Effects of aminophylline therapy on urine output and kidney function in children with acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is a frequent complication of children admitted to the paediatric intensive care unit. One key management modality of AKI is the use of diuretics to reduce fluid overload. Aminophylline, a drug that is well known for its use in the treatment of bronchial asthma, is also purported to have diuretic effects on the kidneys. This retrospective cohort study assesses the effect of aminophylline in critically ill children with AKI. METHODS: A retrospective chart review of children admitted to the paediatric intensive care unit of the Red Cross War Memorial Children's Hospital (RCWMCH) with AKI who received aminophylline (from 2012 to June 2018) was carried out. Data captured and analyzed included demographics, underlying disease conditions, medications, urine output, fluid balance, and kidney function. RESULTS: Data from thirty-four children were analyzed. Urine output increased from a median of 0.4 mls/kg/hr [IQR: 0.1, 1.1] at six hours prior to aminophylline administration to 0.6 mls/kg/hr [IQR: 0.2, 1.9] at six hours and 1.6 mls/kg/hr [IQR:0.2, 4.2] at twenty-four hours post aminophylline therapy. The median urine output significantly varied across the age groups over the 24-h time period post-aminophylline, with the most response in the neonates. There was no significant change in serum creatinine levels six hours post-aminophylline administration [109(IQR: 77, 227)-125.5(IQR: 82, 200) micromole/l] P-value = 0.135. However, there were significant age-related changes in creatinine levels at six hours post-aminophylline therapy. CONCLUSIONS: Aminophylline increases urine output in critically ill children with AKI. A higher resolution version of the Graphical abstract is available as Supplementary information.

Wide Institutional Variability in the Treatment of Pediatric Critical Asthma: A Multicenter Retrospective Study.

OBJECTIVES: Children with status asthmaticus refractory to first-line therapies of systemic corticosteroids and inhaled beta-agonists often receive additional treatments. Because there are no national guidelines on the use of asthma therapies in the PICU, we sought to evaluate institutional variability in the use of adjunctive asthma treatments and associations with length of stay (LOS) and PICU use. DESIGN: Multicenter retrospective cohort study. SETTING: Administrative data from the Pediatric Health Information Systems (PHIS) database. PATIENTS: All inpatients 2-18 years old were admitted to a PHIS hospital between 2013 and 2021 with a diagnostic code for asthma. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: This study included 213,506 inpatient encounters for asthma, of which 29,026 patient encounters included care in a PICU from 39 institutions. Among these PICU encounters, large variability was seen across institutions in both the number of adjunctive asthma therapies used per encounter (min: 0.6, median: 1.7, max: 2.5, p < 0.01) and types of adjunctive asthma therapies (aminophylline, ipratropium, magnesium, epinephrine, and terbutaline) used. The center-level median hospital LOS ranged from 1 (interquartile range [IQR]: 1, 3) to 4 (3, 6) days. Among all the 213,506 inpatient encounters for asthma, the range of asthma admissions that resulted in PICU admission varied between centers from 5.2% to 47.3%. The average number of adjunctive therapies used per institution was not significantly associated with hospital LOS ( p = 0.81) nor the percentage of encounters with PICU admission ( p = 0.47). CONCLUSIONS: Use of adjunctive therapies for status asthmaticus varies widely among large children's hospitals and was not associated with hospital LOS or the percentage of encounters with PICU admission. Wide variance presents an opportunity for standardizing care with evidence-based guidelines to optimize outcomes and decrease adverse treatment effects and hospital costs.

Lipolytic agents for submental fat reduction: Review.

RESULT: The review delves into the realm of reducing submental fat, presenting a comprehensive analysis of various lipolytic agents used in plastic surgery and dermatology. The introduction establishes the context by defining the key indicators of a youthful neck and emphasizing the significant influence of fat in the aging process, particularly in the submental area. The usage of aminophylline involves subcutaneous injections, facilitating fat breakdown by increasing cyclic adenosine monophosphate and inhibiting adenosine receptors. Hypotonic pharmacologic lipo-dissolution induces fat dissolution via injected compounds under pressure, while lipolytic lymphatic drainage employs hyaluronidase to reduce tissue viscosity, aiding fat circulation. Glycerophosphorylcholine containing choline alfoscerate claims to activate fat metabolism, whereas the utilization of phosphatidylcholine combined with deoxycholate lacks cosmetic approval due to safety concerns. Deoxycholic acid has FDA approval for submental fat reduction, yet its mechanisms remain incompletely understood. Understanding the complex anatomy and mechanisms of lipolytic agents is essential for safe and effective submental fat reduction, despite evolving practices and off-label utilization. Clinical guidelines and references support this discussion, offering insights for safer applications.

Effects of Intracerebral Aminophylline Dosing on Catalepsy and Gait in an Animal Model of Parkinson's Disease.

Parkinson's disease (PD) is a progressive disorder characterized by the apoptosis of dopaminergic neurons in the basal ganglia. This study explored the potential effects of aminophylline, a non-selective adenosine A1 and A2A receptor antagonist, on catalepsy and gait in a haloperidol-induced PD model. Sixty adult male Swiss mice were surgically implanted with guide cannulas that targeted the basal ganglia. After seven days, the mice received intraperitoneal injections of either haloperidol (experimental group, PD-induced model) or saline solution (control group, non-PD-induced model), followed by intracerebral infusions of aminophylline. The assessments included catalepsy testing on the bar and gait analysis using the Open Field Maze. A two-way repeated-measures analysis of variance (ANOVA), followed by Tukey's post hoc tests, was employed to evaluate the impact of groups (experimental × control), aminophylline (60 nM × 120 nM × saline/placebo), and interactions. Significance was set at 5%. The results revealed that the systemic administration of haloperidol in the experimental group increased catalepsy and dysfunction of gait that paralleled the observations in PD. Co-treatment with aminophylline at 60 nM and 120 nM reversed catalepsy in the experimental group but did not restore the normal gait pattern of the animals. In the non-PD induced group, which did not present any signs of catalepsy or motor dysfunctions, the intracerebral dose of aminophylline did not exert any interference on reaction time for catalepsy but increased walking distance in the Open Field Maze. Considering the results, this study highlights important adenosine interactions in the basal ganglia of animals with and without signs comparable to those of PD. These findings offer valuable insights into the neurobiology of PD and emphasize the importance of exploring novel therapeutic strategies to improve patient's catalepsy and gait.

Adenosine and γ-aminobutyric acid partially regulate metabolic and ventilatory responses of Damaraland mole-rats to acute hypoxia.

Fossorial Damaraland mole-rats (Fukomys damarensis) mount a robust hypoxic metabolic response (HMR) but a blunted hypoxic ventilatory response (HVR) to acute hypoxia. Although these reflex physiological responses have been described previously, the underlying signalling pathways are entirely unknown. Of particular interest are contributions from γ-aminobutyric acid (GABA), which is the primary inhibitory neurotransmitter in the nervous system of most adult mammals, and adenosine, the accumulation of which increases during hypoxia as a breakdown product of ATP. Therefore, we hypothesized that GABAergic and/or adenosinergic signalling contributes to the blunted HVR and robust HMR in Damaraland mole-rats. To test this hypothesis, we injected adult animals with saline alone (controls), or 100 mg kg-1 aminophylline or 1 mg kg-1 bicuculline, to block adenosine or GABAA receptors, respectively. We then used respirometry, plethysmography and thermal RFID probes to non-invasively measure metabolic, ventilator and thermoregulatory responses, respectively, to acute hypoxia (1 h in 5 or 7% O2) in awake and freely behaving animals. We found that bicuculline had relatively minor effects on metabolism and thermoregulation but sensitized ventilation such that the HVR became manifest at 7% instead of 5% O2 and was greater in magnitude. Aminophylline increased metabolic rate, ventilation and body temperature in normoxia, and augmented the HMR and HVR. Taken together, these findings indicate that adenosinergic and GABAergic signalling play important roles in mediating the robust HMR and blunted HVR in Damaraland mole-rats.

Safety and efficacy of IV theophylline for regadenoson-associated side effect reversal.

BACKGROUND: Aminophylline injection has been on an intermittent nation-wide shortage due to manufacturing delays leaving a need for an alternative reversal agent for regadenoson-associated side effects. Intravenous theophylline should be a logical acceptable pharmacological alternative; however, data regarding its safety and efficacy as a reversal agent are lacking. METHODS: Utilizing electronic medical records at the University of Colorado hospital, we identified patients ≥ 18 years of age who had a pharmacologic stress test using regadenoson during periods of aminophylline shortage (3/1/2013 to 5/31/2013 and 4/1/2018 to 8/30/2018) in which theophylline was used as an alternative antidote for side effect reversal. Intravenous theophylline was prepared by the inpatient pharmacy to a concentration of 0.8 mg/mL in a total volume of 100 mL D5W. Specific side effects and side effect resolution were evaluated. RESULTS: Of the 122 patients evaluated, theophylline was administered in doses ranging from 40 to 75 mg with the majority receiving 40 mg. Complete resolution of regadenoson side effects occurred in 98 patients with 12 experiencing partial resolution and 1 without resolution. No adverse effects or events were reported. CONCLUSION: Due to limited availability of aminophylline, theophylline may be a safe and effective alternative to reverse regadenoson-associated side effects.

Buccal caffeine strips for reversal of adverse symptoms of vasodilator stress.

BACKGROUND: Due to recurrent shortages of aminophylline, intravenous caffeine has emerged as a commonly used, safe and reliable method to treat adverse effects of vasodilator stress agents. We sought to evaluate the safety and effectiveness of buccal caffeine strips which are rapidly absorbed, inexpensive, readily available, and simplify caffeine administration. METHODS: Consecutive patients undergoing regadenoson stress SPECT MPI were assessed for the occurrence of symptoms during testing over an 11-week period at a single metropolitan hospital. Adverse symptoms, including their severity and duration, were recorded at the time of testing. Patient satisfaction was rated on a scale of 1 to 5 (5 being the most satisfied). Patients received reversal with caffeine if symptoms were felt to be significant enough by the patient and physician performing the test. The treatment received alternated week to week between IV caffeine (60 mg) or 100 mg buccal caffeine strips. Caffeine was given at least 3 minutes after tracer injection. A rescue dose of IV caffeine was offered 10 minutes later if indicated. RESULTS: Of the 122 patients enrolled in the study, 70 (57%) were included during buccal caffeine weeks and 52 (43%) during IV caffeine weeks, and only 28 (24%) received reversal with a caffeine agent. Seven (6%) received IV caffeine and 21 (17%) received buccal caffeine. There was no significant difference in symptom duration between IV and buccal caffeine after treatment (152.8 vs 163.4 seconds, P = 0.87). There was no significant difference in initial and final symptom severity between groups. Only 2 patients in the buccal group required rescue IV caffeine for ongoing symptoms and emesis. None of the IV group required a rescue dose. There was no significant difference in patient satisfaction between the groups (2.8 vs 3.2, P = 0.38). CONCLUSION: Buccal caffeine strips are a safe, well tolerated, and effective initial strategy to reverse adverse effects of vasodilator stress in the minority of patients who request it. Buccal caffeine alone or with IV rescue caffeine was highly effective in reversing adverse effects and was free of major adverse clinical events.

Ultrasensitive SERS substrate for label-free therapeutic drug monitoring of chlorpromazine hydrochloride and aminophylline in human serum.

Surface-enhanced Raman spectroscopy (SERS) has been widely used in the field of therapeutic drug monitoring (TDM) because of its powerful fingerprinting capability. In this paper, we used an in situ synthesis method to anchor Ag nanoparticles (AgNPs) on the surface of MIL-101(Cr) to obtain MIL-101(Cr)@Ag. Owing to the large specific surface area and ultra-high porosity of MIL-101(Cr)@Ag, we developed a method for the determination of chlorpromazine hydrochloride (CPZ) and aminophylline (AMP) in human serum by using it as a solid-phase extraction sorbent and SERS substrate. The label-free TDM-SERS method was able to evaluate the levels of CPZ and AMP in serum samples with detection limits as low as 8.91 × 10-2 µg/mL and 3.4 × 10-2 µg/mL, respectively. In addition, influencing factors including sample solution pH, AgNO3 concentration, drug adsorption time, and the amount of sample solution were optimized. This protocol provides a new method with good selectivity, stability, reproducibility, homogeneity, and sensitivity for the determination of small-molecule drug content in serum samples. This label-free TDM-SERS method will help to achieve rapid individualized dosing regimens in clinical practice and has potential applications in the field of TDM.

The diuretic effect of adding aminophylline or theophylline to furosemide in pediatric populations: a systematic review.

The diuretic effect of the combined furosemide and aminophylline/theophylline among pediatric patients remains unclear. The primary aim of this systematic review was to examine the clinical diuretic effects (urine output and fluid balance) of co-administration of furosemide and aminophylline/theophylline as compared to furosemide alone in pediatric population. Ovid MEDLINE, CENTRAL, and EMBASE were searched from its inception until March 2022 for observational studies and randomized controlled trials (RCTs) comparing the administration of furosemide versus furosemide and aminophylline/theophylline in pediatric population. Case reports, case series, commentaries, letters to editors, systematic reviews, and meta-analyses were excluded. Five articles with a total sample population of 187 patients were included in this systematic review. As compared to the furosemide alone, our pooled data demonstrated that co-administration of furosemide and aminophylline/theophylline was associated with higher urine output (mean difference: 2.91 [90% CI 1.54 to 4.27], p < 0.0001, I2 = 90%) and a more negative fluid balance (mean difference - 28.27 [95% CI: - 46.21 to - 10.33], p = 0.002, I2 = 56%) than those who received furosemide alone. CONCLUSION: This is the first paper summarizing the evidence of combined use of furosemide with aminophylline/theophylline in pediatric population. Our systematic review demonstrated that the co-administration of furosemide and aminophylline/theophylline could potentially yield better diuretic effects of urine output and negative fluid balance than furosemide alone in pediatric patients with fluid overload. Given the substantial degree of heterogeneity and low level of evidence, future adequately powered trials are warranted to provide evidence regarding the combined use of aminophylline/theophylline and furosemide as diuretic in the pediatric population. WHAT IS KNOWN: • Fluid overload is associated with poor prognosis for children in the intensive care unit. • The ineffective result of furosemide alone, even at high dose, as diuretic agent for children with diuretic resistant fluid overload in the intensive care unit. WHAT IS NEW: • This is the first systematic review that compares furosemide alone and co-administration of furosemide and aminophylline/theophylline. • This paper showed potential benefit of co-administration of furosemide and aminophylline/theophylline promoting urine output and negative fluid balance compared to furosemide alone.

Doxapram for the prevention and treatment of apnea in preterm infants.

BACKGROUND: Apnea of prematurity is a common problem in preterm infants that may have significant consequences on their development. Methylxanthines (aminophylline, theophylline, and caffeine) are effective in the treatment of apnea of prematurity. Doxapram is used as a respiratory stimulant in cases refractory to the methylxanthine treatment. OBJECTIVES: To evaluate the benefits and harms of doxapram administration on the incidence of apnea and other short-term and longer-term clinical outcomes in preterm infants. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was March 2023. SELECTION CRITERIA: We included randomized controlled trials (RCTs) assessing the role of doxapram in prevention and treatment of apnea of prematurity and prevention of reintubation in preterm infants (less than 37 weeks' gestation). We included studies comparing doxapram with either placebo or methylxanthines as a control group, or when doxapram was used as an adjunct to methylxanthines and compared to methylxanthines alone as a control group. We included studies of doxapram at any dose and route. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were clinical apnea, need for positive pressure ventilation after initiation of treatment, failed apnea reduction after two to seven days, and failed extubation (defined as unable to wean from invasive intermittent positive pressure ventilation [IPPV] and extubate or reintubation for IPPV within one week). We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included eight RCTs enrolling 248 infants. Seven studies (214 participants) provided data for meta-analysis. Five studied doxapram for treatment of apnea in preterm infants. Three studied doxapram to prevent reintubation in preterm infants. None studied doxapram in preventing apnea in preterm infants. All studies administered doxapram intravenously as continuous infusions. Two studies used doxapram as an adjunct to aminophylline compared to aminophylline alone and one study as an adjunct to caffeine compared to caffeine alone. When used to treat apnea, compared to no treatment, doxapram may result in a slight reduction in failed apnea reduction (risk ratio [RR] 0.45, 95% confidence interval [CI] 0.20 to 1.05; 1 study, 21 participants; low-certainty evidence). The evidence is very uncertain about the effect of doxapram on need for positive pressure ventilation after initiation of treatment (RR 0.31, 95% CI 0.01 to 6.74; 1 study, 21 participants; very low-certainty evidence). Doxapram may result in little to no difference in side effects causing cessation of therapy (0 events in both groups; risk difference [RD] 0.00, 95% CI -0.17 to 0.17; 1 study, 21 participants; low-certainty evidence). Compared to alternative treatment, the evidence is very uncertain about the effect of doxapram on failed apnea reduction (RR 1.35, 95% CI 0.53 to 3.45; 4 studies, 84 participants; very low-certainty evidence). The evidence is very uncertain about the effect of doxapram on need for positive pressure ventilation after initiation of treatment (RR 2.40, 95% CI 0.11 to 51.32; 2 studies, 37 participants; very-low certainty evidence; note 1 study recorded 0 events in both groups. Thus, the RR and CIs were calculated from 1 study rather than 2). Doxapram may result in little to no difference in side effects causing cessation of therapy (0 events in all groups; RD 0.00, 95% CI -0.15 to 0.15; 37 participants; 2 studies; low-certainty evidence). As adjunct therapy to methylxanthine, the evidence is very uncertain about the effect of doxapram on failed apnea reduction after two to seven days (RR 0.08, 95% CI 0.01 to 1.17; 1 study, 10 participants; very low-certainty evidence). No studies reported on clinical apnea, chronic lung disease at 36 weeks' postmenstrual age (PMA), death at any time during initial hospitalization, long-term neurodevelopmental outcomes in the three comparisons, and need for positive pressure ventilation and side effects when used as adjunct therapy to methylxanthine. In studies to prevent reintubation, when compared to alternative treatment, the evidence is very uncertain about the effect of doxapram on failed extubation (RR 0.43, 95% CI 0.10 to 1.83; 1 study, 25 participants; very low-certainty evidence). As adjunct therapy to methylxanthine, doxapram may result in a slight reduction in 'clinical apnea' after initiation of treatment (RR 0.36, 95% CI 0.13 to 0.98; 1 study, 56 participants; low-certainty evidence). Doxapram may result in little to no difference in failed extubation (RR 0.92, 95% CI 0.52 to 1.62; 1 study, 56 participants; low-certainty evidence). The evidence is very uncertain about the effect of doxapram on side effects causing cessation of therapy (RR 6.42, 95% CI 0.80 to 51.26; 2 studies, 85 participants; very low-certainty evidence). No studies reported need for positive pressure ventilation, chronic lung disease at 36 weeks' PMA, long-term neurodevelopmental outcomes in the three comparisons; failed extubation when compared to no treatment; and clinical apnea, death at any time during initial hospitalization, and side effects when compared to no treatment or alternative treatment. We identified two ongoing studies, one conducted in Germany and one in multiple centers in the Netherlands and Belgium. AUTHORS' CONCLUSIONS: In treating apnea of prematurity, doxapram may slightly reduce failure in apnea reduction when compared to no treatment and there may be little to no difference in side effects against both no treatment and alternative treatment. The evidence is very uncertain about the need for positive pressure ventilation when compared to no treatment or alternative treatment and about failed apnea reduction when used as alternative or adjunct therapy to methylxanthine. For use to prevent reintubation, doxapram may reduce apnea episodes when administered in adjunct to methylxanthine, but with little to no difference in failed extubation. The evidence is very uncertain about doxapram's effect on death when used as adjunct therapy to methylxanthine and about failed extubation when used as alternative or adjunct therapy to methylxanthine. There is a knowledge gap about the use of doxapram as a therapy to prevent apnea. More studies are needed to clarify the role of doxapram in the treatment of apnea of prematurity, addressing concerns about long-term outcomes. The ongoing studies may provide useful data.

Caffeine versus other methylxanthines for the prevention and treatment of apnea in preterm infants.

BACKGROUND: Methylxanthines, including caffeine, theophylline, and aminophylline, work as stimulants of the respiratory drive, and decrease apnea of prematurity, a developmental disorder common in preterm infants. In particular, caffeine has been reported to improve important clinical outcomes, including bronchopulmonary dysplasia (BPD) and neurodevelopmental disability. However, there is uncertainty regarding the efficacy of caffeine compared to other methylxanthines. OBJECTIVES: To assess the effects of caffeine compared to aminophylline or theophylline in preterm infants at risk of apnea, with apnea, or in the peri-extubation phase. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Epistemonikos, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and clinicaltrials.gov in February 2023. We also checked the reference lists of relevant articles to identify additional studies. SELECTION CRITERIA: Studies: randomized controlled trials (RCTs) and quasi-RCTs Participants: infants born before 34 weeks of gestation for prevention and extubation trials, and infants born before 37 weeks of gestation for treatment trials Intervention and comparison: caffeine versus theophylline or caffeine versus aminophylline. We included all doses and duration of treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We evaluated treatment effects using a fixed-effect model with risk ratio (RR), risk difference (RD), and 95% confidence intervals (CI) for categorical data, and mean, standard deviation, and mean difference for continuous data. We used the GRADE approach to evaluate the certainty of evidence. MAIN RESULTS: We included 22 trials enrolling 1776 preterm infants. The indication for treatment was prevention of apnea in three studies, treatment of apnea in 13 studies, and extubation management in three studies. In three studies, there were multiple indications for treatment, and in one study, the indication for treatment was unclear. In 19 included studies, the infants had a mean gestational age between 28 and 32 weeks and a mean birth weight between 1000 g and 1500 g. One study's participants had a mean gestational age of more than 32 weeks, and two studies had participants with a mean birth weight of 1500 g or more. Caffeine administrated for any indication may result in little to no difference in all-cause mortality prior to hospital discharge compared to other methylxanthines (RR 1.12, 95% CI 0.68 to 1.84; RD 0.02, 95% CI -0.05 to 0.08; 2 studies, 396 infants; low-certainty evidence). Only one study enrolling 79 infants reported components of the outcome moderate to severe neurodevelopmental disability at 18 to 26 months. The evidence is very uncertain about the effect of caffeine on cognitive developmental delay compared to other methylxanthines (RR 0.17, 95% CI 0.02 to 1.37; RD -0.12, 95% CI -0.24 to 0.01; 1 study, 79 infants; very low-certainty evidence). The evidence is very uncertain about the effect of caffeine on language developmental delay compared to other methylxanthines (RR 0.76, 95% CI 0.37 to 1.58; RD -0.07, 95% CI -0.27 to 0.12; 1 study, 79 infants; very low-certainty evidence). The evidence is very uncertain about the effect of caffeine on motor developmental delay compared to other methylxanthines (RR 0.50, 95% CI 0.13 to 1.96; RD -0.07, 95% CI -0.21 to 0.07; 1 study, 79 infants; very low-certainty evidence). The evidence is very uncertain about the effect of caffeine on visual and hearing impairment compared to other methylxanthines. At 24 months of age, visual impairment was seen in 8 out of 11 infants and 10 out of 11 infants in the caffeine and other methylxanthines groups, respectively. Hearing impairment was seen in 2 out of 5 infants and 1 out of 1 infant in the caffeine and other methylxanthines groups, respectively. No studies reported the outcomes cerebral palsy, gross motor disability, and mental development. Compared to other methylxanthines, caffeine may result in little to no difference in BPD/chronic lung disease, defined as 28 days of oxygen exposure at 36 weeks' postmenstrual age (RR 1.40, 95% CI 0.92 to 2.11; RD 0.04, 95% CI -0.01 to 0.09; 3 studies, 481 infants; low-certainty evidence). The evidence is very uncertain about the effect of caffeine on side effects (tachycardia, agitation, or feed intolerance) leading to a reduction in dose or withholding of methylxanthines compared to other methylxanthines (RR 0.17, 95% CI 0.02 to 1.32; RD -0.29, 95% CI -0.57 to -0.02; 1 study, 30 infants; very low-certainty evidence). Caffeine may result in little to no difference in duration of hospital stay compared to other methylxanthines (median (interquartile range): caffeine 43 days (27.5 to 61.5); other methylxanthines 39 days (28 to 55)). No studies reported the outcome seizures. AUTHORS' CONCLUSIONS: Although caffeine has been shown to improve important clinical outcomes, in the few studies that compared caffeine to other methylxanthines, there might be little to no difference in mortality, bronchopulmonary dysplasia, and duration of hospital stay. The evidence is very uncertain about the effect of caffeine compared to other methylxanthines on long-term development and side effects. Although caffeine or other methylxanthines are widely used in preterm infants, there is little direct evidence to support the choice of which methylxanthine to use. More research is needed, especially on extremely preterm infants born before 28 weeks of gestation. Data from four ongoing studies might provide more evidence on the effects of caffeine or other methylxanthines.

A mix of aminophylline and heparin plus nitroglycerin can reduce bradycardia during rotational atherectomy on the right coronary artery and dominant circumflex artery.

BACKGROUND: Rotational atherectomy (RA) may cause bradyarrhythmias and transitory atrioventricular block when performed in the right coronary artery (RCA) or a dominant circumflex (CX) coronary artery. However, there are no studies of a solution that can prevent coronary flow deterioration and bradycardia complications that may occur during RA. We aimed to create an alternative rota-flush solution to minimize the risk of bradycardia and complete atrioventricular block (AVB) that can occur during RA. MATERIALS AND METHODS: The study comprised 60 patients who were randomly divided into two groups: 30 received rotaphylline (= 240 mg aminophylline, 10,000 U unfractionated heparin, and 2000 mcg nitroglycerin to 1000 mL saline), and 30 received the traditional rota-flush (= 10,000 U unfractionated heparin, 2000 mcg nitroglycerin, and 1000 mL saline). The incidence of bradycardia or high-grade AVB (HAVB) during RA, coronary slow-flow phenomenon or no-reflow phenomenon, and coronary spasm were the primary endpoints of the study. Procedure success and RA-related procedural complications were secondary endpoints. RESULTS: The use of rotaphylline was an independent predictor of bradycardia and HAVB after accounting for all other factors (OR: 0.47, 95% CI: 0.24-0.79, p < 0.001). Lesion length (OR: 2.17, 95% CI: 1.24-3.04, p < 0.001), burr-to-artery ratio (OR: 0.59, 95% CI: 0.39-1.68, p < 0.001), and total run duration (OR: 0.79, 95% CI: 0.35-1.43, p < 0.001) were additional independent predictors. CONCLUSION: Bradycardia and the development of HAVB may be avoided by rotaphylline intracoronary infusion during RA applied to the RCA and dominant CX lesions. Multicenter studies including sizable patient populations should be conducted to validate the present findings.

Effects of low-dose furosemide combined with aminophylline on the renal function in septic shock patients.

BACKGROUND: To investigate the effects of low-dose furosemide and aminophylline on the renal function in patients with septic shock. METHODS AND RESULTS: A total of 109 eligible septic shock patients in the intensive care unit were randomly divided into a control group (n = 55) and an intervention group (n = 54). The control group received normal saline, and the intervention group received low-dose furosemide (0.048 mg/kg.h-1) with aminophylline (0.3 mg/kg.h-1). The primary outcomes included the levels of serum creatinine (Scr), creatinine clearance rate (Ccr), blood urea nitrogen (BUN), glomerular filtration rate (GFR), and urine output on admission and on days 3, 7 and 14. The secondary outcomes were the sequential organ failure assessment (SOFA) scores, continuous renal replacement therapy (CRRT) time and intensive care unit (ICU) mortality, hospital mortality and 28-day mortality. There were no significant differences in the levels of Scr, Ccr, BUN, or GFR between the two groups, while the urine output was higher in the intervention group on days 3, 7, and 14. Compared with the control group, the SOFA scores, ICU mortality, hospital mortality and 28-day mortality were significantly lower in the intervention group on days 3, 7, and 14, the CRRT time was shorter, and the cumulative fluid balance was lower on days 3 and 7 in the intervention group. CONCLUSIONS: Although low-dose furosemide and aminophylline have fewer protective effects on the renal function in septic shock patients, they could reduce the CRRT time and improve the prognosis.

Aminophylline at clinically relevant concentrations affects inward rectifier potassium current in a dual way.

Bronchodilator aminophylline may induce atrial or less often ventricular arrhythmias. The mechanism of this proarrhythmic side effect has not been fully explained. Modifications of inward rectifier potassium (Kir) currents including IK1 are known to play an important role in arrhythmogenesis; however, no data on the aminophylline effect on these currents have been published. Hence, we tested the effect of aminophylline (3-100 µM) on IK1 in enzymatically isolated rat ventricular myocytes using the whole-cell patch-clamp technique. A dual steady-state effect of aminophylline was observed; either inhibition or activation was apparent in individual cells during the application of aminophylline at a given concentration. The smaller the magnitude of the control IK1, the more likely the activation of the current by aminophylline and vice versa. The effect was reversible; the relative changes at -50 and -110 mV did not differ. Using IK1 channel population model, the dual effect was explained by the interaction of aminophylline with two different channel populations, the first one being inhibited and the second one being activated. Considering various fractions of these two channel populations in individual cells, varying effects observed in the measured cells could be simulated. We propose that the dual aminophylline effect may be related to the direct and indirect effect of the drug on various Kir2.x subunits forming the homo- and heterotetrameric IK1 channels in a single cell. The observed IK1 changes induced by clinically relevant concentrations of aminophylline might contribute to arrhythmogenesis related to the use of this bronchodilator in clinical medicine.

Alterations in the gut microbiome and metabolome profiles of septic rats treated with aminophylline.

The treatment of sepsis remains a major challenge worldwide. Aminophylline has been shown to have anti-inflammatory effects; however, the role of aminophylline in sepsis, a disease characterized by immune dysregulation, is unknown. In this study, we combined microbiome sequencing and metabolomic assays to investigate the effect of aminophylline administration on the intestinal flora and metabolites in septic rats. Sixty SD rats were randomly divided into three groups: a sham-operated (SC) group, a sepsis model (CLP) group and a CLP + aminophylline treatment (Amino) group. The intestinal flora and metabolic profile of rats in the CLP group were significantly different than those of the SC group, while aminophylline administration resulted in a return to a state similar to healthy rats. Differential abundance analysis showed that aminophylline significantly back-regulated the abundance of Firmicutes, unidentified_Bacteria, Proteobacteria, Lactobacillus, Escherichia-Shigella and other dominant bacteria (P < 0.05) and altered chenodeoxycholic acid, isolithocholic acid and a total of 26 metabolites (variable importance in the projection (VIP) > 1, P < 0.05). In addition, we found that there were significant correlations between differential metabolites and bacterial genera of the Amino and CLP groups. For example, Escherichia-Shigella was associated with 12 metabolites, and Lactobacillus was associated with two metabolites (P < 0.05), suggesting that differences in the metabolic profiles caused by aminophylline were partly dependent on its influence on the gutmicrobiome. In conclusion, this study identified a novel protective mechanism whereby aminophylline could regulate disordered intestinal flora and metabolites in septic rats.

Intravesical aminophylline instillation as an alternative for balloon dilatation prior to semi-rigid ureteroscopic management of distal ureteral stones.

PURPOSE: In a randomized controlled trial, we evaluated the effect of intravesical aminophylline instillation (IVAI) on intraureteral pressure of lower ureter and its use as an alternative to balloon dilatation after failure of advancing semi-rigid ureteroscope through the ureteric orifice without endodilatation. METHODS: Our study included 83 patients with juxta-vesical distal ureteral calculi requiring endodilatation after unsuccessfully introducing the semi-rigid ureteroscope through the ureteric orifice. Patients were randomized into two groups: group A (study group) included 41 patients, where IVAI was used to dilate the ureter and facilitate ureteroscopy (the intraureteral pressure was measured using a pressure transducer connected to an invasive pressure monitor before and 5 min after IVAI), whereas group B (control group) included 42 patients, where balloon dilatation was used prior to ureteroscopy. Perioperative surgical outcomes of ureteroscopy were evaluated in both groups. RESULTS: A statistically significant decrease in mean intraureteral pressure of intravesical ureter was found after IVAI from 12.34 mmHg ± 1.94 before injection to 8.46 mmHg ± 1.94 after injection (P < 0.001). Ureteral injuries, postoperative pain and hematuria were statistically significantly less among the study group compared to the control group (P < 0.05). We did not find statistically significant differences in operative time, need for DJ ureteral stenting or stone-free rate between both groups and no perioperative side effects were associated with IVAI. CONCLUSION: In ureteroscopic management of distal ureteral stones, intravesical aminophylline instillation is safe, inexpensive and effective in reducing intraureteral pressure and achieves comparable outcomes to balloon dilatation with less ureteral injuries, postoperative pain and hematuria.

Plasma Concentration Detection of Aminophylline with Multi-Walled Carbon Nanotube-Modified Electrodes in the Treatment of Ticagrelor-Related Dyspnea.

It was aimed at the plasma concentration detection of aminophylline under multi-walled carbon nanotube (MWNT) modified electrodes and the curative effect of aminophylline for ticagrelor-related dyspnea (TRD). 120 patients with TRD and coronary atherosclerotic heart disease (CAHD) in Wuhan Sixth Hospital Hospital were randomly divided into an intervention group and a control group, with 60 cases in each. The novel chitosan/gold nanoparticles-MWNTs (CTS/Au NPs-MWNTs) composite was prepared for studying the electrochemical behaviors of aminophylline on the electrodes. The clinical curative effect of aminophylline, as well as the levels of peripheral blood T lymphocyte subsets and inflammatory cytokines, was observed in the treatment of TRD. The actual plasma molar concentration of aminophylline was 23.6-47.8 µmol/L. After treatment, the total effective rate in the intervention group was higher than that in the control group significantly (95% VS 65%) (P<0.05). The forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) of the intervention group were better than those of the control group remarkably (P<0.05). The intervention group showed lower levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 as well as the higher IL-10 significantly in serum compared with the control group (P<0.05). After follow-up, there was no cardiovascular death in either group. The CTS/Au NPs-MWNTs could be used for detecting the plasma concentration of aminophylline in blood samples. Aminophylline could notably relieve the clinical symptoms, reduce the inflammatory response, and regulate the immunity of patients with good safety.

Use of ketamine in patients with refractory severe asthma exacerbations: systematic review of prospective studies.

PURPOSE: Asthma is a heterogeneous disease with a wide range of symptoms. Severe asthma exacerbations (SAEs) are characterized by worsening symptoms and bronchospasm requiring emergency department visits. In addition to conventional strategies for SAEs (inhaled ß-agonists, anticholinergics, and systemic corticosteroids), another pharmacological option is represented by ketamine. We performed a systematic review to explore the role of ketamine in refractory SAEs. METHODS: We performed a systematic search on PubMed and EMBASE up to August 12th, 2021. We selected prospective studies only, and outcomes of interest were oxygenation/respiratory parameters, clinical status, need for invasive ventilation and effects on weaning. RESULTS: We included a total of seven studies, five being randomized controlled trials (RCTs, population range 44-92 patients). The two small prospective studies (n = 10 and n = 11) did not have a control group. Four studies focused on adults, and three enrolled a pediatric population. We found a large heterogeneity regarding sample size, age and gender distribution, inclusion criteria (different severity scores, if any) and ketamine dosing (bolus and/or continuous infusion). Of the five RCTs, three compared ketamine to placebo, while one used fentanyl and the other aminophylline. The outcomes evaluated by the included studies were highly variable. Despite paucity of data and large heterogeneity, an overview of the included studies suggests absence of clear benefit produced by ketamine in patients with refractory SAE, and some signals towards side effects. CONCLUSION: Our systematic review does not support the use of ketamine in refractory SAE. A limited number of prospective studies with large heterogeneity was found. Well-designed multicenter RCTs are desirable.

Risk factors that affect the degree of bronchopulmonary dysplasia in very preterm infants: a 5-year retrospective study.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is one of the most common adverse consequence of premature delivery and the most common chronic lung disease in infants. BPD is associated with long-term lung diseases and neurodevelopmental disorders that can persist into the adulthood. The adverse consequences caused by severe BPD are more serious. However, there were few studies on the risk factors for severe BPD. METHODS: This is a retrospective study of preterm infants born less than 32-week gestational age (GA) and diagnosed with BPD. RESULTS: A total of 250 preterm infants with a diagnosis of BPD and GA < 32 weeks were included (137 boys [54.8%] and 113 girls [45.2%]). The birth weight ranged from 700 g to 2010 g and the mean birth weight was 1318.52 g (255.45 g). The GA ranged from 25 weeks to 31 weeks and 6 days (mean, 30 weeks). The number of cases of mild, moderate and severe BPD were 39 (15.6%), 185 (74.0%) and 26 (10.4%), respectively. There were significant differences in the rate of small for gestational age (SGA), intrauterine asphyxia, pulmonary hemorrhage, neonatal respiratory distress syndrome (NRDS), circulatory failure, pulmonary hypertension, patent ductus arteriosus (PDA), pulmonary surfactant (PS), aminophylline, caffeine, glucocorticoids, tracheal intubation, diuretics, and parenteral nutrition length among the three groups (P < 0.05). The time of parenteral nutrition (aOR = 3.343, 95%CI: 2.198 ~ 5.085) and PDA (aOR =9.441, 95%CI: 1.186 ~ 75.128) were independent risk factors for severe BPD compared with mild BPD. PDA (aOR = 5.202, 95%CI: 1.803 ~ 15.010) and aminophylline (aOR = 6.179, 95%CI: 2.200 ~ 17.353) were independent risk factors for severe BPD, while caffeine (aOR = 0.260, 95%CI: 0.092 ~ 0.736) was the protective factor for severe BPD compared with moderate BPD. The time of parenteral nutrition (aOR = 2.972, 95%CI: 1.989 ~ 4.440) and caffeine (aOR = 4.525, 95%CI: 1.042 ~ 19.649) were independent risk factors for moderate BPD compared with mild BPD. Caffeine (aOR = 3.850, 95%CI: 1.358 ~ 10.916) was the independent risk factor for moderate BPD, while PDA (aOR = 0.192, 95%CI: 0.067 ~ 0.555) and aminophylline (aOR = 0.162, 95%CI: 0.058 ~ 0.455) were protective factors for moderate BPD compared with severe BPD. The time of parenteral nutrition (aOR = 0.337, 95%CI: 0.225 ~ 0.503) and caffeine (aOR = 0.221, 95%CI: 0.051 ~ 0.960) were protective factors for mild BPD compared with moderate BPD. The time of parenteral nutrition (aOR = 0.299, 95%CI: 0.197 ~ 0.455) and PDA (aOR = 0.106, 95%CI: 0.013 ~ 0.843) were protective factors for mild BPD compared with severe BPD. CONCLUSION: The time of parenteral nutrition is the risk factor of moderate and severe BPD. PDA and aminophylline are risk factors for severe BPD. The role of caffeine in the severity of BPD is uncertain, and SGA is not related to the severity of BPD. Severe or moderate BPD can be avoided by shortening duration of parenteral nutrition, early treatment of PDA, reducing use of aminophylline and rational use of caffeine. TRIAL REGISTRATION: Retrospectively registered.

Aminophylline in combination with caffeine citrate in neurodevelopmental treatment and follow-up of high-risk preterm infants using GMs assessment.

To explore the application effect of aminophylline combined with caffeine citrate and GMs in the evaluation of neurodevelopmental treatment and follow-up in high-risk preterm infants. A retrospective analysis of 66 high-risk preterm infants admitted to Hengshui People's Hospital from January 2020 to June 2021 was conducted. The children who received only conventional treatment were set as the control group, while those who received aminophylline and caffeine citrate on the basis of conventional treatment were set as the experimental group, 33 cases each group; GMs were used to evaluate the neurodevelopmental function of the children, and the treatment effect was analyzed. The normal proportion of GMs assessment results in the twisting phase and restless movement phase of the experimental group was superior to the control group (P<0.05); The proportion of children with normal neurodevelopment in the experimental group was significantly higher than that in the control group (P<0.05). Aminophylline in combination with caffeine citrate can help promote the neurodevelopment of children and improve their physical health using GMs assessment in the treatment and follow-up of high-risk preterm infants.