoperative AKI. When stratified by AKI stage, those with no AKI again had the highest median weight-adjusted acetaminophen dose (70 [IQR 45–94] mg/kg). Those with stage 1 AKI has the lowest median dose (50 [IQR 26–76] mg/kg), and acetaminophen doses were similar in those with stage 2 and stage 3 AKI as those with no AKI (67 [IQR 43–88] mg/kg, and 66 [IQR 45–87] mg/kg, respectively, p=0.018). Those with no acetaminophen exposure again had the highest rates of AKI, with decreasing incidence in the lowest, middle, and highest acetaminophen dose groups, without statistical significance (Figure 1B). In multivariable analysis, adjusting for the same variables as above, postoperative acetaminophen had a protective effect for AKI, with adjusted odds ratio 0.91 (95% CI 0.84–0.99) for each additional 10 mg/kg (Figure 2). The relationship of continuous acetaminophen dose to adjusted odds for AKI in the validation cohort is shown in Figure 3. When those with no acetaminophen exposure were excluded, acetaminophen exposure remained protective (OR 0.90 per 10 mg/kg, 95% CI 0.82–0.99, p=0.03).

Pooled subgroup analysis

The pooled subgroup analysis included a total of 310 individuals with RACHS score ≥3 from both clinical sites (237 and 73 individuals from the primary cohort and the validation cohort, respectively). After adjusting for clinical site as well as the same covariates as above, acetaminophen dose (mg/kg) in this subgroup again showed a protective effect for AKI (OR 0.86, 95% CI 0.81–0.93, for each additional 10 mg/kg, eFigure 1).

Discussion

We present the finding of a protective association of acetaminophen for AKI in children who undergo cardiac surgery. The weight-adjusted total dose of acetaminophen given in the first 48 hours after surgery was inversely correlated with incidence of AKI in the primary cohort using the dichotomous indicator of acetaminophen exposure, acetaminophen dose as a continuous variable, and after adjusting for potential confounders including age, CPB time, RDW, RACHS score, postoperative hypotension, and nephrotoxin exposures. Given this novel finding, we sought to confirm these observations in an independent data set, where after adjusting for confounding variables which were not balanced across acetaminophen exposure groups, the protective effect of acetaminophen was again observed. Subgroup analyses of only those patients who received acetaminophen and those with RACHS score ≥3, representing more clinically homogenous patients, yielded consistent results.

The hypothesis that acetaminophen may be protective against AKI in the setting of cardiac surgery stemmed from several observations. In a case-control study of adults undergoing cardiac surgery, the 10 individuals with postoperative AKI had higher intraoperative peak free hemoglobin concentrations than risk-matched controls (289.0 vs. 104.4 mg/dL, p=0.01).³⁰ This association was replicated in a cohort study of 60 children undergoing surgery requiring CPB, where those with AKI had greater increase in plasma hemoglobin concentration (53.9 vs. 38.3 mg/dL, p=0.03), and increase in plasma hemoglobin was an independent risk factor for AKI (OR 1.02 (95% CI 1.00–1.03) per mg/dL increase).²⁹ The mechanism whereby free hemoglobin leads to nephrotoxicity is postulated to be through lipid peroxidation, catalyzed by oxidized cell-free hemoglobin, a process that can be inhibited by acetaminophen.^32,40

Cell-free hemoglobin was also associated with death in a retrospective observational study of critically ill adults with sepsis, and acetaminophen exposure had a protective association with in-hospital mortality.³¹ Interestingly, in the subset of patients with no detectable plasma hemoglobin, there was no protective effect of acetaminophen. This potential protective effect of acetaminophen was evaluated prospectively in the Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis (ACROSS) Trial. This single-center, randomized, placebo-controlled trial of acetaminophen 1g enterally every 6 hours for 3 days found no difference in the primary endpoint, F₂-Isoprostanes at day 3 (a measure of oxidative injury) or hospital mortality, but did observe that acetaminophen treatment impacted secondary outcomes. Namely, acetaminophen lowered F2-Isoprostanes at day 2 (24 vs. 36 pg/mL, p=0.047) and serum creatinine at day 3 (1.0 vs. 1.3 mg/dl, p=0.039).³³ In another randomized trial including 700 adult ICU patients with fever, there was no difference in the primary outcome (ICU-free days), nor was there a difference in the peak creatinine in the first week after randomization.⁴¹ This negative result may indicate that acetaminophen has protective effects only in specific patient populations.

There have been two pilot studies of the impact of acetaminophen on lipid peroxidation in patients undergoing CPB. In a prospective double-blind clinical trial, 60 adult patients were treated with four doses of intravenous acetaminophen over 24 hours (1g for those >50kg and 15mg/kg for those <50kg) or placebo starting prior to initiation of CPB.⁴² The primary outcome was oxidative stress, measured by plasma and urine F2-Isoprostanes and isofurans. The acetaminophen treatment group had smaller increases in plasma isofuran concentrations compared to the placebo group (p=0.05), though there were no significant differences between groups in plasma F2-Isoprostanes, urinary markers of lipid peroxidation, or AKI. The second pilot study randomized 30 children to be treated with four doses of intravenous acetaminophen (15 mg/kg for age ≥2 years and 12.5mg/kg for age <2 years) or placebo, starting before the start of CPB.⁴³ As in the adult trial, acetaminophen attenuated increases in plasma isofurans (p=0.02), but there were no differences between the intervention and control groups in F₂-Isoprostanes, AKI prevalence, AKI severity, or the AKI biomarker NGAL. There were several limitations to these pilot studies, including limited power due to the small number of participants and the administration of one or more doses of acetaminophen before and during CPB, when circulating concentration of the drug may not have reached therapeutic levels due to hemodilution. These studies were not definitive in determining the potential role of acetaminophen to protect against AKI in patients with elevated cell-free hemoglobin.

Our results indicate a modest effect size for acetaminophen with respect to AKI. Namely, we see an approximately 10% reduction in AKI risk for each additional 10 mg/kg administered in the first 48 hours after surgery (one typical dose of acetaminophen). In the subgroup analysis of those with RACHS score ≥3, we observed a 14% reduction per 10 mg/kg of additional acetaminophen. The ideal dose for renal protection while avoiding dose-related hepatotoxicity or other adverse events has not been established. There may be several sources of inter-individual variability contributing to differences in the exposure and response to acetaminophen in both adults and children.^44,45 Further delineation of individualized therapeutic concentrations through a precision medicine approach may be required to maximize benefit and minimize risk of acetaminophen use.

Our study has several limitations. This is a retrospective, observational study. Thus, causality between acetaminophen exposure and reduced incidence of AKI cannot be established. The apparent protective effect of acetaminophen may be due to residual confounding. Patients with acetaminophen exposure had fewer risk factors for AKI. Furthermore, these patients may have the most frequent serum creatinine testing, increasing AKI detection. We have attempted to control for this potential confounding through multivariable analysis, adjusting for factors such as age, bypass time, and RACHS score. Despite inclusion of these variables, acetaminophen remained protective. Our analyses of the sensitivity of our data to unmeasured confounding indicate that our data are robust. Of note, those with AKI had fewer exposures to highly nephrotoxic drugs, an observation we have seen in multiple cohorts^3,37 and that may be due to avoidance of these drugs among high-risk patients. Another limitation of our study comes from the definition of AKI. We used the consensus KDIGO definition based on serum creatinine, but did not define AKI based on urine output (which may be inaccurately represented in these retrospective data sets) or biomarkers such as NGAL or cystatin C.⁴⁶ Our initial finding from one tertiary referral center was validated in independent data from a second tertiary referral center. However, these results may not be generalizable to institutions with different patient mix, operative procedures, and postoperative care.

In summary, in two independent cohorts of children undergoing cardiac surgery, we observed a dose-dependent inverse relationship between postoperative receipt of acetaminophen and development of AKI. Taken together with other retrospective and prospective studies showing protective effects of acetaminophen for AKI in several conditions associated with release of cell-free hemoglobin, these findings provide compelling rationale to justify prospective evaluation of acetaminophen for prevention of AKI in children undergoing CPB.

Key Points

Question:

Does early postoperative acetaminophen reduce the incidence of acute kidney injury in children who undergo cardiac surgery?

Findings:

In this retrospective observational study, acetaminophen exposure in the first postoperative 48 hours was associated with lower rate of acute kidney injury in pediatric patients who underwent cardiac surgery in primary and validation cohorts from 2 tertiary referral children’s hospitals.

Meaning:

Postoperative use of acetaminophen may protect pediatric cardiac surgery patients from acute kidney injury.