Cardiopulmonary bypass is associated with hemolysis and acute kidney injury in neonates, infants, and children*

Abstract

Objectives: This pilot study assesses the degree of hemolysis induced by cardiopulmonary bypass and determines its association with acute kidney injury in pediatric patients. Further, it evaluates the degree to which the use of urinary biomarkers neutrophil gelatinase-associated lipocalin and cystatin C correlate with the presence of acute kidney injury and hemolysis following cardiopulmonary bypass.

Design: Prospective observational study.

Setting: A 13-bed pediatric cardiac ICU in a university hospital.

Patients: Children undergoing cardiac surgery with the use of cardiopulmonary bypass.

Interventions: None.

Measurements and main results: Blood and urine samples were obtained at multiple time points before and after cardiopulmonary bypass. Hemolysis was assessed by measuring levels of plasma hemoglobin and haptoglobin. Acute kidney injury was defined as a doubling in serum creatinine from preoperative baseline and by using the pediatric-modified RIFLE criteria. Urinary neutrophil gelatinase-associated lipocalin and cystatin C levels were measured. A total of 40 patients (range, 3 d to 4.8 yr) were enrolled. Plasma hemoglobin levels increased markedly on separation from cardiopulmonary bypass with a concurrent decrease in haptoglobin. This was associated with an increase in protein oxidation in the plasma. Hemolysis was more evident in younger patients with a longer duration of bypass and in those requiring a blood-primed circuit. Forty percent of patients had a doubling in serum creatinine and acute kidney injury was developed in 88% of patients when defined by the pediatric-modified RIFLE criteria. Controlling for cardiopulmonary bypass time, persistently elevated levels of plasma hemoglobin were associated with a five-fold increase in acute kidney injury. Further, urinary neutrophil gelatinase-associated lipocalin measured 2 hours after separation from cardiopulmonary bypass was associated with acute kidney injury and with elevations in plasma hemoglobin.

Conclusions: Cardiopulmonary bypass in pediatric patients results in significant hemolysis, which is associated with the development of acute kidney injury. The biomarker neutrophil gelatinase-associated lipocalin correlates with both acute kidney injury and hemolysis in this population.

Figure 1. Cardiopulmonary bypass is associated with hemolysis

Plasma obtained from study patients immediately pre- and 0, 2, 6, 24, 48, and 72 hours post-cardiopulmonary bypass was analyzed for plasma hemoglobin (A) and haptoglobin (B). Groups were compared by one-way ANOVA. Paired t-tests were performed if the ANOVA was found to be significant to assess the change from baseline at each time point. Data are expressed as means with 95% confidence intervals, *p<0.001versus pre-cardiopulmonary bypass values.

Figure 2. Hemolysis is associated with duration of cardiopulmonary bypass time, patient age, complexity of repair, and a blood-primed circuit

Association between peak change in plasma free hemoglobin following cardiopulmonary bypass and cardiopulmonary bypass time (minutes) (R² = 0.16) (A), age (months) (R² = 0.27) (B), surgical complexity as defined by Aristotle basic score (R² = 0.18) (C), and blood-primed cardiopulmonary bypass pump (D) were assessed by linear regression, p≤0.01 for all variables.

Figure 3. Protein oxidation increases immediately following cardiopulmonary bypass

Carbonyl content in plasma was measured immediately pre- and at 0, 2, 6, 24, 48, and 72 hours post-cardiopulmonary bypass to assess protein oxidation. Data are expressed as means with 95% confidence interval. Three representative blots are shown.

Figure 4. Acute kidney injury is associated with the use of cardiopulmonary bypass

Acute kidney injury, measured as fold change in baseline serum creatinine is shown for all patients (A) and for patients stratified by age (B). Data are expressed as means with 95% confidence interval, *p<0.05. Percentage of patients after cardiopulmonary bypass in each category of pRIFLE score at maximal level of injury during the study period is shown for all patients (C) and for patients stratified by age (D).

Figure 5. Urinary neutrophil gelatinase-associated lipocalin is associated with cardiopulmonary bypass-induced acute kidney injury

Urinary neutrophil gelatinase-associated lipocalin (A, B) and cystatin C (C, D) levels were measured pre- and at 2, 6, and 24 hours post-cardiopulmonary bypass and stratified by the presence or absence of acute kidney injury as diagnosed by doubling in serum creatinine and pRIFLE criteria of “Injury” or greater. Data are expressed as means with 95% confidence interval, *p<0.001.