This is the first multicenter prospective study using the current accepted standard definition of AKI with the intent of examining the risks, characteristics and outcomes of AKI in pediatric cardiac surgery. We found an AKI incidence of 42% in children undergoing heart surgery. Prior to 2005 there were no studies of cardiac surgery associated AKI using the currently accepted definition. These studies used definitions ranging from doubling of serum creatinine to requirement of dialysis. Pederson et al (1
) performed one of the larger single center prospective studies enrolling children from 1993 to 2002 and used dialysis as their AKI definition. They found that 11.5% of their patients developed AKI. However, the use of dialysis as the definition of AKI is concerning since most clinicians agree that AKI develops before the need for dialysis. Besides the problems with the definition of AKI, the authors also found that there was a length time bias resulting in the rate of AKI changing significantly during the long study period. All of the prospective studies of CS-AKI after 2005 were from a single center, Cincinnati Children’s Hospital (15
), that was designed with the intent to discover and validate new biomarkers and thus limited their generalizability. Nevertheless these studies found that the incidence of AKI, defined by a ≥ 50% SCr rise, ranged from 28 to 52%. In a recent large study of CS-AKI by Zappitelli et al (2
) 35.9% of all children having cardiac surgery developed AKI. This was slightly lower than the AKI incidence from our study. However, our study was limited to children undergoing cardiopulmonary bypass, and their study was retrospective and based on a single center cohort thus limiting ascertainment of clinical factors. The present study was devised in a comprehensive manner to reliably determine a generalizable AKI event rate so future studies can utilize this.
Analysis of preoperative risk factors demonstrated that even after adjustment for surgical complexity (RACHS-1 category) and CPB time, children who were in the youngest age group were at higher risk for developing AKI compared to the older age groups. The reason for this is not completely clear. Though full term infants are usually born with their full complement of nephrons, maximal GFR is not achieved until about 2 years of age (30
). Thus, children less than 2 years old may be more susceptible to the ischemic and inflammatory insults that may be occurring in patients undergoing heart surgery.
No patients from the RACHS-1 category 1 surgeries developed AKI. Examples of these surgeries include simple ASD closures and repair of partially anomalous pulmonary veins. This is not surprising since these surgeries are less complex and relatively quick with low CPB times (24
). Additionally, we did not find an association of increased risk of AKI with increased surgical complexity by RACHS-1 category. However, in our study exclusion of patients less than 30 days old also led to omitting RACHS-1 category 5 or 6 patients, a group with high likelihood of developing AKI. Given the complexity associated with defining AKI in newborns this will be an important population to study further.
Consistent with numerous past studies, we found that longer CPB times were associated with an increased risk of AKI. Moreover, we found an interesting linear relation between increasing bypass time and increasing AKI. The mechanism for this is probably due to a combination of ischemia, loss of pulsatile flow and progressive inflammation which adds to kidney injury (32
). Further research into issues such as temperature, pressure and the amount and type of bypass circuit flows will be needed to explore this relationship. Strategies to limit bypass time may help decrease the rate of cardiac surgery-associated AKI. Although we controlled for RACHS-1 category in the multivariate analysis of CPB, it is possible that in children who have surgery requiring bypass the duration may also be a marker for case complexity and severity of the congenital anomaly.
Our study highlights the importance of studying AKI as a risk and as an outcome separately in children from adults; especially since the epidemiology is completely different. Adults undergoing cardiac surgery typically have several pre-operative cardiovascular risk factors such as diabetes, peripheral vascular disease, and chronic kidney injury. These same risk factors often emerge as pre-operative cardiovascular risk factors for developing AKI in adults (33
). In children with congenital heart disease these factors are not usually present. In fact most children do not have any other co-morbidities. Risk factors for AKI in children are usually limited to the age of the child and the severity of insult (e.g. CPB time).
Pre-operative serum creatinine was lower in the group of patients who developed AKI. However, this was most likely due to expected age-associated lower SCr values, which is evidenced by the fact that pre-operative baseline estimated GFR was not statistically different between the AKI and non-AKI groups.
We also found that a large proportion of patients who developed AKI were exposed to nephrotoxic drugs. In our cohort 15% were exposed to gentamicin and 56% to non-steroidal anti-inflammatories (NSAIDs). NSAIDs in the pediatric CS-AKI population are mostly used to provide postoperative analgesia without the side effects of sedation and respiratory depression. This combination is thought to allow earlier wean from mechanical ventilation. Gentamicin is a commonly used drug in younger children to empirically treat gram negative infections. The extent to which use of these drugs is independently associated with AKI development or AKI severity should be the focus of future studies in order to determine whether there is a need to change our current practice.
In our exploration of the phenotype of AKI, we found that in more than half the patients, AKI was diagnosed by SCr criteria by day 1 and by day 2 in 97%. The day of diagnosis is earlier than seen in recent studies using the current definition of AKI, where only 40–67% of patients met the AKI definition within two days of the operation (15
). This discrepancy may be due to intraoperative factors related to surgical or perfusionist technique and perioperative factors such as volume administration and timing of diuresis. We found that in about half of AKI patients, AKI only lasted for 1 day and that 76% of these patients had AKI resolution by the end of 2 days, similar to the findings from the retrospective study by Zappitelli et al (2
In terms of outcomes associated with AKI, we found that those who developed AKI were more likely to remain on mechanical ventilation for a longer period of time. The reason for this is likely to be multifactorial including increased fluid retention in the lungs, restrictive lung disease due to interstitial edema, and prolongation of sedation secondary to decreased drug elimination because of AKI (34
). The heterogenous cohort of congenital heart patients makes assessment of variables that reflect risk for pulmonary edema, such as central venous pressure, B-type natriuretic peptide, and fluid balance difficult. They may be confounded by variables such as postoperative right ventricular dysfunction, right ventricular hypertrophy, residual lesions, and low cardiac output states. The present study was not designed to examine the mechanisms of lung injury that might explain the association between AKI and prolonged mechanical ventilation. Future studies should attempt to elucidate the reasons behind this relation.
The duration of PICU stay and hospital stay was longer in those with AKI compared to those without AKI, suggesting that CS-AKI is associated with an increased use of hospital resources and increased overall health cost. This is consistent with recent studies of AKI (16
). Although the association between AKI and in hospital mortality did not reach significance, there was a strong trend that is consistent with the association that has been demonstrated in the adult literature (35
There are some limitations to our study. First, our study consisted predominantly of white patients, thus limiting generalizability to other racial groups. Second, our AKI definition did not include urine output as we did not record hourly urine output. However, in one pediatric study, addition of urine output did not substantially add to the classification by serum creatinine (21
). In addition the use of intraoperative ultrafiltration and early postoperative diuretics would confound the urine output variable as a marker of AKI. Finally, we recognize that our definition of intraoperative hypotension is not necessarily synonymous with inadequate kidney perfusion or oxygen delivery. It may be that utilization of certain cardiopulmonary bypass flows along with reducing metabolic demand provides the support needed even in the setting of low blood pressures. However, a recent prospective study indicating an association between AKI and the difference between preoperative and intraoperative blood pressure in adults indicates a need for further investigation into this issue (37
). Additionally, we feel that given our exclusion of neonates, the lack of coronary artery surgeries, and that we only had 4 patients with circulatory arrest, there is little chance of confounding by this problem.