Initial Experience Using Aminophylline to Improve Renal Dysfunction in the Pediatric Cardiovascular ICU David M. Axelrod, MD1; Andrew T. Anglemyer, PhD, MPH2; Sara F. Sherman-Levine, CPNP1; Aihua Zhu, MD1; Paul C. Grimm, MD3; Stephen J. Roth, MD, MPH1; Scott M. Sutherland, MD3 Objective: To determine if aminophylline administration is associated with improved creatinine clearance and greater urine output in children with acute kidney injury in the cardiovascular ICU. Design: Single-center retrospective cohort study. Setting: Pediatric cardiovascular ICU, university-affiliated children’s hospital. Patients: Children with congenital or acquired heart disease in the cardiovascular ICU who received aminophylline to treat oliguric acute kidney injury and fluid overload. Interventions: Patients received aminophylline after consultation with a pediatric nephrologist. Data were collected retrospectively over 7 days to assess if aminophylline was associated with improvement in creatinine clearance, urine output, and fluid o verload. Measurements and Main Results: Thirty-one patients received 52 aminophylline courses. Over the 7-day study period, serum creatinine decreased from a mean of 1.13 ± 0.91 to 0.87 ± 0.83 mg/dL (–0.05 mg/dL/d, p < 0.001). A concomitant increase was seen in estimated glomerular filtration rate from a mean of 50.0 ± 30.0 to 70.6 ± 58.1 mL/min/1.73 m2 (+3.66 mL/min/1.73 m2/d, p < 0.001). Average daily urine output increased by 0.22 mL/kg/hr (p < 0.001), Division of Cardiology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA. 2 Institute for Global Health and Department of Clinical Pharmacy, School of Pharmacy, University of California San Francisco, San Francisco, CA. 3 Division of Nephrology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA. Supported, in part, by the NIH Clinical and Translational Science Award NIH/NCRR CTSA 1UL1 RR025744 for the Stanford Center for Clinical and Translational Education and Research (Spectrum) and by the Lucile Packard Foundation for Children’s Health. Dr. Axelrod received grant support from the NIH Clinical and Translational Science Award for the Stanford Center for Clinical and Translational Education and Research and the Lucile Packard Foundation for Children's Health and consulted for Astellas Pharmaceuticals. Dr. Anglemyer received payment from Stanford University for statistical and methodologic assistance for this project and worked with Stanford for a number of manuscripts as an independent epidemiologist. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected] Copyright © 2013 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/01.pcc.0000436473.12082.2f 1
Pediatric Critical Care Medicine
and fluid overload decreased on average by 0.42% per day in the 7-day study period (p = 0.005). Although mean furosemide dose increased slightly (0.12 mg/kg/d, p = 0.01), hydrochlorothiazide dosing did not significantly change over the study period. There were no complications related to aminophylline administration. Conclusions: Our study suggests that aminophylline therapy may be associated with significantly improved renal excretory function and may augment urine output in children who experience oliguric acute kidney injury in the cardiovascular ICU. Additionally, we did not identify any aminophylline-related side effects in this high-risk cardiac population. Future prospective studies are necessary to confirm the safety profile and to ensure that the beneficial effects are independent of other clinical interventions. (Pediatr Crit Care Med 2014; 15:21–27) Key Words: acute kidney injury; aminophylline; congenital heart defect; intensive care; ischemia-reperfusion injury; oliguria
A
cute kidney injury (AKI) is a common complication seen among children requiring critical care and is associated with substantial morbidity and mortality (1–6). AKI is especially common in patients with congenital and acquired heart disease; the prevalence of AKI following pediatric cardiac surgery ranges from 28% to 52% (2, 4, 6–9). These children are often at increased risk for AKI due to nephrotoxin exposure, uncorrected or residual heart defects, a low cardiac output state, and sepsis. Additionally, surgical correction and palliation of heart defects often require cardiopulmonary bypass (CPB), which has been associated with a higher prevalence of AKI, likely due to renal ischemia-reperfusion injury (8, 9). The postoperative development of AKI has important implications as even small transient increases in serum creatinine have been associated with poorer outcomes (2); severe AKI events have been shown to be associated with a five-fold to nine-fold increase in mortality (8). AKI is almost always associated with fluid overload (FO), which has similarly been associated with poorer outcomes in many critically ill pediatric populations (10–12). Diuretics are www.pccmjournal.org
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the cornerstone of FO management in the setting of oliguric AKI; however, they are not always efficacious, do not address the underlying renal injury, and have the potential to worsen renal function (13, 14). Although standardized definitions and novel biomarkers have facilitated AKI diagnosis (3, 4, 6, 7, 15), our ability to improve outcomes among children with AKI has been hampered by the lack of effective therapies to treat or prevent AKI in at-risk populations. One potential adjuvant AKI therapy is aminophylline, a methylxanthine adenosine receptor antagonist that inhibits adenosine-mediated renal vasoconstriction (16–19) and may increase urine output by inhibiting type IV phosphodiesterase (20, 21). Clinically, it has been used to increase urine output and augment diuresis in patients with heart failure (16), perinatal asphyxia (22–24), neonatal apnea and respiratory distress (25), contrast-induced nephropathy (18), diuretic-refractory FO (26–28), and tacrolimus-induced AKI (19, 29, 30). Clinical trials and retrospective reviews have demonstrated the safety and efficacy of aminophylline use in preventing AKI in neonates and children, but its use has not been described in pediatric patients with congenital or acquired heart disease. Furthermore, due to its potential to cause tachyarrhythmias at higher serum concentrations, establishing the safety of aminophylline use in this population is important. The primary objective of this study was to assess the effect of aminophylline on renal function and urine output in children with AKI in the setting of acquired or congenital heart disease. We hypothesized that aminophylline would be associated with an improvement in both estimated glomerular filtration rate (eGFR) and urine output in children with AKI in the pediatric cardiovascular ICU (CVICU). The rationale of the study is based on the potential ability of aminophylline to block tubuloglomerular feedback and reduce glomerular arteriolar vasoconstriction by inhibiting intrarenal adenosine signaling. Our secondary objective was to determine if low-dose aminophylline was associated with tachycardia or clinically significant side effects in this pediatric cardiac population.
MATERIALS AND METHODS This study is a retrospective analysis of patients who received aminophylline to treat renal insufficiency and/or oliguria in the pediatric CVICU at the Lucile Packard Children’s Hospital at Stanford. Patients were identified through the Inpatient Pharmacy Database; all children admitted to the CVICU who received aminophylline between March 1, 2010, and December 31, 2010, were considered for inclusion. Patients who received aminophylline for bronchodilation or asthma management were excluded from the analysis; patients with sepsis or systemic inflammatory response syndrome were not excluded. Any patient who received at least one dose of aminophylline for treatment of AKI in the CVICU was included for analysis. The diagnosis of AKI and the decision to administer aminophylline were made on clinical grounds in consultation with the Pediatric Nephrology service when patients had a creatinine elevated from their normal baseline, oliguria, and/or FO that affected hemodynamics and/or respiratory mechanics. All 22
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patients included in this study experienced increased creatinine from baseline, oliguria, and/or FO refractory to diuretic therapy. In a post hoc analysis, patients were classified with AKI staging according to the 2012 Kidney Disease/Improving Global Outcomes (KDIGO) consensus AKI definition (31). This research protocol was approved by the Stanford University Institutional Review Board. Patients who received multiple treatment courses of aminophylline during the same CVICU admission were included in the study, and different treatment courses were considered independent events if they were separated by at least 4 days. For 42 of the 52 treatment courses (81%), aminophylline was administered as a 5 mg/kg IV load followed by 1.8 mg/kg IV every 6 hours; this is a protocol that has been standardized by our Pediatric Nephrology service after extrapolation from previously published reports (23, 29, 30, 32, 33). We maintained a target serum theophylline concentration of 5–10 μg/ mL; serum trough theophylline concentrations were assessed within the first 24 hours of aminophylline administration and subsequently at the discretion of the treating physician. Seven treatment courses (13.5%) were via continuous IV infusion (mean dose, 0.44 ± 0.14 mg/kg/hr; range, 0.3–0.6 mg/kg/hr). Three patients (5.8%) received 5 mg/kg IV loading doses followed by maintenance doses of 0.4–2.6 mg/kg IV Q6 hours. Because we treated all patients with the goal of a serum theophylline concentration of 5–10 μg/mL, we did not analyze subgroups of different dosing regimens. Data were manually extracted from the medical record and included demographic information, details of hospital/ICU admission, surgery performed, CPB and aortic cross-clamp times, details of aminophylline administration (including date, dose, and duration of therapy), laboratory values including blood urea nitrogen and creatinine, total fluid intake and output data including urine output (measured by either indwelling Foley catheter or by diaper weight), date of tracheal extubation, inotrope doses, major ICU complications (death, arrhythmia, and seizure), and diuretic dosing. Because aminophylline is a salt of theophylline, the standard laboratory measure of aminophylline dosing is a serum theophylline concentration. All serum theophylline concentrations drawn during the study period were recorded. A modified inotrope score (IS) was calculated as follows: dopamine plus dobutamine plus (milrinone × 10) plus (epinephrine × 100), as described by Wernovsky et al (34). eGFR was estimated using the Schwartz method (35). All variables were collected from the day prior to initiation of aminophylline (day –1, specifically identified as the calendar day in the CVICU before drug dosing), the day aminophylline was begun (day 0), and the 5 days following initiation of aminophylline (days 1–5). Our primary outcome variables were the change in serum creatinine and eGFR following initiation of aminophylline, using the serum creatinine concentration from the day prior to initiation (day –1) as the baseline value. Secondary outcome variables included the change in urine output and FO following administration of aminophylline. FO was defined as follows: Percentage of FO = (fluid in – fluid out) × 100% ⁄ ICU admission weight. January 2014 • Volume 15 • Number 1
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We performed linear mixed-effects regression analyses to estimate changes in serum creatinine, eGFR, and urine output over time. The distribution of residuals was evaluated using normality assumption plots. Our unit of analysis was the treatment course received (n = 52), assuming independence between treatment courses. However, we also performed sensitivity analyses of only the first treatment course received per child (n = 31) which yielded similar results. We analyzed both the total number of aminophylline treatment courses (n = 52) and the first treatment course of each individual patient (n = 31). The results from the analysis of the 52 treatment courses are presented here, although separate analysis of the first treatment course in the 31 patients revealed no statistically different findings. Unless otherwise indicated, data are presented as mean ± sd. All analyses were performed in R (R Development Core Team, Vienna, Austria).
Table 1. Demographics of 31 Patients Administered Aminophylline to Treat Acute Kidney Injury Mean (sd), n = 31
Characteristic
Gender, n (%) Male
16 (52)
Female
15 (48)
Bypass, n
23
Bypass time (min)
100 (65) 18
Cross clamp, n Cross clamp time (min)
100 (65)
Age (yr)
RESULTS Demographics A total of 35 patients received 56 treatment courses of aminophylline in the CVICU; four patients (four treatment courses) were excluded because they received aminophylline for bronchodilation/asthma rather than treatment of AKI, leaving a total of 31 patients (52 treatment courses) for this analysis. Of the 31 patients, 13 received multiple treatment courses of aminophylline during their CVICU stay (mean 2.6 ± 1.1 treatment courses per patient). For patients who received more than one treatment course, the mean time interval between courses was 22 ± 26 days. In the week prior to aminophylline administration, there was a significant reduction in renal function; the mean eGFR (in all 52 treatment courses) decreased from 79.6 ± 57.1 to 44.5 ± 27.2 mL/min/1.73 m2 (p < 0.001). Additionally, AKI was present at aminophylline initiation 73.1% of the time (38 of 52): 23.1% (12 of 52) classified as stage 1 AKI, 19.2% (10 of 52) classified as stage 2 AKI, and 30.8% (16 of 52) classified as stage 3 AKI. In the 14 instances where the KDIGO AKI criteria were not met, milder elevations in serum creatinine concentrations, oliguria, and/or diuretic-resistant FO were present. Demographic data for the 31 patients are included in Table 1. Twenty-two patients (71%) had congenital heart disease and nine (29%) had cardiomyopathy, had heart failure, or had undergone heart transplantation. The mean age was 3.8 ± 5.3 years and the mean weight was 17 ± 21.6 kg. The cohort was highly dependent on critical care support as evidenced by the mean duration of mechanical ventilation of 33.1 ± 58.9 days and the mean IS of 8.6 ± 6. Mean IS was similar between the day prior to (day –1) aminophylline administration (7.5 ± 6.4) and days 0–2 following aminophylline initiation (8.6 ± 6.9, p = 0.1; 7.7 ± 6.7, p = 0.7; 6.9 ± 6.5, p = 0.3, respectively). Notably, mean IS was significantly lower on days 3–5 when compared with the day prior to (day –1) aminophylline initiation (6.0 ± 6.3, p = 0.02; 5.7 ± 6.4, p = 0.02; 5.4 ± 6.8 p = 0.01). Twenty-three patients required CPB (mean time, 184 ± 120 min) and 18 required aortic cross clamp (mean, 100 ± 65 min). Five patients had underlying renal abnormalities: one had a renal transplant, one had a Pediatric Critical Care Medicine
3.8 (5.3)
Weight (kg)
17.0 (21.6)
ICU length of stay (d)
63.2 (69.2)
Deaths, n
8
Surgical procedure, n
27
Cardiac transplantation
5
Ventricular assist device
3
Aorta/arch repair
4
Tetralogy of Fallot with major aortopulmonary collateral arteries repair
2
Extracorporeal membrane oxygenation cannulation
2
Mitral valve repair
2
Pulmonary artery plasty/unifocalization
2
Other (arterial switch operation, pulmonary artery band, Blalock-Taussig shunt, double outlet right ventricle repair)
5
duplicated urinary collecting system, one had a unilateral multicystic dysplastic kidney, one had a horseshoe kidney, and one had a solitary kidney following nephrectomy of an aplastic kidney. No patients received adenosine during their aminophylline course. Mean CVICU length of stay was 63.2 ± 69.2 days, and all-cause in-hospital mortality for the cohort was 26% (8 of 31). Aminophylline Treatment Course Based on prior experience and extrapolation from prior reports (22, 26), our pediatric nephrologists recommended adjusting all aminophylline dosing regimens to maintain serum theophylline concentrations between 5 and 10 μg/mL. One hundred fifty drug concentrations were drawn during the study period with a mean concentration of 7.1 ± 4.3 μg/mL. The average length of aminophylline dosing was 5.3 ± 4.8 days. For the 25 patients who received aminophylline after cardiac surgery, the initial course of aminophylline was administered a mean of 15.8 ± 34.2 days after surgery. Three patients received aminophylline a mean of 45.3 ± 55.6 days before cardiac surgery; all www.pccmjournal.org
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three of these patients carried a diagnosis of dilated cardiomyopathy and two progressed to mechanical circulatory support (one on extracorporeal membrane oxygenation [ECMO] and one on a ventricular assist device). Three patients did not undergo cardiac surgery and received aminophylline a mean of 2.7 days after hospital admission (range, 0–7 d); two of these patients had dilated cardiomyopathy and one had congenital heart disease resulting in heart failure. Creatinine/eGFR Serum creatinine decreased from a mean of 1.13 ± 0.91 mg/ dL on the day before aminophylline administration to a mean of 0.87 ± 0.83 mg/dL on day 5 after aminophylline administration or approximately 0.05 ± 0.01 mg/dL/d of aminophylline administration (p < 0.001). eGFR increased from a mean of 50.0 ± 30 mL/min/1.73 m2 before aminophylline administration to a mean of 70.6 ± 58.1 mL/min/1.73 m2 on day 5 or approximately 3.7 ± 0.63 mL/min/1.73 m2/d of aminophylline administration (p < 0.001). Figures 1 and 2 illustrate the decrease in serum creatinine and the increase in creatinine clearance over time, respectively. Notably, there was no statistically significant effect of FO on serum creatinine concentration over time (p = 0.88). We found similar results when only the first aminophylline course for each patient was considered; serum creatinine decreased and eGFR increased (0.07 mg/dL/d, p < 0.001; 4.5 mL/min/1.73 m2/d, p < 0.001, respectively). Diuretic Data, Urine Output, and FO During the 7-day study period, patients received 1.8 ± 1.0 different diuretics (range, 0–4). The most commonly administered diuretics were furosemide (40 of 52, 77%) and hydrochlorothiazide (38 of 52, 73%). Of 52 treatment courses, 17 (33%) coincided with at least one dose of bumetanide and six coincided
Figure 1. Average serum creatinine over the aminophylline course. When compared with the day prior to aminophylline administration (day –1), serum creatinine declined significantly while patients received aminophylline (p < 0.001).
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Figure 2. Average glomerular filtration rate over the aminophylline course. When compared with the day prior to aminophylline administration (day –1), estimated glomerular filtration rate (eGFR) increased significantly while patients received aminophylline (p < 0.001).
with at least one dose of metolazone (12%). Figure 3 displays the mean doses of furosemide and hydrochlorothiazide over the aminophylline course and their qualitative relationship to urine output. Linear mixed-effects regression models demonstrated that during the aminophylline treatment course, furosemide dose increased significantly (+0.12 ± 0.04 mg/kg/d, p = 0.01), but there was no significant increase in hydrochlorothiazide dose (+0.23 ± 0.22 mg/kg/d, p = 0.29). Similarly, the linear mixed-effects regression models demonstrated a significant increase in urine output (+0.22 ± 0.04 mL/kg/hr/d, p < 0.001) and a concomitant significant decrease in FO (–0.42% ± 0.15% per day, p = 0.005) over the aminophylline treatment course. Total mean fluid intake was not significantly different on day –1 compared with days 0–5 of aminophylline dosing
Figure 3. Diuretics and urine output over time. Average (Avg) diuretic doses (in mg/kg/d) were calculated among patients who received those diuretics. When compared with the day prior to aminophylline administration, urine output (asterisk) (p < 0.001) and furosemide dose (closed square) (p = 0.01) increased significantly. The dose of hydrochlorothiazide (closed circle) did not increase significantly (p = 0.29). January 2014 • Volume 15 • Number 1
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(p = 0.27–0.88). When only the first aminophylline course for each patient was considered, hydrochlorothiazide dose and urine output increased (+0.17 mg/kg/d, p < 0.01; +0.23 mL/kg/hr/d, p < 0.001, respectively), whereas FO decreased (–0.39% per day, p = 0.04) and furosemide dosing remained unchanged (+0.03 mg/kg/d, p = 0.56). Complications One patient required hemodialysis and subsequently died, one had a cerebrovascular accident, and one patient had atrial flutter while being cannulated for ECMO which was successfully cardioverted to sinus tachycardia. Two patients who received aminophylline had a history of tachycardia. One patient had a history of atrioventricular reciprocating tachycardia (AVRT), and amiodarone therapy was prescribed to treat the underlying dysrhythmia; no tachycardia occurred during the aminophylline treatment course. The second patient had a history of ventricular tachycardia (VT) and experienced recurrent VT 4 days after cessation of aminophylline therapy; the VT was successfully controlled with amiodarone administration. No other episodes of tachyarrhythmia occurred. No patients experienced clinical seizures. Review of the daily progress notes did not reveal any evidence of vomiting, nausea, irritability, or insomnia during the aminophylline treatment courses.
DISCUSSION In this study, we administered aminophylline to children admitted to the CVICU who experienced oliguric AKI refractory to standard diuretic therapy. We found that initiation of aminophylline therapy was associated with a significant reduction in serum creatinine values and a concomitant improvement in estimated renal excretory function. Additionally, aminophylline was associated with increased urine output and a reduction in overall FO burden. There were no major ICU complications associated with aminophylline administration in this critically ill pediatric cardiac population. However, because this was not a randomized trial, we cannot confirm the safety of aminophylline. Our findings are consistent with prior studies of aminophylline in a number of different pediatric populations. Both Jenik et al (22) and Bakr (23) performed randomized controlled trials of theophylline in asphyxiated term neonates and found improved renal function in their treatment groups. Similarly, Bhat et al (24) studied a single theophylline dose in term neonates with asphyxia; creatinine and urinary β-2-microglobulin excretion decreased after treatment. Bell et al (26) studied patients in the PICU who were diuretic dependent and reported an increase in urine output of more than 80% in patients treated with a single dose of aminophylline. Other studies of adenosine receptor antagonists, however, have contradicted these findings. The most notable of these was the Placebo-controlled Randomized study of the selective A1-adenosine receptor antagonist rolofylline for patients hospitalised with AHF and volume Overload to assess Treatment Effect on Congestion and renal function (PROTECT) study of more than 2,000 adult patients with acute congestive heart failure and renal failure (36). In that Pediatric Critical Care Medicine
population, rolofylline administration resulted in a decrease in mean body weight but did not impact the prevalence of renal failure. Although this is a large and powerful study among adults, rolofylline, unlike aminophylline, inhibits only a single adenosine receptor subtype. Additionally, it is possible that its findings do not strictly translate to the pediatric CVICU population, since adult congestive heart failure often coexists with chronic systemic venous hypertension, diabetes mellitus, and arterial hypertension. Our preliminary study, although significantly smaller, does suggest that in the pediatric CVICU population, aminophylline may improve both renal function and augment urine output in the setting of oliguric AKI. Aminophylline has similar pharmacokinetic properties to theophylline. Peak serum concentration is reached within 30 minutes after an IV dose, and the elimination half-life varies with age: approximately 3.5 hours for children, 8.5 hours for adults, and as high as 20 hours for premature neonates (37). Based on the pharmacokinetic data and previously published reports (22, 23, 26, 38), we initiated IV aminophylline therapy with a 5 mg/kg load followed by a 1.8 mg/kg dose every 6 hours. We targeted a theophylline concentration of 5–10 μg/ mL, which is approximately half the concentration targeted when aminophylline is used to treat bronchoconstriction (39). Aminophylline and theophylline affect the renal vasculature by nonspecifically blocking adenosine receptors at theophylline concentrations of 2–3 μg/mL and by inhibiting type IV phosphodiesterase at theophylline concentrations of more than 10 μg/mL (26). During the study period, we were able to maintain average concentrations of approximately 7 μg/mL without side effects, such as tachyarrhythmias or clinical seizures. Even in two patients with a history of documented tachycardia (VT and AVRT), aminophylline was used safely and did not result in exacerbation of the underlying arrhythmia. Additionally, no patients required adenosine therapy for the diagnosis or treatment of arrhythmias during our study period. Because aminophylline blocks adenosine receptors, careful attention to the dosing of adenosine is required for patients receiving aminophylline (specifically, higher doses of adenosine may be required). The complications described in our patients did not appear to be temporally related to aminophylline dosing; however, the retrospective nature of this study limits our ability to state this with certainty. The ability to reverse or mitigate renal dysfunction and improve urine output and fluid balance is critically important given the morbidity and mortality effects associated with AKI and FO. AKI in children undergoing corrective cardiac surgery has been independently associated with longer length of stay, a greater need for mechanical ventilation, and higher hospital mortality rates (2, 4). FO, which is commonly associated with AKI, has also been associated with longer duration of mechanical ventilation, poorer oxygenation, prolonged ICU and hospital length of stay, and greater mortality (10, 11). The deleterious effects of FO may be even more pronounced in children with heart failure or following cardiac surgery as it leads to increased tissue edema in the lungs and chest wall; management of these complications often leads to longer lengths of www.pccmjournal.org
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stay with increased risk for nosocomial infections. Given the morbidity and mortality associated with AKI and FO, the ability to mitigate these complications may have beneficial effects on patient outcomes. It is possible that preventing or reducing the severity of AKI and effectively treating FO could shorten ICU stays and lessen morbidity and mortality. Our retrospective study has several limitations, and it is important to interpret our results in their context. Improvement in eGFR and urine output could have been caused by an improved cardiac function over time. Although mean IS did decrease during the treatment course, we have no objective measures of cardiac output to suggest that improved cardiac function led to improved creatinine clearance and urine output. It is also important to note that patients were receiving diuretics during the period of aminophylline administration; thus, it is likely that these medications contributed to the effects on urine output and FO. However, it is unlikely that the diuretics are responsible for the creatinine and eGFR improvements seen in our study as diuretics have been associated with worsening renal function (13, 14). Third, it was not possible to analyze the complete medication administration record for each patient, and it is therefore possible that elimination of nephrotoxins contributed to the improved renal function. Additionally, although all patients in the study were admitted to the CVICU and experienced renal dysfunction, the patient diagnoses and underlying causes of AKI are not uniform. Aminophylline dosing was not uniform in our patients, although serum concentrations were similar in patients with different dosing regimens. Laboratory evaluation of serum theophylline concentrations was not performed on a standard schedule, since the use of aminophylline in this study was monitored by the attending physician and not part of a randomized trial. Similarly, the timing of aminophylline administration was not uniform because patients experienced AKI at variable times after their initial CVICU admission. Unfortunately, the small size of our cohort did not allow for subgroup analyses. Thus, it is possible that our findings are not generalizable to all CVICU populations or types of AKI. Additionally, the diagnosis of AKI was made entirely on clinical grounds. Future studies should include more specific creatinine-based definitions of AKI, such as pediatric Risk, Injury, Failure, Loss, End-Stage, Acute Kidney Injury Network, or KDIGO (7, 31, 40).
CONCLUSIONS In conclusion, this is the first report of the use of aminophylline specifically in pediatric cardiac patients with oliguric AKI. We found that aminophylline may augment the effect of conventional diuretic therapies, while also reducing serum creatinine concentrations and improving estimated creatinine clearance. We believe that further prospective study of aminophylline in the setting of oliguric AKI in the pediatric CVICU is warranted.
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Cardiac Intensive Care 24. Bhat MA, Shah ZA, Makhdoomi MS, et al: Theophylline for renal function in term neonates with perinatal asphyxia: A randomized, placebocontrolled trial. J Pediatr 2006; 149:180–184 25. Cattarelli D, Spandrio M, Gasparoni A, et al: A randomised, double blind, placebo controlled trial of the effect of theophylline in prevention of vasomotor nephropathy in very preterm neonates with respiratory distress syndrome. Arch Dis Child Fetal Neonatal Ed 2006; 91:F80–F84 26. Bell M, Jackson E, Mi Z, et al: Low-dose theophylline increases urine output in diuretic-dependent critically ill children. Intensive Care Med 1998; 24:1099–1105 27. Lochan SR, Adeniyi-Jones S, Assadi FK, et al: Coadministration of theophylline enhances diuretic response to furosemide in infants during extracorporeal membrane oxygenation: A randomized controlled pilot study. J Pediatr 1998; 133:86–89 28. Huet F, Semama D, Grimaldi M, et al: Effects of theophylline on renal insufficiency in neonates with respiratory distress syndrome. Intensive Care Med 1995; 21:511–514 29. McLaughlin GE, Land MP, Rossique-Gonzalez M: Effect of aminophylline on urine flow in children with tacrolimus-induced renal insufficiency. Transplant Proc 2000; 32:817–820 30. McLaughlin GE, Abitbol CL: Reversal of oliguric tacrolimus nephrotoxicity in children. Nephrol Dial Transplant 2005; 20:1471–1475 31. Section 2: AKI definition. Kidney Int Suppl 2012; 2:19–36 32. Ng GY, Baker EH, Farrer KF: Aminophylline as an adjunct diuretic for neonates—A case series. Pediatr Nephrol 2005; 20:220–222
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33. Mazkereth R, Laufer J, Jordan S, et al: Effects of theophylline on renal function in premature infants. Am J Perinatol 1997; 14:45–49 34. Wernovsky G, Wypij D, Jonas RA, et al: Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants. A comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation 1995; 92:2226–2235 35. Schwartz GJ, Brion LP, Spitzer A: The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am 1987; 34:571–590 36. Cotter G, Dittrich HC, Weatherley BD, et al; Protect Steering Committee, Investigators, and Coordinators: The PROTECT pilot study: A randomized, placebo-controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment. J Card Fail 2008; 14:631–640 37. Mulla H, Nabi F, Nichani S, et al: Population pharmacokinetics of theophylline during paediatric extracorporeal membrane oxygenation. Br J Clin Pharmacol 2003; 55:23–31 38. Pretzlaff RK, Vardis RJ, Pollack MM: Aminophylline in the treatment of fluid overload. Crit Care Med 1999; 27:2782–2785 39. National Asthma Education and Prevention Program TEP on the D and M of A (2007) Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Available at: http://www-ncbi-nlm-nih-gov. laneproxy.stanford.edu/books/NBK7232/. Accessed 22 January 2013 40. Mehta RL, Kellum JA, Shah SV, et al; Acute Kidney Injury Network: Acute Kidney Injury Network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007; 11:R31
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and fluid overload decreased on average by 0.42% per day in the 7-day study period (p = 0.005). Although mean furosemide dose increased slightly (0.12 mg/kg/d, p = 0.01), hydrochlorothiazide dosing did not significantly change over the study period. There were no complications related to aminophylline administration. Conclusions: Our study suggests that aminophylline therapy may be associated with significantly improved renal excretory function and may augment urine output in children who experience oliguric acute kidney injury in the cardiovascular ICU. Additionally, we did not identify any aminophylline-related side effects in this high-risk cardiac population. Future prospective studies are necessary to confirm the safety profile and to ensure that the beneficial effects are independent of other clinical interventions. (Pediatr Crit Care Med 2014; 15:21–27) Key Words: acute kidney injury; aminophylline; congenital heart defect; intensive care; ischemia-reperfusion injury; oliguria
A
cute kidney injury (AKI) is a common complication seen among children requiring critical care and is associated with substantial morbidity and mortality (1–6). AKI is especially common in patients with congenital and acquired heart disease; the prevalence of AKI following pediatric cardiac surgery ranges from 28% to 52% (2, 4, 6–9). These children are often at increased risk for AKI due to nephrotoxin exposure, uncorrected or residual heart defects, a low cardiac output state, and sepsis. Additionally, surgical correction and palliation of heart defects often require cardiopulmonary bypass (CPB), which has been associated with a higher prevalence of AKI, likely due to renal ischemia-reperfusion injury (8, 9). The postoperative development of AKI has important implications as even small transient increases in serum creatinine have been associated with poorer outcomes (2); severe AKI events have been shown to be associated with a five-fold to nine-fold increase in mortality (8). AKI is almost always associated with fluid overload (FO), which has similarly been associated with poorer outcomes in many critically ill pediatric populations (10–12). Diuretics are www.pccmjournal.org
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the cornerstone of FO management in the setting of oliguric AKI; however, they are not always efficacious, do not address the underlying renal injury, and have the potential to worsen renal function (13, 14). Although standardized definitions and novel biomarkers have facilitated AKI diagnosis (3, 4, 6, 7, 15), our ability to improve outcomes among children with AKI has been hampered by the lack of effective therapies to treat or prevent AKI in at-risk populations. One potential adjuvant AKI therapy is aminophylline, a methylxanthine adenosine receptor antagonist that inhibits adenosine-mediated renal vasoconstriction (16–19) and may increase urine output by inhibiting type IV phosphodiesterase (20, 21). Clinically, it has been used to increase urine output and augment diuresis in patients with heart failure (16), perinatal asphyxia (22–24), neonatal apnea and respiratory distress (25), contrast-induced nephropathy (18), diuretic-refractory FO (26–28), and tacrolimus-induced AKI (19, 29, 30). Clinical trials and retrospective reviews have demonstrated the safety and efficacy of aminophylline use in preventing AKI in neonates and children, but its use has not been described in pediatric patients with congenital or acquired heart disease. Furthermore, due to its potential to cause tachyarrhythmias at higher serum concentrations, establishing the safety of aminophylline use in this population is important. The primary objective of this study was to assess the effect of aminophylline on renal function and urine output in children with AKI in the setting of acquired or congenital heart disease. We hypothesized that aminophylline would be associated with an improvement in both estimated glomerular filtration rate (eGFR) and urine output in children with AKI in the pediatric cardiovascular ICU (CVICU). The rationale of the study is based on the potential ability of aminophylline to block tubuloglomerular feedback and reduce glomerular arteriolar vasoconstriction by inhibiting intrarenal adenosine signaling. Our secondary objective was to determine if low-dose aminophylline was associated with tachycardia or clinically significant side effects in this pediatric cardiac population.
MATERIALS AND METHODS This study is a retrospective analysis of patients who received aminophylline to treat renal insufficiency and/or oliguria in the pediatric CVICU at the Lucile Packard Children’s Hospital at Stanford. Patients were identified through the Inpatient Pharmacy Database; all children admitted to the CVICU who received aminophylline between March 1, 2010, and December 31, 2010, were considered for inclusion. Patients who received aminophylline for bronchodilation or asthma management were excluded from the analysis; patients with sepsis or systemic inflammatory response syndrome were not excluded. Any patient who received at least one dose of aminophylline for treatment of AKI in the CVICU was included for analysis. The diagnosis of AKI and the decision to administer aminophylline were made on clinical grounds in consultation with the Pediatric Nephrology service when patients had a creatinine elevated from their normal baseline, oliguria, and/or FO that affected hemodynamics and/or respiratory mechanics. All 22
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patients included in this study experienced increased creatinine from baseline, oliguria, and/or FO refractory to diuretic therapy. In a post hoc analysis, patients were classified with AKI staging according to the 2012 Kidney Disease/Improving Global Outcomes (KDIGO) consensus AKI definition (31). This research protocol was approved by the Stanford University Institutional Review Board. Patients who received multiple treatment courses of aminophylline during the same CVICU admission were included in the study, and different treatment courses were considered independent events if they were separated by at least 4 days. For 42 of the 52 treatment courses (81%), aminophylline was administered as a 5 mg/kg IV load followed by 1.8 mg/kg IV every 6 hours; this is a protocol that has been standardized by our Pediatric Nephrology service after extrapolation from previously published reports (23, 29, 30, 32, 33). We maintained a target serum theophylline concentration of 5–10 μg/ mL; serum trough theophylline concentrations were assessed within the first 24 hours of aminophylline administration and subsequently at the discretion of the treating physician. Seven treatment courses (13.5%) were via continuous IV infusion (mean dose, 0.44 ± 0.14 mg/kg/hr; range, 0.3–0.6 mg/kg/hr). Three patients (5.8%) received 5 mg/kg IV loading doses followed by maintenance doses of 0.4–2.6 mg/kg IV Q6 hours. Because we treated all patients with the goal of a serum theophylline concentration of 5–10 μg/mL, we did not analyze subgroups of different dosing regimens. Data were manually extracted from the medical record and included demographic information, details of hospital/ICU admission, surgery performed, CPB and aortic cross-clamp times, details of aminophylline administration (including date, dose, and duration of therapy), laboratory values including blood urea nitrogen and creatinine, total fluid intake and output data including urine output (measured by either indwelling Foley catheter or by diaper weight), date of tracheal extubation, inotrope doses, major ICU complications (death, arrhythmia, and seizure), and diuretic dosing. Because aminophylline is a salt of theophylline, the standard laboratory measure of aminophylline dosing is a serum theophylline concentration. All serum theophylline concentrations drawn during the study period were recorded. A modified inotrope score (IS) was calculated as follows: dopamine plus dobutamine plus (milrinone × 10) plus (epinephrine × 100), as described by Wernovsky et al (34). eGFR was estimated using the Schwartz method (35). All variables were collected from the day prior to initiation of aminophylline (day –1, specifically identified as the calendar day in the CVICU before drug dosing), the day aminophylline was begun (day 0), and the 5 days following initiation of aminophylline (days 1–5). Our primary outcome variables were the change in serum creatinine and eGFR following initiation of aminophylline, using the serum creatinine concentration from the day prior to initiation (day –1) as the baseline value. Secondary outcome variables included the change in urine output and FO following administration of aminophylline. FO was defined as follows: Percentage of FO = (fluid in – fluid out) × 100% ⁄ ICU admission weight. January 2014 • Volume 15 • Number 1
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We performed linear mixed-effects regression analyses to estimate changes in serum creatinine, eGFR, and urine output over time. The distribution of residuals was evaluated using normality assumption plots. Our unit of analysis was the treatment course received (n = 52), assuming independence between treatment courses. However, we also performed sensitivity analyses of only the first treatment course received per child (n = 31) which yielded similar results. We analyzed both the total number of aminophylline treatment courses (n = 52) and the first treatment course of each individual patient (n = 31). The results from the analysis of the 52 treatment courses are presented here, although separate analysis of the first treatment course in the 31 patients revealed no statistically different findings. Unless otherwise indicated, data are presented as mean ± sd. All analyses were performed in R (R Development Core Team, Vienna, Austria).
Table 1. Demographics of 31 Patients Administered Aminophylline to Treat Acute Kidney Injury Mean (sd), n = 31
Characteristic
Gender, n (%) Male
16 (52)
Female
15 (48)
Bypass, n
23
Bypass time (min)
100 (65) 18
Cross clamp, n Cross clamp time (min)
100 (65)
Age (yr)
RESULTS Demographics A total of 35 patients received 56 treatment courses of aminophylline in the CVICU; four patients (four treatment courses) were excluded because they received aminophylline for bronchodilation/asthma rather than treatment of AKI, leaving a total of 31 patients (52 treatment courses) for this analysis. Of the 31 patients, 13 received multiple treatment courses of aminophylline during their CVICU stay (mean 2.6 ± 1.1 treatment courses per patient). For patients who received more than one treatment course, the mean time interval between courses was 22 ± 26 days. In the week prior to aminophylline administration, there was a significant reduction in renal function; the mean eGFR (in all 52 treatment courses) decreased from 79.6 ± 57.1 to 44.5 ± 27.2 mL/min/1.73 m2 (p < 0.001). Additionally, AKI was present at aminophylline initiation 73.1% of the time (38 of 52): 23.1% (12 of 52) classified as stage 1 AKI, 19.2% (10 of 52) classified as stage 2 AKI, and 30.8% (16 of 52) classified as stage 3 AKI. In the 14 instances where the KDIGO AKI criteria were not met, milder elevations in serum creatinine concentrations, oliguria, and/or diuretic-resistant FO were present. Demographic data for the 31 patients are included in Table 1. Twenty-two patients (71%) had congenital heart disease and nine (29%) had cardiomyopathy, had heart failure, or had undergone heart transplantation. The mean age was 3.8 ± 5.3 years and the mean weight was 17 ± 21.6 kg. The cohort was highly dependent on critical care support as evidenced by the mean duration of mechanical ventilation of 33.1 ± 58.9 days and the mean IS of 8.6 ± 6. Mean IS was similar between the day prior to (day –1) aminophylline administration (7.5 ± 6.4) and days 0–2 following aminophylline initiation (8.6 ± 6.9, p = 0.1; 7.7 ± 6.7, p = 0.7; 6.9 ± 6.5, p = 0.3, respectively). Notably, mean IS was significantly lower on days 3–5 when compared with the day prior to (day –1) aminophylline initiation (6.0 ± 6.3, p = 0.02; 5.7 ± 6.4, p = 0.02; 5.4 ± 6.8 p = 0.01). Twenty-three patients required CPB (mean time, 184 ± 120 min) and 18 required aortic cross clamp (mean, 100 ± 65 min). Five patients had underlying renal abnormalities: one had a renal transplant, one had a Pediatric Critical Care Medicine
3.8 (5.3)
Weight (kg)
17.0 (21.6)
ICU length of stay (d)
63.2 (69.2)
Deaths, n
8
Surgical procedure, n
27
Cardiac transplantation
5
Ventricular assist device
3
Aorta/arch repair
4
Tetralogy of Fallot with major aortopulmonary collateral arteries repair
2
Extracorporeal membrane oxygenation cannulation
2
Mitral valve repair
2
Pulmonary artery plasty/unifocalization
2
Other (arterial switch operation, pulmonary artery band, Blalock-Taussig shunt, double outlet right ventricle repair)
5
duplicated urinary collecting system, one had a unilateral multicystic dysplastic kidney, one had a horseshoe kidney, and one had a solitary kidney following nephrectomy of an aplastic kidney. No patients received adenosine during their aminophylline course. Mean CVICU length of stay was 63.2 ± 69.2 days, and all-cause in-hospital mortality for the cohort was 26% (8 of 31). Aminophylline Treatment Course Based on prior experience and extrapolation from prior reports (22, 26), our pediatric nephrologists recommended adjusting all aminophylline dosing regimens to maintain serum theophylline concentrations between 5 and 10 μg/mL. One hundred fifty drug concentrations were drawn during the study period with a mean concentration of 7.1 ± 4.3 μg/mL. The average length of aminophylline dosing was 5.3 ± 4.8 days. For the 25 patients who received aminophylline after cardiac surgery, the initial course of aminophylline was administered a mean of 15.8 ± 34.2 days after surgery. Three patients received aminophylline a mean of 45.3 ± 55.6 days before cardiac surgery; all www.pccmjournal.org
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three of these patients carried a diagnosis of dilated cardiomyopathy and two progressed to mechanical circulatory support (one on extracorporeal membrane oxygenation [ECMO] and one on a ventricular assist device). Three patients did not undergo cardiac surgery and received aminophylline a mean of 2.7 days after hospital admission (range, 0–7 d); two of these patients had dilated cardiomyopathy and one had congenital heart disease resulting in heart failure. Creatinine/eGFR Serum creatinine decreased from a mean of 1.13 ± 0.91 mg/ dL on the day before aminophylline administration to a mean of 0.87 ± 0.83 mg/dL on day 5 after aminophylline administration or approximately 0.05 ± 0.01 mg/dL/d of aminophylline administration (p < 0.001). eGFR increased from a mean of 50.0 ± 30 mL/min/1.73 m2 before aminophylline administration to a mean of 70.6 ± 58.1 mL/min/1.73 m2 on day 5 or approximately 3.7 ± 0.63 mL/min/1.73 m2/d of aminophylline administration (p < 0.001). Figures 1 and 2 illustrate the decrease in serum creatinine and the increase in creatinine clearance over time, respectively. Notably, there was no statistically significant effect of FO on serum creatinine concentration over time (p = 0.88). We found similar results when only the first aminophylline course for each patient was considered; serum creatinine decreased and eGFR increased (0.07 mg/dL/d, p < 0.001; 4.5 mL/min/1.73 m2/d, p < 0.001, respectively). Diuretic Data, Urine Output, and FO During the 7-day study period, patients received 1.8 ± 1.0 different diuretics (range, 0–4). The most commonly administered diuretics were furosemide (40 of 52, 77%) and hydrochlorothiazide (38 of 52, 73%). Of 52 treatment courses, 17 (33%) coincided with at least one dose of bumetanide and six coincided
Figure 1. Average serum creatinine over the aminophylline course. When compared with the day prior to aminophylline administration (day –1), serum creatinine declined significantly while patients received aminophylline (p < 0.001).
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Figure 2. Average glomerular filtration rate over the aminophylline course. When compared with the day prior to aminophylline administration (day –1), estimated glomerular filtration rate (eGFR) increased significantly while patients received aminophylline (p < 0.001).
with at least one dose of metolazone (12%). Figure 3 displays the mean doses of furosemide and hydrochlorothiazide over the aminophylline course and their qualitative relationship to urine output. Linear mixed-effects regression models demonstrated that during the aminophylline treatment course, furosemide dose increased significantly (+0.12 ± 0.04 mg/kg/d, p = 0.01), but there was no significant increase in hydrochlorothiazide dose (+0.23 ± 0.22 mg/kg/d, p = 0.29). Similarly, the linear mixed-effects regression models demonstrated a significant increase in urine output (+0.22 ± 0.04 mL/kg/hr/d, p < 0.001) and a concomitant significant decrease in FO (–0.42% ± 0.15% per day, p = 0.005) over the aminophylline treatment course. Total mean fluid intake was not significantly different on day –1 compared with days 0–5 of aminophylline dosing
Figure 3. Diuretics and urine output over time. Average (Avg) diuretic doses (in mg/kg/d) were calculated among patients who received those diuretics. When compared with the day prior to aminophylline administration, urine output (asterisk) (p < 0.001) and furosemide dose (closed square) (p = 0.01) increased significantly. The dose of hydrochlorothiazide (closed circle) did not increase significantly (p = 0.29). January 2014 • Volume 15 • Number 1
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(p = 0.27–0.88). When only the first aminophylline course for each patient was considered, hydrochlorothiazide dose and urine output increased (+0.17 mg/kg/d, p < 0.01; +0.23 mL/kg/hr/d, p < 0.001, respectively), whereas FO decreased (–0.39% per day, p = 0.04) and furosemide dosing remained unchanged (+0.03 mg/kg/d, p = 0.56). Complications One patient required hemodialysis and subsequently died, one had a cerebrovascular accident, and one patient had atrial flutter while being cannulated for ECMO which was successfully cardioverted to sinus tachycardia. Two patients who received aminophylline had a history of tachycardia. One patient had a history of atrioventricular reciprocating tachycardia (AVRT), and amiodarone therapy was prescribed to treat the underlying dysrhythmia; no tachycardia occurred during the aminophylline treatment course. The second patient had a history of ventricular tachycardia (VT) and experienced recurrent VT 4 days after cessation of aminophylline therapy; the VT was successfully controlled with amiodarone administration. No other episodes of tachyarrhythmia occurred. No patients experienced clinical seizures. Review of the daily progress notes did not reveal any evidence of vomiting, nausea, irritability, or insomnia during the aminophylline treatment courses.
DISCUSSION In this study, we administered aminophylline to children admitted to the CVICU who experienced oliguric AKI refractory to standard diuretic therapy. We found that initiation of aminophylline therapy was associated with a significant reduction in serum creatinine values and a concomitant improvement in estimated renal excretory function. Additionally, aminophylline was associated with increased urine output and a reduction in overall FO burden. There were no major ICU complications associated with aminophylline administration in this critically ill pediatric cardiac population. However, because this was not a randomized trial, we cannot confirm the safety of aminophylline. Our findings are consistent with prior studies of aminophylline in a number of different pediatric populations. Both Jenik et al (22) and Bakr (23) performed randomized controlled trials of theophylline in asphyxiated term neonates and found improved renal function in their treatment groups. Similarly, Bhat et al (24) studied a single theophylline dose in term neonates with asphyxia; creatinine and urinary β-2-microglobulin excretion decreased after treatment. Bell et al (26) studied patients in the PICU who were diuretic dependent and reported an increase in urine output of more than 80% in patients treated with a single dose of aminophylline. Other studies of adenosine receptor antagonists, however, have contradicted these findings. The most notable of these was the Placebo-controlled Randomized study of the selective A1-adenosine receptor antagonist rolofylline for patients hospitalised with AHF and volume Overload to assess Treatment Effect on Congestion and renal function (PROTECT) study of more than 2,000 adult patients with acute congestive heart failure and renal failure (36). In that Pediatric Critical Care Medicine
population, rolofylline administration resulted in a decrease in mean body weight but did not impact the prevalence of renal failure. Although this is a large and powerful study among adults, rolofylline, unlike aminophylline, inhibits only a single adenosine receptor subtype. Additionally, it is possible that its findings do not strictly translate to the pediatric CVICU population, since adult congestive heart failure often coexists with chronic systemic venous hypertension, diabetes mellitus, and arterial hypertension. Our preliminary study, although significantly smaller, does suggest that in the pediatric CVICU population, aminophylline may improve both renal function and augment urine output in the setting of oliguric AKI. Aminophylline has similar pharmacokinetic properties to theophylline. Peak serum concentration is reached within 30 minutes after an IV dose, and the elimination half-life varies with age: approximately 3.5 hours for children, 8.5 hours for adults, and as high as 20 hours for premature neonates (37). Based on the pharmacokinetic data and previously published reports (22, 23, 26, 38), we initiated IV aminophylline therapy with a 5 mg/kg load followed by a 1.8 mg/kg dose every 6 hours. We targeted a theophylline concentration of 5–10 μg/ mL, which is approximately half the concentration targeted when aminophylline is used to treat bronchoconstriction (39). Aminophylline and theophylline affect the renal vasculature by nonspecifically blocking adenosine receptors at theophylline concentrations of 2–3 μg/mL and by inhibiting type IV phosphodiesterase at theophylline concentrations of more than 10 μg/mL (26). During the study period, we were able to maintain average concentrations of approximately 7 μg/mL without side effects, such as tachyarrhythmias or clinical seizures. Even in two patients with a history of documented tachycardia (VT and AVRT), aminophylline was used safely and did not result in exacerbation of the underlying arrhythmia. Additionally, no patients required adenosine therapy for the diagnosis or treatment of arrhythmias during our study period. Because aminophylline blocks adenosine receptors, careful attention to the dosing of adenosine is required for patients receiving aminophylline (specifically, higher doses of adenosine may be required). The complications described in our patients did not appear to be temporally related to aminophylline dosing; however, the retrospective nature of this study limits our ability to state this with certainty. The ability to reverse or mitigate renal dysfunction and improve urine output and fluid balance is critically important given the morbidity and mortality effects associated with AKI and FO. AKI in children undergoing corrective cardiac surgery has been independently associated with longer length of stay, a greater need for mechanical ventilation, and higher hospital mortality rates (2, 4). FO, which is commonly associated with AKI, has also been associated with longer duration of mechanical ventilation, poorer oxygenation, prolonged ICU and hospital length of stay, and greater mortality (10, 11). The deleterious effects of FO may be even more pronounced in children with heart failure or following cardiac surgery as it leads to increased tissue edema in the lungs and chest wall; management of these complications often leads to longer lengths of www.pccmjournal.org
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stay with increased risk for nosocomial infections. Given the morbidity and mortality associated with AKI and FO, the ability to mitigate these complications may have beneficial effects on patient outcomes. It is possible that preventing or reducing the severity of AKI and effectively treating FO could shorten ICU stays and lessen morbidity and mortality. Our retrospective study has several limitations, and it is important to interpret our results in their context. Improvement in eGFR and urine output could have been caused by an improved cardiac function over time. Although mean IS did decrease during the treatment course, we have no objective measures of cardiac output to suggest that improved cardiac function led to improved creatinine clearance and urine output. It is also important to note that patients were receiving diuretics during the period of aminophylline administration; thus, it is likely that these medications contributed to the effects on urine output and FO. However, it is unlikely that the diuretics are responsible for the creatinine and eGFR improvements seen in our study as diuretics have been associated with worsening renal function (13, 14). Third, it was not possible to analyze the complete medication administration record for each patient, and it is therefore possible that elimination of nephrotoxins contributed to the improved renal function. Additionally, although all patients in the study were admitted to the CVICU and experienced renal dysfunction, the patient diagnoses and underlying causes of AKI are not uniform. Aminophylline dosing was not uniform in our patients, although serum concentrations were similar in patients with different dosing regimens. Laboratory evaluation of serum theophylline concentrations was not performed on a standard schedule, since the use of aminophylline in this study was monitored by the attending physician and not part of a randomized trial. Similarly, the timing of aminophylline administration was not uniform because patients experienced AKI at variable times after their initial CVICU admission. Unfortunately, the small size of our cohort did not allow for subgroup analyses. Thus, it is possible that our findings are not generalizable to all CVICU populations or types of AKI. Additionally, the diagnosis of AKI was made entirely on clinical grounds. Future studies should include more specific creatinine-based definitions of AKI, such as pediatric Risk, Injury, Failure, Loss, End-Stage, Acute Kidney Injury Network, or KDIGO (7, 31, 40).
CONCLUSIONS In conclusion, this is the first report of the use of aminophylline specifically in pediatric cardiac patients with oliguric AKI. We found that aminophylline may augment the effect of conventional diuretic therapies, while also reducing serum creatinine concentrations and improving estimated creatinine clearance. We believe that further prospective study of aminophylline in the setting of oliguric AKI in the pediatric CVICU is warranted.
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