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.

Simulated Assessment of Pharmacokinetically Guided Dosing for Investigational Treatments of Pediatric Patients With Coronavirus Disease 2019.

Importance: Children of all ages appear susceptible to severe acute respiratory syndrome coronavirus 2 infection. To support pediatric clinical studies for investigational treatments of coronavirus disease 2019 (COVID-19), pediatric-specific dosing is required. Objective: To define pediatric-specific dosing regimens for hydroxychloroquine and remdesivir for COVID-19 treatment. Design, Setting, and Participants: Pharmacokinetic modeling and simulation were used to extrapolate investigated adult dosages toward children (March 2020-April 2020). Physiologically based pharmacokinetic modeling was used to inform pediatric dosing for hydroxychloroquine. For remdesivir, pediatric dosages were derived using allometric-scaling with age-dependent exponents. Dosing simulations were conducted using simulated pediatric and adult participants based on the demographics of a white US population. Interventions: Simulated drug exposures following a 5-day course of hydroxychloroquine (400 mg every 12 hours × 2 doses followed by 200 mg every 12 hours × 8 doses) and a single 200-mg intravenous dose of remdesivir were computed for simulated adult participants. A simulation-based dose-ranging study was conducted in simulated children exploring different absolute and weight-normalized dosing strategies. Main Outcomes and Measures: The primary outcome for hydroxychloroquine was average unbound plasma concentrations for 5 treatment days. Additionally, unbound interstitial lung concentrations were simulated. For remdesivir, the primary outcome was plasma exposure (area under the curve, 0 to infinity) following single-dose administration. Results: For hydroxychloroquine, the physiologically based pharmacokinetic model analysis included 500 and 600 simulated white adult and pediatric participants, respectively, and supported weight-normalized dosing for children weighing less than 50 kg. Geometric mean-simulated average unbound plasma concentration values among children within different developmental age groups (32-35 ng/mL) were congruent to adults (32 ng/mL). Simulated unbound hydroxychloroquine concentrations in lung interstitial fluid mirrored those in unbound plasma and were notably lower than in vitro concentrations needed to mediate antiviral activity. For remdesivir, the analysis included 1000 and 6000 simulated adult and pediatric participants, respectively. The proposed pediatric dosing strategy supported weight-normalized dosing for participants weighing less than 60 kg. Geometric mean-simulated plasma area under the time curve 0 to infinity values among children within different developmental age-groups (4315-5027 ng × h/mL) were similar to adults (4398 ng × h/mL). Conclusions and Relevance: This analysis provides pediatric-specific dosing suggestions for hydroxychloroquine and remdesivir and raises concerns regarding hydroxychloroquine use for COVID-19 treatment because concentrations were less than those needed to mediate an antiviral effect.

Dexmedetomidine Pharmacokinetics and a New Dosing Paradigm in Infants Supported With Cardiopulmonary Bypass.

BACKGROUND: Dexmedetomidine is increasingly used off-label in infants and children with cardiac disease during cardiopulmonary bypass (CPB) and in the postoperative period. Despite its frequent use, optimal dosing of dexmedetomidine in the setting of CPB has not been identified but is expected to differ from dosing in those not supported with CPB. This study had the following aims: (1) characterize the effect of CPB on dexmedetomidine clearance (CL) and volume of distribution (V) in infants and young children; (2) characterize tolerance and sedation in patients receiving dexmedetomidine; and (3) identify preliminary dosing recommendations for infants and children undergoing CPB. We hypothesized that CL would decrease, and V would increase during CPB compared to pre- or post-CPB states. METHODS: Open-label, single-center, opportunistic pharmacokinetics (PK) and safety study of dexmedetomidine in patients ≤36 months of age administered dexmedetomidine per standard of care via continuous infusion. We analyzed dexmedetomidine PK data using standard nonlinear mixed effects modeling with NONMEM software. We compared model-estimated PK parameters to those from historical patients receiving dexmedetomidine before anesthesia for urologic, lower abdominal, or plastic surgery; after low-risk cardiac or craniofacial surgery; or during bronchoscopy or nuclear magnetic resonance imaging. We investigated the influence of CPB-related factors on PK estimates and used the final model to simulate dosing recommendations, targeting a plasma concentration previously associated with safety and efficacy (0.6 ng/mL). We used the Wilcoxon rank sum test to evaluate differences in dexmedetomidine exposure between infants with hypotension or bradycardia and those who did not develop these adverse events. RESULTS: We collected 213 dexmedetomidine plasma samples from 18 patients. Patients had a median (range) age of 3.3 months (0.1-34.0 months) and underwent CPB for 161 minutes (63-394 minutes). We estimated a CL of 13.4 L/h/70 kg (95% confidence interval, 2.6-24.2 L/h/70 kg) during CPB, compared to 42.1 L/h/70 kg (95% confidence interval, 38.7-45.8 L/h/70 kg) in the historical patients. No specific CPB-related factor had a statistically significant effect on PK. A loading dose of 0.7 µg/kg over 10 minutes before CPB, followed by maintenance infusions through CPB of 0.2 or 0.25 µg/kg/h in infants with postmenstrual ages of 42 or 92 weeks, respectively, maintained targeted concentrations. We identified no association between dexmedetomidine exposure and selected adverse events (P = .13). CONCLUSIONS: CPB is associated with lower CL during CPB in infants and young children compared to those not undergoing CPB. Further study should more closely investigate CPB-related factors that may influence CL.

Population Pharmacokinetic/Pharmacodynamic Modeling of Methylprednisolone in Neonates Undergoing Cardiopulmonary Bypass.

Methylprednisolone is used in neonates to modulate cardiopulmonary bypass (CPB)-induced inflammation, but optimal dosing and exposure are unknown. We used plasma methylprednisolone and interleukin (IL)-6 and IL-10 concentrations from neonates enrolled in a randomized trial comparing one vs. two doses of methylprednisolone to develop indirect response population pharmacokinetic/pharmacodynamic models characterizing the exposure-response relationships. We applied the models to simulate methylprednisolone dosages resulting in the desired IL-6 and -10 exposures, known mediators of CPB-induced inflammation. A total of 64 neonates (median weight 3.2 kg, range 2.2-4.3) contributed 290 plasma methylprednisolone concentrations (range 1.07-12,700 ng/mL) and IL-6 (0-681 pg/mL) and IL-10 (0.1-1125 pg/mL). Methylprednisolone plasma exposure following a single 10 mg/kg intravenous dose inhibited IL-6 and stimulated IL-10 production when compared with placebo. Higher (30 mg/kg) or more frequent (twice) dosing did not confer additional benefit. Clinical efficacy studies are needed to evaluate the effect of optimized dosing on outcomes.

Population Pharmacokinetics of Milrinone in Infants, Children, and Adolescents.

Milrinone is a type 3 phosphodiesterase inhibitor used to improve cardiac output in critically ill infants and children. Milrinone is primarily excreted unchanged in the urine, raising concerns for toxic accumulation in the setting of renal dysfunction of critical illness. We developed a population pharmacokinetic model of milrinone using nonlinear mixed-effects modeling in NONMEM to perform dose-exposure simulations in children with variable renal function. We included children aged <21 years who received intravenous milrinone per clinical care. Plasma milrinone concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay (range 1-5000 ng/mL). We performed dose-exposure simulations targeting steady-state therapeutic concentrations of 100-300 ng/mL previously established in adults and children with cardiac dysfunction. We simulated concentrations over 48 hours in typical subjects with decreasing creatinine clearance (CrCl), estimated using the updated bedside Schwartz equation. Seventy-four patients contributed 111 plasma samples (concentration range, 4-634 ng/mL). The median (range) postmenstrual age (PMA) was 3.7 years (0-18), and median weight (WT) was 13.1 kg (2.6-157.7). The median serum creatinine and CrCl were 0.5 mg/dL (0.1-3.1) and 117.2 mL/min/1.73 m2 (13.1-261.3), respectively. A 1-compartment model characterized the pharmacokinetic data well. The final model parameterization was: Clearance (L/h) = 15.9*(WT [kg] / 70)0.75 * (PMA1.12 / (67.71.12 +PMA1.12 )*(CrCl / 117)0.522 ; and Volume of Distribution (L) = 32.2*(WT [kg] / 70). A loading dose of 50 µg/kg followed by a continuous infusion of 0.5 µg/kg/min resulted in therapeutic concentrations, except when CrCl was severely impaired at ≤30 mL/min/1.73 m2 . In this setting, a 25 µg/kg loading dose and 0.25 µg/kg/min continuous infusion resulted in therapeutic exposures.

Population Pharmacokinetics/Pharmacodynamics of 3,4-Diaminopyridine Free Base in Patients With Lambert-Eaton Myasthenia.

Lambert-Eaton myasthenia (LEM) is a rare autoimmune disorder associated with debilitating muscle weakness. There are limited treatment options and 3,4-diaminopyridine (3,4-DAP) free base is an investigational orphan drug used to treat LEM-related weakness. We performed a population pharmacokinetic/pharmacodynamic (PK/PD) analysis using 3,4-DAP and metabolite concentrations collected from a phase II study in patients with LEM. The Triple Timed Up & Go (3TUG) assessment, which measures lower extremity weakness, was the primary outcome measure. A total of 1,270 PK samples (49 patients) and 1,091 3TUG data points (32 randomized patients) were included in the PK/PD analysis. A two-compartment and one-compartment model for parent and metabolite, respectively, described the PK data well. Body weight and serum creatinine partially explained the variability in clearance for the final PK model. A fractional inhibitory maximum effect (Emax ) model characterized the exposure-response relationship well. The PK/PD model was applied to identify a suggested dosing approach for 3,4-DAP free base.

Population Pharmacokinetics of Dexmedetomidine in Infants.

Despite limited pharmacokinetic (PK) data, dexmedetomidine is increasingly being used off-label for sedation in infants. We aimed to characterize the developmental PK changes of dexmedetomidine during infancy. In this open-label, single-center PK study of dexmedetomidine in infants receiving dexmedetomidine per clinical care, ≤10 blood samples per infant were collected. A set of structural PK models and residual error models were explored using nonlinear mixed-effects modeling in NONMEM. Covariates including postmenstrual age (PMA), serum creatinine, and recent history of cardiac surgery requiring cardiopulmonary bypass were investigated for their influence on PK parameters. Univariable generalized estimating equation models were used to evaluate the association of hypotension with dexmedetomidine concentrations. A total of 89 PK samples were collected from 20 infants with a median PMA of 44 weeks (range, 33-61). The median maximum dexmedetomidine infusion dose during the study period was 1.8 µg/(kg·h) (0.5-2.5), and 16/20 infants had a maximum dose >1 µg/(kg·h). A 1-compartment model best described the data. Younger PMA was a significant predictor of lower clearance. Infants with a history of cardiac surgery had ∼40% lower clearance compared to those without a history of cardiac surgery. For infants with PMA of 33 to 61 weeks and body weight of 2 to 6 kg, the estimated clearance and volume of distribution were 0.87 to 2.65 L/(kg·h) and 1.5 L/kg, respectively. No significant associations were found between dexmedetomidine concentrations and hypotension. Infants with younger PMA and recent cardiac surgery may require relatively lower doses of dexmedetomidine to achieve exposure similar to older patients and those without cardiac surgery.

Thromboprophylaxis with fondaparinux in high-risk postoperative patients with renal insufficiency.

Fondaparinux is an antithrombin-dependent factor Xa inhibitor that is used for thromboprophylaxis of patients undergoing hip fracture surgery, hip or knee replacement, or abdominal surgery. It is cleared by the kidney and should be used with caution in patients with renal impairment and avoided in patients with severe renal insufficiency. Recently, several studies have demonstrated that a lower dose of fondaparinux in patients with moderate renal impairment appears to be safe and effective. The purpose of this study was to obtain pharmacokinetic and clinical data on the use of prophylactic fondaparinux in patients with renal insufficiency undergoing major abdominal surgery for cancer (n=8) or orthopedic surgery (n=1). Anti-factor Xa levels were obtained, and a published population pharmacokinetic model for fondaparinux was fit to the data. The data were analyzed using NONMEM software. Fondaparinux did not appear to accumulate in these patients, even when the drug was administered for up to twelve days. Pharmacokinetic analysis revealed that the apparent clearance in this population, who were primarily undergoing cancer surgery, was similar to prior studies in orthopedic surgery patients. In contrast, lower estimates were obtained for volume of distribution and absorption rate constant parameters. None of the patients sustained a hemorrhagic complication attributable to fondaparinux. One patient developed hypoxia in the setting of transient atrial fibrillation and clinical suspicion for pulmonary embolism, but this was not confirmed radiographically. These results support the use of 1.5mg of fondaparinux every 24hours for thromboprophylaxis in patients with renal insufficiency undergoing high-risk surgical procedures.

Sildenafil exposure and hemodynamic effect after Fontan surgery.

OBJECTIVE: Determine sildenafil exposure and hemodynamic effect in children after Fontan single-ventricle surgery. DESIGN: Prospective dose-escalation trial. SETTING: Single-center pediatric catheterization laboratory. PATIENTS: Nine children post Fontan single-ventricle surgical palliation and undergoing elective cardiac catheterization: median (range) age and weight, 5.2 years (2.5-9.4 yr) and 16.3 kg (9.5-28.1 kg). Five children (55%) were boys, and six of nine (67%) had a systemic right ventricle. INTERVENTIONS: Catheterization and echocardiography performed before and immediately after single-dose IV sildenafil (0.25, 0.35, or 0.45 mg/kg over 20 min). MEASUREMENTS AND MAIN RESULTS: Peak sildenafil and desmethyl sildenafil concentration, change in hemodynamic variables measured by cardiac catheterization and echocardiography. Maximum sildenafil concentrations ranged from 124 to 646 ng/mL and were above the in vitro threshold needed for 77% phosphodiesterase type-5 inhibition in eight of nine children and 90% inhibition in seven of seven children with doses more than or equal to 0.35 mg/kg. Sildenafil improved stroke volume (+22%, p = 0.05) and cardiac output (+10%, p = 0.01) with no significant change in heart rate in eight of nine children. Sildenafil also lowered systemic (-16%, p = 0.01) and pulmonary vascular resistance index in all nine children (median baseline pulmonary vascular resistance index 2.4 [range, 1.3-3.7]; decreased to 1.9 [0.8-2.7] Wood Units × m; p = 0.01) with no dose-response effect. Pulmonary arterial pressures decreased (-10%, p = 0.02) and pulmonary blood flow increased (9%, p = 0.02). There was no change in myocardial performance index and no adverse events. CONCLUSIONS: After Fontan surgery, sildenafil infusion acutely improves cardiopulmonary hemodynamics, increasing cardiac index. For the range of doses studied, exposure was within the acute safety range reported in adult subjects.

Sildenafil exposure and hemodynamic effect after stage II single-ventricle surgery.

OBJECTIVES: To determine sildenafil exposure and hemodynamic effect in children after stage II single-ventricle surgery. DESIGN: Prospective, dose escalation trial. SETTING: Single-center, pediatric catheterization laboratory. PATIENTS: Twelve children poststage II single-ventricle surgical palliation and undergoing elective cardiac catheterization: median age 1.9 years (range, 0.8, 4.0), weight 11 kg (8, 13), nine females, and 10 with a single right ventricle. INTERVENTIONS: Catheterization and echocardiography performed before and immediately after single-dose IV sildenafil (0.125, 0.25, 0.35, or 0.45 mg/kg over 20 min). MEASUREMENTS: Peak sildenafil and desmethyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography including indexed pulmonary vascular resistance, and myocardial performance. MAIN RESULTS: Maximum sildenafil concentrations ranged from 92 to 775 ng/mL and were above the in vitro threshold needed for 77% phosphodiesterase type 5 (PDE-5) inhibition in 80% of subjects and 90% inhibition in 80% of subjects with doses ≥0.35 mg/kg. Sildenafil lowered pulmonary vascular resistance index in all 12 subjects (median pulmonary vascular resistance index 2.2 [range, 1.6, 7.9]; decreased to 1.7 [1.2, 5.4] WU × m; p < 0.01) with no dose-response effect. Sildenafil improved pulmonary blood flow (+8% [0, 20], p = 0.04) and saturations (+2% [0, 16], p = 0.04) in those with baseline pulmonary vascular resistance index ≥ 2 WU × m (n = 7). Change in saturations correlated inversely with change in pulmonary vascular resistance index (r = 0.74, p < 0.01). Sildenafil also lowered mean blood pressure (-12% [-20, +10]; p = 0.04). There was no change in cardiac index and no effect on myocardial performance. There were no adverse events. CONCLUSIONS: Sildenafil demonstrated nonlinear exposure with high interindividual variability but was well tolerated and effectively lowered pulmonary vascular resistance index in all subjects. Sildenafil did not acutely improve myocardial performance or increase cardiac index.

Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation.

BACKGROUND: Candida infections are a leading cause of infectious disease-related death in infants supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics; thus, standard fluconazole dosing in children on ECMO may result in suboptimal drug exposure. This study determined the pharmacokinetics of fluconazole in infants on ECMO. METHODS: Infants <120 days of age received either intravenous fluconazole prophylaxis (25 mg/kg once a week) or treatment (12 mg/kg daily) while on ECMO. Paired plasma samples were collected preoxygenator and postoxygenator around doses 1 and 2 to calculate pharmacokinetic indices and describe oxygenator extraction. A 1-compartment model was fit to the data using nonlinear regression. Surrogate pharmacodynamic targets for efficacy were evaluated. RESULTS: Ten infants were enrolled. After dose 1 (n = 9), the median clearance was 17 mL/kg/h, the median volume of distribution was 1.5 L/kg and the median exposure in the first 24 hours (area under the curve from 0 to 24 hours) was 322 h × mg/L. After multiple doses (n = 7), the median clearance was 22 mL/kg/h, the median volume of distribution was 1.9 L/kg and the area under the curve from 0 to 24 hours was 352 h × mg/L. After dose 1, 78% of infants achieved the prophylaxis target, whereas only 11% achieved the therapeutic target. Oxygenator extraction of fluconazole was minimal (-2.0%, standard deviation 15.0), and extraction was not correlated with age of the ECMO circuit (ρ= -0.05). There were no adverse events related to fluconazole. CONCLUSIONS: Infants on ECMO had higher volume of distribution but similar clearance when compared with historical controls not on ECMO. In infants on ECMO, a fluconazole dose of 25 mg/kg weekly provides adequate exposure for prophylaxis against Candida infections. However, higher doses may be needed for treatment.