Journal of Pediatric Surgery (2011) 46, 630–635
www.elsevier.com/locate/jpedsurg
Acute kidney injury in congenital diaphragmatic hernia requiring extracorporeal life support: an insidious problem Samir K. Gadepalli a,⁎, David T. Selewski b , Robert A. Drongowski a , George B. Mychaliska a a
Department of Pediatric Surgery, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MI 48105, USA Department of Pediatrics, Division of Pediatric Nephrology, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MI 48105, USA b
Received 20 July 2010; revised 14 November 2010; accepted 19 November 2010
Key words: Congenital diaphragmatic hernia; Extracorporeal life support; Acute kidney injury; Continuous renal replacement therapy; Neonate; Acute renal failure; Volume overload
Abstract Purpose: Patients with congenital diaphragmatic hernia (CDH) requiring extracorporeal life support (ECLS) are at increased risk for acute kidney injury (AKI). We hypothesized that AKI would be associated with increased mortality. We further hypothesized that vasopressor requirement, nephrotoxic medications, and infections would be associated with AKI. Methods: We performed a retrospective chart review in all patients with CDH requiring ECLS from 1999 to 2009 (n = 68). Patient variables that could potentiate renal failure were collected. We used a rise in creatinine from baseline by the RIFLE (risk, 1.5×; injury, 2×; failure, 3×; loss; and end-stage renal disease) criteria to define AKI. Statistical analysis was performed via SPSS (SPSS, Chicago, IL) using Student t test and χ2 analysis, with P b .05 being considered significant. Results: Survival to hospital discharge was 37 (54.4%) of 68. Acute kidney injury was identified in 48 (71%) of 68 patients, with 15 (22% of all patients) qualifying as injury and 33 (49% of all patients) qualifying as failure by the RIFLE criteria. Patients who qualified as failure by the RIFLE criteria had a significant decrease in survival (27.3% with failure vs 80% without failure; P = .001). Patients who qualified as failure also had increased length of ECLS (314 ± 145 vs 197 ± 115 hours; P = .001) and decreased ventilator-free days in the first 60 days (1.39 ± 5.3 vs 20.17 ± 17.4 days; P = .001). There was no significant difference in survival when patients qualified as risk or injury. Conclusions: This is the first report using a systematic definition of AKI in patients with CDH on ECLS. There is a high incidence of AKI in these patients, and when it progresses to failure, it is associated with higher mortality, increased ECLS duration, and increased ventilator days. This highlights the importance of recognizing AKI in patients with CDH requiring ECLS and the potential benefit of preventing progression of AKI or early intervention. © 2011 Elsevier Inc. All rights reserved.
⁎ Corresponding author. Tel.: +1 734 764 4151; fax: +1 734 936 9784. E-mail addresses:
[email protected] (S.K. Gadepalli),
[email protected] (D.T. Selewski),
[email protected] (R.A. Drongowski),
[email protected] (G.B. Mychaliska). 0022-3468/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2010.11.031
Congenital diaphragmatic hernia (CDH) is characterized by incomplete diaphragmatic development leading to the presence of abdominal organs in the thoracic cavity, resulting in varying degrees of pulmonary hypoplasia and
AKI in CDH requiring ECLS an insidious problem pulmonary hypertension. The incidence of CDH has remained relatively stable at 2 to 4:10,000 live births [1,2]. Therapies used to treat severe CDH include inhaled nitric oxide [3], high-frequency oscillatory ventilation [4,5], surfactant [6,7], and extracorporeal life support (ECLS) [8,9]. Despite these interventions, morbidity and mortality of patients with severe CDH remain high, with an overall survival of 69% and 40% to 50% among patients receiving ECLS [10-12]. Several studies have sought to identify variables that would stratify the risk of mortality in patients with CDH requiring ECLS [11-14]. Acute kidney injury (AKI) and the requirement for continuous renal replacement therapy (CRRT) or dialysis have been identified as potentially important risk factors for mortality in patients with CDH requiring ECLS [12-14]. Acute kidney injury is known to be associated with increased morbidity and mortality but remains relatively poorly defined in the neonatal period [15-19]. Newborns in the intensive care unit are at particular risk for AKI from repeated episodes of hypotension, multiorgan failure, infection, and exposure to nephrotoxic agents. Acute kidney injury in neonates is unique in that the nonoliguric form is common, making it difficult to define [15-20]. Acute kidney injury has been defined in adults and children using the RIFLE (risk, injury, failure, loss, and end-stage renal disease) criteria to allow better characterization for clinical care and for research [21,22]. Adult and pediatric studies have shown that AKI is an independent risk factor for morbidity and mortality in the critical care setting [21,23-25]. This study further elucidates the association of AKI and mortality in patients with CDH requiring ECLS. This is the first study in patients with CDH on ECLS that systematically defines and characterizes AKI. The authors hypothesized that variables common to patients with CDH on ECLS such as vasopressor support, nephrotoxic medications, diuretic therapy, duration of ECLS, and infections would be associated with AKI.
1. Methods This study was approved by the University of Michigan Institutional Review Board before data collection and analysis. From 1999 to 2009, 68 consecutive patients with CDH required ECLS. The medical records of these patients were retrospectively analyzed, collecting demographic data, variables associated with AKI, and outcome data. We collected data on prenatal diagnosis, mode of delivery, gestational age, sex, race, birth weight, Apgar scores, blood gases at birth, ventilation strategies, and need for ECLS. Congenital diaphragmatic hernia data included the defect side and size, contents, and method of operative repair. Comorbidities including cardiac disease, noncardiac congenital anomalies, and chromosome abnormalities were recorded.
631 Acute kidney injury was defined using the RIFLE criteria, which stratifies patients based on rise in creatinine instead of using creatinine clearance (Table 1) [21,22]. Because a newborn's creatinine reflects maternal creatinine in the first week of life [15], estimated creatinine clearance is not a reliable indicator of a newborn's true creatinine clearance. The pediatric RIFLE criteria depend on calculating creatinine clearance and therefore are limited in this patient population. Furthermore, these criteria were initially studied in patients older than 1 month [24]. Therefore, we used the RIFLE criteria because it is known that a newborn's creatinine should fall during the first week of life, and any rise in creatinine reflects AKI. The RIFLE criteria stratify patients based on a rise in creatinine and have been recently studied in a large pediatric critical care population [21]. Variables known to induce or be associated with AKI investigated included volume status, birth weight, weight at surgery and at initiation of CRRT, diuretic exposure, nephrotoxic antibiotics, and vasopressor requirements. The volume status was defined using the following equation: % over birth weight = [(patient weight − birth weight)/birth weight] · 100%. Outcome variables included length of ECLS runs, ventilator-free days in 60 days, hospital days, presence of renal failure, placement on CRRT, postsurgical complications, and survival. Follow-up data for the patients were obtained at an average of 1 year of age. Severity index of CDH was used to determine the likelihood of survival in our patient population. The CDH Study Group equation uses 5-minute Apgar scores and birth weight to predict survival in a patient with CDH [26]. The predicted survival was used to stratify the CDH severity of our cohort. Patients were placed on ECLS if a “gentle ventilation” strategy failed [27]. During this study period, most patients underwent surgical repair after ECLS decannulation. If patients could not be weaned from ECLS at approximately 2 weeks, they underwent repair on ECLS. Statistical analysis using SPSS (SPSS, Chicago, IL) was performed, with P b .05 considered significant. Student t tests, analysis of variance, χ2 test, and correlation tables were used to determine significance between variables and effect on outcome. The presence of AKI, use of CRRT, and affect on outcome variables were also analyzed.
Table 1 Acute kidney injury was defined using the RIFLE criteria by a rise in serum creatinine to define each classification applied to our patient cohort [21,22] Classification
Rise in creatinine
Risk Injury Failure Loss End-stage renal disease
150% 200% 300% Failure N4 wk Failure N3 mo
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2. Results Between 1999 and 2009, a total of 165 patients were treated for CDH, with a 75% survival. A total of 68 (41%) of 165 patients with CDH were placed on ECLS (see Table 2). A total of 48 (71%) of 68 patients had evidence of AKI, with 15 (22% of all patients) qualifying as injury and 33 (49% of all patients) qualifying as failure by the RIFLE criteria. A total of 11 (16%) of 68 patients required CRRT. Patients who required CRRT were an average of 43% volume up from their birth weight at initiation. Of the patients who qualified as failure, only 27.3% survived vs 80% of those without renal failure (P = .001), an absolute increased mortality of 52.7%. Similarly, patients with renal failure also had lower 5-minute Apgar scores (4.64 ± 1.88 vs 6.32 ± 1.87; P = .001), decreased number of ventilator-free days in the first 60 days (1.39 ± 5.3 vs 20.17 ± 17.4 days; P = .001), and increased length of ECLS (314 ± 145 vs 197 ± 115 hours; P = .001) (Table 3). Of the 68 patients, 54 were repaired: 13 repaired primarily (24%), 36 (67%) using a diaphragmatic patch, and 5 (9%) using a muscle flap. For abdominal closure, a silo was used in 17 patients (31.5%); a patch was required for final closure in 14 (25.9%), and the rest were closed primarily. The presence of renal failure did not correlate with the following variables: birth weight, estimated gestational age (EGA), diuretic days, or antibiotic days (Table 3). Renal failure correlated with the side of CDH but did not correlate with liver in the chest, stomach in the chest, size of CDH, presence of severe cardiac defects, or use of vasopressors (Table 4). Survival in our patient group was 37 (54%) of 68. The expected survival using the CDH Study Group equation was also 53%. Moreover, the CDH severity index formula also correlated with the presence of renal failure (P = .002) and length of ECLS (P = .007). Table 2 Demographic data showing number and percentage of patients in each category
Sex Male Female Side Left sided Right sided Type of delivery NSVD Induced vaginal Planned cesarean delivery Emergent cesarean delivery Diagnosed prenatally Associated anomalies Severe cardiac defects Chromosomal anomalies NSVD, normal spontaneous vaginal delivery.
n
%
38 30
55.9 44.1
54 14
79.4 20.6
23 19 13 13 51
33.8 27.9 19.1 19.1 75.0
11 1
16.2 1.5
Table 3 Renal failure is associated with decreased ventilatorfree days in the first 60 days, increased length of ECLS, and Apgar score at 5 minutes of life Variable
Renal failure Yes (mean ± SD)
Birth weight (kg) EGA (wk) Apgar at 1 min Apgar at 5 min Length of ECLS (h) Days of life at extubation Ventilator-free days in the first 60 d Days in hospital Volume status at surgery (% over birth weight) Days of diuretic therapy Days of antibiotic therapy
P No (mean ± SD)
2.86 ± 0.64 3.02 ± 0.52 37.56 ± 2.42 38.25 ± 1.48 2.85 ± 1.52 3.62 ± 1.94 4.64 ± 1.88 6.32 ± 1.87 314 ± 145 197 ± 115 37.03 ± 23.87 31.58 ± 20.00 1.39 ± 5.33 20.17 ± 17.40
.27 .17 .076 .001 .001 .33 .001
56.39 ± 58.27 53.94 ± 41.71 .84 20.0 ± 13.0 19.0 ± 13.1 .87 62.91 ± 80.86 41.74 ± 40.62 .17 28.06 ± 35.6 16.4 ± 18.05 .09
3. Discussion The mortality in patients with severe CDH requiring ECLS is approximately 40% to 50% [10-12]. Survival in our patients was 54%, which is consistent with the published survival rates. The relative severity of our patients with CDH and expected outcome are consistent with predicted outcomes using the previously reported CDH Study Group
Table 4
Factors potentially associated with renal failure
Variable
Renal failure
Liver in chest Yes No Stomach in chest Yes No Severe cardiac defect Yes No Use of vasopressors Yes No Side of CDH Right Left Size of CDH defect Mild Moderate Severe Agenesis
P
Yes (%)
No (%)
17 (53) 7 (32)
15 (47) 15 (68)
.17
19 (59) 14 (39)
13 (41) 22 (61)
.14
7 (64) 31 (54)
4 (36) 26 (46)
.34
29 (50) 4 (40)
29 (50) 6 (60)
.74
3 (21) 30 (56)
11 (79) 24 (44)
.04
1 (33) 1 (17) 8 (42) 13 (50)
2 (67) 5 (83) 11 (58) 13 (50)
.51
Right-sided CDH defects correlated with renal failure, but the reminder was not significant
AKI in CDH requiring ECLS an insidious problem equation [26]. Acute kidney injury is known to be an independent risk factor for mortality in critically ill neonates [15-19], especially in patients with CDH requiring ECLS [13,14]. Previous studies in these patients have used very limited definitions of AKI, which likely underestimates the contribution of renal failure to increased mortality in this patient population. Our study demonstrates a clear association between renal failure and increased mortality, with an absolute decrease in survival of 52.7% for patients who qualified as failure by the RIFLE criteria. Abnormalities associated with AKI that can lead to increased mortality include volume overload, electrolyte abnormalities, acidosis, and nutritional issues [17]. Rozmiarek et al [14] first reported the relationship between AKI and mortality in patients with CDH on ECLS in a study of 111 patients assessing early vs late surgical repair in 2004. The incidence of renal failure reported was 26% in nonsurvivors and 6% in survivors (P b .01). Tiruvoipati et al [13] recently reported the results of a chart review of patients with CDH requiring ECLS and found that 18 (35%) of 52 developed renal failure (4 survived and 14 died; P b .001). These case series are limited by the fact that they do not systematically define AKI. These studies likely underestimate the true incidence of AKI given their narrow definition of renal failure. The incidence of AKI and renal failure in our study differs markedly from the 2 previously mentioned studies but is in line with a recently published study reviewing the incidence of AKI in 48 cardiac patients requiring ECLS in a pediatric intensive care unit. Smith et al [28] showed an incidence of 71.7% of acute renal failure, virtually identical to our incidence of AKI of 71%, but the overall 49% failure rate in our study is slightly lower. Smith et al used an extrapolation of the pediatric RIFLE criteria, with the addition of volume overload to their definition in a slightly older patient population. The use of the pediatric RIFLE criteria and the addition of volume overload to their definition vs the use of the RIFLE criteria in our study may explain the differing incidence of failure. In our study, patients who had AKI without qualifying as failure did not have increased risk of mortality, highlighting a potential benefit of early recognition of AKI to prevent progression of AKI. Therefore, we investigated elements that can be associated with AKI in neonates in the neonatal intensive care unit, specifically patients with CDH on ECLS, such as diuretic use, vasopressor use, nephrotoxic medications, and sepsis. We did not find any association between vasopressor use, diuretic exposure or infections, and AKI. Patients with AKI were more likely to have elevated levels of known nephrotoxic antibiotics (gentamicin and vancomycin). This is the first study to stratify patients with different degrees of AKI. This may provide the clinician with a marker for earlier intervention. We did not find an association in these variables; this requires further study for potentially modifiable risk factors for AKI. A total of 11 patients with AKI went on to require CRRT. This represents 29.7% of the patients who qualified as failure
633 in this study or 16.1% of all patients. The use of CRRT is lower than that reported by Tiruvoipati et al [13] of 35% in 52 patients and by the Extracorporeal Life Support Organization Registry report of 36% [29]. In our study, 19% of patients requiring CRRT survived, similar to the 22% survival rate reported by Tiruvoipati et al [13]. The previously mentioned study by Smith et al [28] in pediatric cardiac patients requiring ECLS had a higher rate of use of CRRT at 58.7% but did not report mortality. Our study differs significantly in the rate of initiation of CRRT from the previous studies and may reflect institutional treatment algorithms. A delay in initiation of CRRT may also explain increased mortality in this group. Volume overload often is an issue in patients with CDH requiring ECLS. There are several factors that contribute to volume overload in patients with CDH requiring ECLS including the severity of their illness and requirements for blood products. It is also known that patients with CDH have a propensity to retain fluid, so they are prone to fluid overload [30]. A potentially modifiable factor in patients with CDH who develop AKI with volume overload is the timing of initiation of CRRT. When performed in line with ECLS, CRRT has been shown to help improve volume status while decreasing diuretic exposure [31]. Another benefit is the ability to improve nutrition because neonates with CDH on ECLS are routinely volume restricted and often receive suboptimal nutrition. The degree of volume overload at the initiation of CRRT is associated with increased mortality [32-35], increasing significantly when patients reach greater than 10% volume overload [35]. In 2007, the American College of Critical Care Medicine set 10% fluid overload as a recommended time for intervention in critically ill patients [36]. At our institution, it is a standard of care not to remove greater than 3 mL/kg per hour of fluid while on CRRT based on the dry weight, a practice common and consistent with other institutions [28]. In our study, the patients receiving CRRT were 43% above their estimated dry weight at the initiation of CRRT. Given the previously mentioned fluid removal rate, which allows for removal of 6% to 7% of the body weight per day, it would take 6 to 7 days for these patients to achieve their dry weight, as compared with 1 to 2 days if the same patient was placed on CRRT at 10% volume overload. Given these factors, patients with CDH may benefit from earlier intervention and initiation of CRRT, especially in the context of recently published pediatric data on volume overload and mortality; however, further prospective trials to determine efficacy of such an approach must be conducted before changing standard practice. This study is the first to systematically classify AKI in CDH patents requiring ECLS. A limitation of this study is that whereas the RIFLE system has been studied in pediatric patients [21], it has not been completely validated in neonates. This study is also limited by the fact that creatinine is known to be a poor marker of kidney function in neonates but remains the most readily available laboratory test at this
634 time [15]. Another limitation is the fact that this is a retrospective, single-center study, which makes it difficult to generalize the results. A prospective, multi-institutional study is required to evaluate more aggressive interventions for AKI and volume overload in this patient population. Many important questions remain: “Does earlier initiation of CRRT reduce mortality?” “Is AKI a cause or an effect?” and “Can the progression of AKI be prevented?” This study shows that the incidence of AKI in patients with CDH on ECLS is likely higher than those previously published. Using the RIFLE criteria to define AKI, there is a significant increase in mortality for patients who reach the failure classification. Earlier recognition of AKI (during risk or injury) may be important in improving mortality in this patient population. Based on the findings in this study, our institutional practice has evolved. We consult the pediatric nephrology team earlier in the course of AKI (risk or injury) and initiate CRRT earlier when there is a less volume overload. Our preliminary results are promising, but further study is required.
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