Edited by: James Donald Fortenberry, Children’s Healthcare of Atlanta, USA; Emory University School of Medicine, USA
Reviewed by: Rajit Basu, Cincinnati Children’s Hospital Medical Center, USA; Michael Shoykhet, Washington University in St. Louis School of Medicine, USA; Christopher W. Mastropietro, Riley Hospital for Children, USA
This article was submitted to Pediatric Critical Care, a section of the journal Frontiers in Pediatrics.
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Aminophylline, the ethylenediamine salt of theophylline, is a well-established medication that promotes bronchodilatation by increasing the tissue concentrations of cyclic adenine monophosphate (cAMP) via phosphodiesterase inhibition (
Given these potential renal and anti-inflammatory benefits, and its well-established benefit on bronchoconstriction, aminophylline may benefit a number of critically ill children with a variety of conditions. However, the data to support the use of aminophylline in this patient population is not well established. We undertook a prospective, open-label, and single arm study of the physiologic effects of aminophylline in a tertiary care pediatric intensive care unit (PICU). We hypothesized that aminophylline use would augment urine output and decrease inflammation in critically ill children.
All patients less than 18 years of age admitted to the PICU who were prescribed aminophylline were screened for inclusion. Patients were excluded if they weighed less than 2.3 kg or if their initial hemoglobin concentration was less than 8 g/dL to minimize the risk associated with the extra blood draw required for the study. The Institutional Review Board of the Pennsylvania State University College of Medicine approved the protocol and informed consent was obtained for all patients enrolled.
The use and dosing of aminophylline was independent of the study and was at the discretion of the clinical team. In our PICU, aminophylline administration is protocolized using an intermittent dosing regimen with a goal theophylline trough of 4–8 μg/mL (Figure
Data were collected at baseline prior to the administration of aminophylline, and then again, 24 h after the initiation of therapy. Collected data consisted of demographics, diagnoses, medications, and vital signs. In addition, data were obtained to assess the impact of aminophylline on renal function, inflammation, and pulmonary function as described below.
Data collected for the assessment of renal function consisted of serum blood urea nitrogen (BUN) and creatinine concentrations, diuretic use, and urine output. For the baseline determination of urine output, the previous 24 h prior to aminophylline administration was used. If urine was not collected for an entire 24 h prior to the aminophylline administration, the urine output for the entire time period prior to aminophylline administration was determined and standardized in terms of milliliters per kilogram per hour. Urine output was also determined by age group to assess if a relationship existed between aminophylline effect and age.
Data collected for the assessment of inflammation consisted of white blood cell counts, C-reactive protein (CRP) concentrations, glucose concentrations, and anti-inflammatory medication use. Those patients with elevated CRP concentrations, defined
Data collected relevant to the assessment of pulmonary function included blood gas results, pulse oximeter recordings, and ventilator settings. Additionally, airway resistance and compliance (both static and dynamic) were determined for intubated patients using the assessment tools of the Servo-I ventilator (Maquet Critical Care, Rastatt, Germany) with the patient sedated and not actively breathing over the ventilator.
Descriptive statistics were performed for all variables; means, standard errors of the mean, medians, and interquartile ranges (IQR). There were two primary outcomes of interest; the effect of aminophylline on urine output and on concentrations of inflammatory cytokines with its impact on pulmonary function being a secondary outcome of interest. Consequently, a Wilcoxon Signed Rank test was performed to compare 24-h after aminophylline therapy values to baseline. To account for potential confounding effects of concomitant medications, total dosages were quantitated and four of the authors (Steven E. Lucking, Gary D. Ceneviva, Neal J. Thomas, Robert F. Tamburro) reviewed all medications and independently determined if there was an increase, a decrease, or no change in the dosing of other diuretics (for renal analysis) and anti-inflammatory medications (for inflammation analysis) across the two time points of the study. The authors were blinded to all outcomes of interest at the time of these determinations. If the authors were not in concordance, the case was discussed until all differences were resolved. A subset analysis was performed on only those patients who received the same or less of these other medications for their respective assessments. An alpha value of 0.05 defined statistical significance. Statistical analyses were performed using version 9 of the SAS statistical software program (SAS Institute, Inc., Cary, NC, USA).
Thirty-six patients were enrolled; 35 were available for analysis because one patient died within hours of enrollment (Figure
Variables | |
---|---|
Mean | 51.5 ± 11.5 |
Median | 14.8 [IQR: 1.6, 102.5] |
Males | 23 (66%) |
Females | 12 (34%) |
White | 23 (66%) |
Hispanic | 10 (29%) |
African American | 2 (6%) |
Bronchiolitis | 9 (26%) |
Cardiac disease | 6 (17%) |
Sepsis | 6 (17%) |
Pneumonia | 4 (11%) |
Bronchopulmonary dysplasia | 3 (9%) |
Near drowning | 2 (6%) |
Neuromuscular disease | 2 (6%) |
Tracheal ring | 1 (3%) |
Thoracic mass | 1 (3%) |
Status asthmaticus | 1 (3%) |
Bilateral disease | 27 (77%) |
Unilateral disease | 3 (9%) |
Clear | 5 (14%) |
Invasive ventilation | 28 (80%) |
BiLevel Positive Airway Pressure (BiPAP) | 3 (9%) |
Nasal cannula | 2 (6%) |
High flow nasal cannula (VapoTherm®) | 1 (3%) |
Face mask | 1 (3%) |
Thirty-four patients had pre- and post-aminophylline urine output assessed; one patient was excluded from this analysis because of concomitant diabetes insipidus. Among these 34 patients, the urine output increased from a median of 3.5 [IQR: 2.0, 5.0] at baseline to 4.2 [IQR: 2.7, 5.6] at 24-h with a median increase of 1.0 mL/kg/h ([IQR: −0.1, 1.5],
Variable | Baseline value | 24-h value | |
---|---|---|---|
Urine output |
3.6 ± 0.4 (3.5 [2.0, 5.0]) | 4.7 ± 0.5 (4.2 [2.7, 5.6]) | 0.0004 |
BUN |
20.7 ± 3.1 (13.5 [8.0, 27.0]) | 22.5 ± 3.9 (15.0 [9.0, 25.0]) | 0.16 |
Creatinine |
0.70 ± 0.15 (0.38 [0.27, 0.55]) | 0.75 ± 0.19 (0.34 [0.30, 0.55]) | 0.99 |
Urine output |
3.6 ± 0.5 (3.4 [1.9, 5.1]) | 4.4 ± 0.6 (3.5 [2.3, 5.5]) | 0.05 |
BUN |
24.0 ± 4.0 (14.5 [10.5, 33.5]) | 26.7 ± 5.1 (15.0 [10.0, 28.0]) | 0.15 |
Creatinine |
0.75 ± 0.18 (0.41 [0.32, 0.69]) | 0.81 ± 0.24 (0.37 [0.31, 0.66]) | 0.30 |
Thirty-one patients received concomitant diuretics during the study period. Ten patients received increased diuretic therapy during the 24 h of aminophylline therapy. Consequently, urine output was assessed among the 24 patients that received the same or less concomitant diuretics during the 24 h after the start of aminophylline as during the previous 24 h. Within this subset, the urine output significantly increased with a median increase of 0.5 mL/kg/h per patient ([IQR: −0.3, 1.3],
In an attempt to determine if there was an effect of age on response to aminophylline, urine output was assessed by age group among the 24 patients that received the same or less concomitant diuretics during the 24 h after the start of aminophylline. Although the numbers are small in each age group, aminophylline appeared to be more effective in the children less than 10 years of age as compared to those over 10 years of age (Figure
There was no change in white blood cell count or glucose concentration between the two time points and comparable results were obtained for these parameters for both the entire cohort and for the subset with elevated CRP concentrations (Table
Variable | Baseline value | 24-h value | |
---|---|---|---|
White blood cell |
11.4 ± 2.0 (9.4 [7.5, 11.2]) | 10.9 ± 1.6 (10.0 [6.5, 12.8]) | 0.76 |
Glucose |
125.6 ± 8.7 (119 [97, 145]) | 127.7 ± 7.9 (121 [106, 143]) | 0.99 |
IL-6 |
156.1 ± 89.7 (27.0 [9.4, 172.0]) | 37.3 ± 13.9 (9.4 [4.3, 20.0]) | <0.0001 |
IL-8 |
199.7 ± 69.3 (89 [51, 141]) | 202.7 ± 98.1 (64 [34, 99]) | 0.05 |
IL-10 |
211.5 ± 113.1 (40.0 [20.0, 58.0]) | 72.9 ± 34.6 (21.0 [14.0, 33.0]) | 0.001 |
TNF-alpha |
15.4 ± 3.1 (12.0 [7.5, 17.0]) | 11.0 ± 1.6 (8.5 [6.8, 12.0]) | 0.26 |
IL-6 |
180.2 ± 105.9 (27.0 [12.7, 183.0]) | 42.4 ± 16.3 (7.6 [4.3, 56.5]) | <0.0001 |
IL-8 |
218.7 ± 81.7 (85.5 [49.5, 164.0]) | 225.4 ± 116.1 (61.0 [33.5, 157.0]) | 0.09 |
IL-10 |
106.1 ± 53.5 (33.0 [16.5, 48.5]) | 78.7 ± 41.0 (17.0 [13.5, 30.0]) | 0.009 |
TNF-alpha |
12.8 ± 2.5 (10.5 [6.8, 14.0]) | 10.8 ± 1.9 (8.0 [6.5, 12.0]) | 0.26 |
Twenty-eight patients received invasive mechanical ventilation at baseline; three others required non-invasive bilateral positive airway pressure. Twenty-seven (77%) patients had bilateral lung involvement based on their chest radiograph (Table
Twenty-four patients were invasively ventilated at both time points (prior to aminophylline and at 24-h after the start of aminophylline) and underwent assessment of respiratory function. Among this group, there were no statistically significant differences in static compliance (median change 0.40 mL/cm H2O [IQR: −0.45, 0.80],
Entire cohort intubated and ventilated at both time points ( |
|||
---|---|---|---|
Variable | Baseline value | 24-h value | |
Static compliance |
9.5 ± 2.1 (4.4 [2.8, 14.6]) | 12.4 ± 3.0 (5.3 [3.0, 16.4]) | 0.33 |
Dynamic compliance |
8.6 ± 1.9 (3.7 [2.3, 14.7]) | 11.3 ± 3.0 (4.0 [2.3, 18.4]) | 0.08 |
Resistance |
106.1 ± 13.8 (100 [34, 137]) | 102.3 ± 19.5 (79 [34, 142]) | 0.29 |
pH | 7.42 ± 0.01 (7.43 [7.39, 7.47]) | 7.46 ± 0.01 (7.46 [7.42, 7.49]) | 0.002 |
SF ratio |
240 ± 14 (232.5 [190, 325]) | 248 ± 15 (245 [194, 323.3]) | 0.17 |
Aminophylline was administered as a continuous infusion in 3 of the 35 (9%) patients; the others received it via intermittent dosing. Among the three patients who received aminophylline as a continuous infusion, the 24-h serum theophylline concentrations were 10.5, 12.1, and 13.9 μg/mL. The median 24-h serum trough theophylline concentration for the patients who received intermittent dosing was 3.7 with a range of 1.1–9.4 μg/mL [IQR: 2.8, 5.8].
Side effects were identified in 7 of the 35 patients (20%) (all receiving intermittent dosing) during their intensive care course, primarily occurring
Diagnoses | Side effect | Day | Associated clinical condition |
---|---|---|---|
S/P cardiopulmonary arrest | Increased NG output | 3 | Cardiomyopathy |
Hypoxic ischemic encephalopathy | |||
Pneumonia | PVCs/bradycardia | 2 | Pulmonary hypertension |
Obstructive sleep apnea | Sinus arrhythmia | PVCs resolved with potassium and magnesium therapy | |
Severe septic shock AML | SVT/VT Junctional tachycardia | 3 | Hypotensive, febrile, oliguric, acidotic; died 3 days later |
ASD repaired 11 years ago | |||
Severe septic shock Necrotizing enterocolitis | SVT | 3 | SVT occurred following albuterol and aminophylline dose; resolved with vagal maneuver |
Pneumonia | Sinus tachycardia | 2 | Heart rate in the 190–210 |
SMA type 1 | |||
RSV bronchiolitis TOF (previously repaired) | PACs | 2 | PACs resolved with potassium |
RSV bronchiolitis | Agitation | 7 |
In this prospective, open-label, single arm, single center study, the use of aminophylline in critically ill children appeared to be associated with an increase in urine output and a decrease in cytokines of paramount importance to the inflammatory process.
The use of aminophylline for renal protection from acute kidney injury (AKI) is not novel. The efficacy of aminophylline for renal protection has been reported in cisplatin- (
The purported renal benefits of aminophylline have been attributed to two mechanisms: adenosine receptor blockade at low dosage and type IV phosphodiesterase inhibition at high levels. Adenosine is the putative mediator of tubuloglomerular feedback (
In addition to its effect on the kidneys, significant reductions in cytokines IL-6, IL-10, and to a lesser degree IL-8, were detected following 24 h of aminophylline therapy. Aminophylline has been found to influence the immune response in other reports. Studies have demonstrated that aminophylline can suppress the release of eosinophil cationic protein (
The mechanism by which aminophylline suppresses inflammation is not entirely established. It has been demonstrated that its anti-inflammatory effect can occur at doses significantly smaller than typical bronchodilator doses (i.e., concentrations lower than those needed to produce phosphodiesterase inhibition) (
Additionally, aminophylline exerts a number of beneficial effects on pulmonary function via phosphodiesterase inhibition, adenosine receptor antagonism, and increased catecholamine release. In addition to bronchodilation, it has also been found to decrease mucosal edema (
Any conclusions drawn from this report regarding aminophylline use must be tempered by the obvious study limitations, and the potential for significant side effects. First, the uncontrolled design of this study confounds any definitive interpretation of the results. It is impossible to determine if the improvement in urine output and the reductions reported in cytokine concentrations were truly the result of aminophylline therapy or the natural course of disease. Although the study patients consisted of a diverse group of diagnoses at variable stages of their disease course, a true effect of aminophylline on urine output and inflammation can only be discerned with the use of an appropriate control group. Second, the study is limited by the small sample size and the diverse patient population. Although the small sample size clearly limits the analysis of the study data and its extrapolation, it is important to note that this study population is larger than any of the previous reports assessing the diuretic and anti-inflammatory properties of aminophylline in critically ill infants and children. Moreover, an analysis by age group was conducted to minimize some of the heterogeneity associated with the large age range of study patients. Finally, the apparent benefits of aminophylline therapy for this patient population must be balanced against the potential for adverse sequelae associated with its use. Although pulmonary, renal and inflammatory effects were assessed for only 24 h, side effects beyond the 24-h study period were reported for completeness.
In light of these clear and acknowledged weaknesses and concerns, the results of this study cannot be considered definitive and the use of aminophylline cannot be routinely recommended for the purposes of augmenting urine output and/or decreasing inflammation in critically ill children. Current national guidelines only suggest that a single dose of theophylline may be administered to neonates with severe perinatal asphyxia at risk for AKI (
Neal Thomas serves as a consultant for Discovery Laboratories and receives funding for his efforts. Gretchen Brummel works as a consultant for Lexicomp, a “Pharma-free” drug information vendor, and receives pay for her services. She is a former Lexicomp employee. Robert Tamburro and Neal Thomas receive funding including salary support from the United States Food and Drug Administration Office of Orphan Product Development Grant Program. We have no other conflicts to disclose.
This study was conducted with the financial support of the Children’s Miracle Network of Penn State Hershey Children’s Hospital.