Population Pharmacokinetics of Caffeine in Neonates with Congenital Heart Disease and Associations with Acute Kidney Injury.

Cardiac surgery-associated acute kidney injury (CS-AKI) occurs in approximately 65% of neonates undergoing cardiac surgery on cardiopulmonary bypass and contributes to morbidity and mortality. Caffeine may reduce CS-AKI by counteracting adenosine receptor upregulation after bypass, but pharmacokinetics (PK) in this population are unknown. The goal of our analysis is to address knowledge gaps in age-, disease-, and bypass-related effects on caffeine disposition and explore preliminary associations between caffeine exposure and CS-AKI using population PK modeling techniques and an opportunistic, electronic health record-integrated trial design. We prospectively enrolled neonates receiving preoperative caffeine per standard of care and collected PK samples. We retrospectively identified neonates without caffeine exposure undergoing surgery on bypass as a control cohort. We followed US Food and Drug Administration guidance for population PK model development using NONMEM. Effects of clinical covariates on PK parameters were evaluated. We simulated perioperative exposures and used multivariable logistic regression to evaluate the association between caffeine exposure and CS-AKI. Twenty-seven neonates were included in model development. A 1-compartment model with bypass time as a covariate on clearance and volume of distribution best fit the data. Twenty-three neonates with caffeine exposure and 109 controls were included in the exposure-response analysis. Over half of neonates developed CS-AKI. On multivariable analysis, there were no significant differences between CS-AKI with and without caffeine exposure. Neonates with single-ventricle heart disease without CS-AKI had consistently higher simulated caffeine exposures. Our results highlight areas for further study to better understand disease- and bypass-specific effects on drug disposition and identify populations where caffeine may be beneficial.

Using Pharmacokinetic Modeling and Electronic Health Record Data to Predict Clinical and Safety Outcomes after Methylprednisolone Exposure during Cardiopulmonary Bypass in Neonates.

Background: Infants undergoing cardiac surgery with cardiopulmonary bypass (CPB) frequently receive intraoperative methylprednisolone (MP) to suppress CPB-related inflammation; however, the optimal dosing strategy and efficacy of MP remain unclear. Methods: We retrospectively analyzed all infants under 90 days-old who received intra-operative MP for cardiac surgery with CPB from 2014-2017 at our institution. We combined real-world dosing data from the electronic health record (EHR) and two previously developed population pharmacokinetic/pharmacodynamic models to simulate peak concentration (Cmax) and area under the concentration-time curve for 24 h (AUC24) for MP and the inflammatory cytokines interleukin-6 (IL-6) and interleukin-10 (IL-10). We evaluated the relationships between post-operative, safety, and other clinical outcomes obtained from the EHR with each predicted exposure using non-parametric tests. Results: A total of 142 infants with median post-natal age 8 (interquartile range [IQR]: 5, 37) days received a total dose of 30 (19, 49) mg/kg of MP. Twelve (8%) died, 37 (26%) met the composite post-operative outcome, 114 (80%) met the composite safety outcome, and 23 (16%) had a major complication. Predicted median Cmax and AUC24 IL-6 exposure was significantly higher for infants meeting the composite post-operative outcome and those with major complications. Predicted median Cmax and AUC24 MP exposure was significantly higher for infants requiring insulin. No exposure was associated with death or other safety outcomes. Conclusions: Pro-inflammatory IL-6, but not MP exposure, was associated with post-operative organ dysfunction, suggesting current MP dosing may not adequately suppress IL-6 or increase IL-10 to impact clinical outcomes. Prospective study will be required to define the optimal exposure-efficacy and exposure-safety profiles in these infants.

Association of Urine Biomarkers With Acute Kidney Injury and Fluid Overload in Infants After Cardiac Surgery: A Single Center Ancillary Cohort of the Steroids to Reduce Systemic Inflammation After Infant Heart Surgery Trial.

To examine the association between three perioperative urine biomarker concentrations (urine cystatin C [uCysC], urine neutrophil gelatinase-associated lipocalin [uNGAL], and urine kidney injury molecule 1 [uKIM-1]), and cardiac surgery-associated acute kidney injury (CS-AKI) and fluid overload (FO) in infants with congenital heart disease undergoing surgery on cardiopulmonary bypass. To explore how urine biomarkers are associated with distinct CS-AKI phenotypes based on FO status. DESIGN: Ancillary prospective cohort study. SETTING: Single U.S. pediatric cardiac ICU. PATIENTS: Infants less than 1 year old enrolled in the Steroids to Reduce Systemic Inflammation after Infant Heart Surgery trial (NCT03229538) who underwent heart surgery from June 2019 to May 2020 and opted into biomarker collection at a single center. Infants with preoperative CS-AKI were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty infants met inclusion criteria. Median (interquartile) age at surgery was 103 days (5.5-161 d). Modified Kidney Disease Improving Global Outcomes-defined CS-AKI was diagnosed in 22 (55%) infants and 21 (53%) developed FO. UCysC and uNGAL peaked in the early postoperative period and uKIM-1 peaked later. In unadjusted analysis, bypass time was longer, and Vasoactive-Inotropic Score at 24 hours was higher in infants with CS-AKI. On multivariable analysis, higher uCysC (odds ratio [OR], 1.023; 95% CI, 1.004-1.042) and uNGAL (OR, 1.019; 95% CI, 1.004-1.035) at 0-8 hours post-bypass were associated with FO. UCysC, uNGAL, and uKIM-1 did not significantly correlate with CS-AKI. In exploratory analyses of CS-AKI phenotypes, uCysC and uNGAL were highest in CS-AKI+/FO+ infants. CONCLUSIONS: In this study, uCysC and uNGAL in the early postoperative period were associated with FO at 48 hours. UCysC, uNGAL, and uKIM-1 were not associated with CS-AKI. Further studies should focus on defining expected concentrations of these biomarkers, exploring CS-AKI phenotypes and outcomes, and establishing clinically meaningful endpoints for infants post-cardiac surgery.

A systematic review of clinical study evidence for pulmonary vasodilator therapy following surgery with cardiopulmonary bypass in children with CHD.

OBJECTIVES: Complications from pulmonary hypertension are one of the leading contributors to morbidity and mortality post-cardiopulmonary bypass surgery in children with CHD. Pulmonary vasodilator therapies are commonly used post-operatively, but the optimal target patient population, therapy choice, timing of therapy initiation, and duration of therapy are not well defined. METHODS: We used PubMed and EMBASE to identify studies from 2000 to 2020 investigating the use of pulmonary vasodilator therapy post-cardiopulmonary bypass in children aged 0-18 years. To ensure eligibility criteria, studies were systematically reviewed by two independent reviewers. RESULTS: We identified 26 studies of 42,971 children across four medication classes; 23 were single centre, 14 were prospective, and 11 involved randomisation (four of which employed a placebo-control arm). A disproportionate number of children were from a single retrospective study of 41,872 patients. Definitions varied, but change in pulmonary haemodynamics was the most common primary outcome, used in 14 studies. Six studies had clinical endpoints, with mortality the primary endpoint for two studies. Treatment with inhaled nitric oxide, iloprost, and sildenafil all resulted in improved haemodynamics in specific cohorts of children with post-operative pulmonary hypertension, although improved outcomes were not consistently demonstrated across all treated children. Iloprost may be a cheaper alternative to inhaled nitric oxide with similar haemodynamic response. CONCLUSION: Studies were predominantly single-centre, a control arm was rarely used in randomised studies, and haemodynamic endpoints varied significantly. Further research is needed to reduce post-operative morbidity and mortality from pulmonary hypertension in children with CHD.

Association Between Digoxin Use and Cardiac Function in Infants With Single-Ventricle Congenital Heart Disease During the Interstage Period.

OBJECTIVES: To examine the association between digoxin use and cardiac function assessed by echocardiographic indices in infants with single-ventricle (SV) congenital heart disease (CHD) during the interstage period. DESIGN: Retrospective cohort study. SETTING: Fifteen North American hospitals. PATIENTS: Infants discharged home following stage 1 palliation (S1P) and prior to stage 2 palliation (S2P). Infants with no post-S1P and pre-S2P echocardiograms were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 373 eligible infants who met inclusion criteria, 140 (37.5%) were discharged home on digoxin. In multivariable linear and logistic regressions, we found that compared with infants discharged home without digoxin, those discharged with digoxin had a smaller increase in end-systolic volume (ß = -8.17 [95% CI, -15.59 to -0.74]; p = 0.03) and area (ß = -1.27 [-2.45 to -0.09]; p = 0.04), as well as a smaller decrease in ejection fraction (ß = 3.38 [0.47-6.29]; p = 0.02) and fractional area change (ß = 2.27 [0.14-4.41]; p = 0.04) during the interstage period. CONCLUSIONS: Digoxin may partially mitigate the expected decrease in cardiac function during the interstage period through its positive inotropic effects. Prospective clinical trials are needed to establish the pharmacokinetics, safety, and efficacy of digoxin use in SV CHD.

A systematic review of the evidence supporting post-operative antithrombotic use following cardiopulmonary bypass in children with CHD.

OBJECTIVES: To determine the optimal antithrombotic agent choice, timing of initiation, dosing and duration of therapy for paediatric patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: We used PubMed and EMBASE to systematically review the existing literature of clinical trials involving antithrombotics following cardiac surgery from 2000 to 2020 in children 0-18 years. Studies were assessed by two reviewers to ensure they met eligibility criteria. RESULTS: We identified 10 studies in 1929 children across three medications classes: vitamin K antagonists, cyclooxygenase inhibitors and indirect thrombin inhibitors. Four studies were retrospective, five were prospective observational cohorts (one of which used historical controls) and one was a prospective, randomised, placebo-controlled, double-blind trial. All included were single-centre studies. Eight studies used surrogate biomarkers and two used clinical endpoints as the primary endpoint. There was substantive variability in response to antithrombotics in the immediate post-operative period. Studies of warfarin and aspirin showed that laboratory monitoring levels were frequently out of therapeutic range (variably defined), and findings were mixed on the association of these derangements with bleeding or thrombotic events. Heparin was found to be safe at low doses, but breakthrough thromboembolic events were common. CONCLUSION: There are few paediatric prospective randomised clinical trials evaluating antithrombotic therapeutics post-cardiac surgery; most studies have been observational and seldom employed clinical endpoints. Standardised, validated endpoints and pragmatic trial designs may allow investigators to determine the optimal drug, timing of initiation, dosing and duration to improve outcomes by limiting post-operative morbidity and mortality related to bleeding or thrombotic events.

A systematic review of the evidence supporting post-operative diuretic use following cardiopulmonary bypass in children with Congenital Heart Disease.

BACKGROUND: Paediatric cardiac surgery on cardiopulmonary bypass induces substantial physiologic changes that contribute to post-operative morbidity and mortality. Fluid overload and oedema are prevalent complications, routinely treated with diuretics. The optimal diuretic choice, timing of initiation, dose, and interval remain largely unknown. METHODS: To guide clinical practice and future studies, we used PubMed and EMBASE to systematically review the existing literature of clinical trials involving diuretics following cardiac surgery from 2000 to 2020 in children aged 0-18 years. Studies were assessed by two reviewers to ensure that they met eligibility criteria. RESULTS: We identified nine studies of 430 children across four medication classes. Five studies were retrospective, and four were prospective, two of which included randomisation. All were single centre. There were five primary endpoints - urine output, acute kidney injury, fluid balance, change in serum bicarbonate level, and required dose of diuretic. Included studies showed early post-operative diuretic resistance, suggesting higher initial doses. Two studies of ethacrynic acid showed increased urine output and lower diuretic requirement compared to furosemide. Children receiving peritoneal dialysis were less likely to develop fluid overload than those receiving furosemide. Chlorothiazide, acetazolamide, and tolvaptan demonstrated potential benefit as adjuncts to traditional diuretic regimens. CONCLUSIONS: Early diuretic resistance is seen in children following cardiopulmonary bypass. Ethacrynic acid appears superior to furosemide. Adjunct diuretic therapies may provide additional benefit. Study populations were heterogeneous and endpoints varied. Standardised, validated endpoints and pragmatic trial designs may allow investigators to determine the optimal diuretic, timing of initiation, dose, and interval to improve post-operative outcomes.

A systematic review of the evidence supporting post-operative medication use in congenital heart disease.

BACKGROUND: Targeted drug development efforts in patients with CHD are needed to standardise care, improve outcomes, and limit adverse events in the post-operative period. To identify major gaps in knowledge that can be addressed by drug development efforts and provide a rationale for current clinical practice, this review evaluates the evidence behind the most common medication classes used in the post-operative care of children with CHD undergoing cardiac surgery with cardiopulmonary bypass. METHODS: We systematically searched PubMed and EMBASE from 2000 to 2019 using a controlled vocabulary and keywords related to diuretics, vasoactives, sedatives, analgesics, pulmonary vasodilators, coagulation system medications, antiarrhythmics, steroids, and other endocrine drugs. We included studies of drugs given post-operatively to children with CHD undergoing repair or palliation with cardiopulmonary bypass. RESULTS: We identified a total of 127 studies with 51,573 total children across medication classes. Most studies were retrospective cohorts at single centres. There is significant age- and disease-related variability in drug disposition, efficacy, and safety. CONCLUSION: In this study, we discovered major gaps in knowledge for each medication class and identified areas for future research. Advances in data collection through electronic health records, novel trial methods, and collaboration can aid drug development efforts in standardising care, improving outcomes, and limiting adverse events in the post-operative period.

An evidence-based review of the use of vasoactive and inotropic medications in post-operative paediatric patients after cardiac surgery with cardiopulmonary bypass from 2000 to 2020.

BACKGROUND: Infants with moderate-to-severe CHD frequently undergo cardiopulmonary bypass surgery in childhood. Morbidity and mortality are highest in those who develop post-operative low cardiac output syndrome. Vasoactive and inotropic medications are mainstays of treatment for these children, despite limited evidence supporting their use. METHODS: To help inform clinical practice, as well as the conduct of future trials, we performed a systematic review of existing literature on inotropes and vasoactives in children after cardiac surgery using the PubMed and EMBASE databases. We included studies from 2000 to 2020, and the patient population was defined as birth - 18 years of age. Two reviewers independently reviewed studies to determine final eligibility. RESULTS: The final analysis included 37 papers. Collectively, selected studies reported on 12 different vasoactive and inotropic medications in 2856 children. Overall evidence supporting the use of these drugs in children after cardiopulmonary bypass was limited. The majority of studies were small with 30/37 (81%) enrolling less than 100 patients, 29/37 (78%) were not randomised, and safety and efficacy endpoints differed widely, limiting the ability to combine data for meta-analyses. CONCLUSION: Vasoactive and inotropic support remain critical parts of post-operative care for children after cardiopulmonary bypass surgery. There is a paucity of data for the selection and dosing of vasoactives and inotropes for these patients. Despite the knowledge gaps that remain, numerous recent innovations create opportunities to rethink the conduct of clinical trials in this high-risk population.

Association between preoperative respiratory support and outcomes in paediatric cardiac surgery.

BACKGROUND: Preoperative mechanical ventilation is associated with morbidity and mortality following CHD surgery, but prior studies lack a comprehensive analysis of how preoperative respiratory support mode and timing affects outcomes. METHODS: We retrospectively collected data on children <18 years of age undergoing cardiac surgery at an academic tertiary care medical centre. Using multivariable regression, we examined the association between modes of preoperative respiratory support (nasal cannula, high-flow nasal cannula/noninvasive ventilation, or invasive mechanical ventilation), escalation of preoperative respiratory support, and invasive mechanical ventilation on the day of surgery for three outcomes: operative mortality, postoperative length of stay, and postoperative complications. We repeated our analysis in a subcohort of neonates. RESULTS: A total of 701 children underwent 800 surgical procedures, and 40% received preoperative respiratory support. Among neonates, 243 patients underwent 253 surgical procedures, and 79% received preoperative respiratory support. In multivariable analysis, all modes of preoperative respiratory support, escalation in preoperative respiratory support, and invasive mechanical ventilation on the day of surgery were associated with increased odds of prolonged length of stay in children and neonates. Children (odds ratio = 3.69, 95% CI 1.2-11.4) and neonates (odds ratio = 8.97, 95% CI 1.31-61.14) on high-flow nasal cannula/noninvasive ventilation had increased odds of operative mortality compared to those on room air. CONCLUSION: Preoperative respiratory support is associated with prolonged length of stay and mortality following CHD surgery. Knowing how preoperative respiratory support affects outcomes may help guide surgical timing, inform prognostic conversations, and improve risk stratification models.

Sildenafil Exposure in the Neonatal Intensive Care Unit.

OBJECTIVE: Pulmonary hypertension causes substantial morbidity and mortality in infants. Although Food and Drug Administration approved to treat pulmonary arterial hypertension in adults, sildenafil is not approved for infants. We sought to describe sildenafil exposure and associated diagnoses and outcomes in infants. STUDY DESIGN: Retrospective cohort of neonates discharged from more than 300 neonatal intensive care units from 2001 to 2016. RESULTS: Sildenafil was administered to 1,336/1,161,808 infants (0.11%; 1.1 per 1,000 infants); 0/35,977 received sildenafil in 2001 versus 151/90,544 (0.17%; 1.7 per 1,000 infants) in 2016. Among infants <32 weeks' gestational age (GA) with enough data to determine respiratory outcome, 666/704 (95%) had bronchopulmonary dysplasia (BPD). Among infants ≥32 weeks GA, 248/455 (55%) had BPD and 76/552 (14%) were diagnosed with meconium aspiration. Overall, 209/921 (23%) died prior to discharge. CONCLUSION: The use of sildenafil has increased since 2001. Exposed infants were commonly diagnosed with BPD. Further studies evaluating dosing, safety, and efficacy of sildenafil are needed.

Association of Atrial Septal Defects and Bronchopulmonary Dysplasia in Premature Infants.

OBJECTIVE: To evaluate the association between the presence of an atrial septal defect (ASD) and the odds of developing bronchopulmonary dysplasia (BPD) in premature infants. STUDY DESIGN: We identified a cohort of infants that underwent at least one echocardiogram assessment, birth weight 501-1249 g, and gestational age 23-30 weeks discharged from the neonatal intensive care unit from 2004 to 2016. We used a BPD risk estimator to calculate the predicted risk of developing BPD at 6 postnatal ages within the first 28 days of life. We examined the association between the presence of an ASD and the development of BPD using 2 multivariable logistic regression models for each BPD risk severity on each postnatal day. The first model adjusted for predicted BPD risk and the second added therapeutic interventions for BPD. RESULTS: Of 20 496 infants from 228 NICUs who met inclusion criteria, 8892 (43%) were diagnosed with BPD and 1314 (6%) had an ASD. BPD was present in 48% of infants with an ASD and 43% of infants without an ASD. In infants with an ASD, the OR of developing BPD was higher after adjusting for predicted risk of BPD plus therapeutic interventions, regardless of postnatal age or predicted BPD risk severity. CONCLUSIONS: The presence of an ASD was associated with an increased odds of BPD in this cohort. Future trials should consider ASD as a potentially modifiable risk factor in this vulnerable population.

Acetylcysteine and fenoldopam. Promising new approaches for preventing effects of contrast nephrotoxicity.

The prevalence of nephrotoxic effects after administration of contrast material is increasing. Other than good hydration before the radiological procedure, previous attempts to prevent the effects of contrast nephrotoxicity have been ineffective. Fenoldopam and acetylcysteine are possible preventive medications being used in selected cases. Both drugs await approval from the Food and Drug Administration for use in preventing contrast-induced nephrotoxic effects. The onset of action of the 2 drugs differs, and each drug has different pharmacological actions. Determining which drug should be used is based on whether the patient can be given anything by mouth, whether the procedure is emergent, cost, degree of renal insufficiency before the radiological procedure, blood pressure, and whether the patient has diabetes. Further studies will determine if one drug is preferred over the other or if their combined use is the preferred approach for high-risk patients. Future options could include an intravenous form of acetylcysteine and an oral form of fenoldopam.