Complications following the Fontan procedure include prolonged pleural drainage and readmission for effusions. To address these complications, a post-Fontan management pathway was implemented with primary goals of reducing chest tube duration/reinsertion rates and decreasing hospital length of stay and readmissions.

Fontan patients were identified by retrospective chart review (2017–2019) to obtain baseline data for chest tube duration/reinsertion rates, hospital length of stay, and readmission rates for effusion. A post-Fontan management pathway was implemented (2020–2021) utilising post-operative vasopressin, nasal cannula oxygen until chest tube removal, and discharge regimen of three times daily diuretics, sildenafil, and afterload reducing medications. Patients were followed to evaluate primary outcomes.

The pre- and post-pathway groups were similar in single ventricle morphology, demographics, and pre-operative haemodynamics. Forty-three and 36 patients were included in the pre- and post-pathway cohorts, respectively. There were statistically significant reductions in chest tube duration (8 vs. 5 days, p ≤ 0.001), chest tube output on post-operative day 4 (20.4 vs. 9.9 mL/kg/day, p = 0.003), and hospital readmission rates for effusion (13[30%] vs. 3[8%], p = 0.02) compared to baseline. There was an absolute reduction in hospital length of stay (11 vs. 9.5 days, p = 0.052). When combining average cost savings for the Fontan hospitalisations, readmissions for effusion, and cardiac catheterisations within 6 months of Fontan completion, there was a $325,144 total cost savings for 36 patients following pathway implementation.

Implementation of a post-Fontan management pathway resulted in significant reductions in chest tube duration and output, and readmission rates for effusion in the perioperative period.

Despite the prevalence of antidepressant-related sexual side effects, comparisons of treatments for these problematic side effects are lacking.

To address this, we performed a systematic review and Bayesian network meta-analysis to compare interventions for antidepressant-induced sexual dysfunction in adults. Using PubMed and clinicaltrials.gov, we identified published and unpublished prospective treatment trials from 1985 to September 2020 (primary outcome: the Arizona sexual experience scale [ASEX] score). The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation framework.

We identified 57 citations (27 randomized controlled trials, 66 treatment arms, 27 open-label trials, and 3 crossover trials) that evaluated 33 interventions (3108 patients). In the systematic review, 44% (25/57) of trials reported successful interventions; this was more common in open-label (70%, 19/27) compared to placebo-controlled studies (22%, 6/27). In the meta-analysis of placebo-controlled studies that used the ASEX (N = 8), pycnogenol was superior to placebo (standardized mean difference: −1.8, 95% credible interval [CrI]: [−3.7 to 0.0]) and there was evidence that, at a 6% threshold, sildenafil improved sexual dysfunction (standardized mean difference: −1.2, 95% CrI [−2.5 to 0.1]). In the meta-analysis including single-arm studies (15 studies), treatment response was more common with sildenafil, tianeptine, maca, tiagabine, and mirtazapine compared to placebo, but these differences failed to reach statistical significance.

While heterogeneity across randomized controlled trials complicates identifying the single best intervention, multiple trials suggest that sildenafil ameliorates antidepressant-induced sexual dysfunction. More randomized controlled trials are needed to examine the putative efficacy of other interventions.

To investigate the long-term effects of juvenile sub-chronic sildenafil (SIL) treatment on the depressive-like behaviour and hippocampal brain-derived neurotrophic factor (BDNF) levels of adult Sprague-Dawley (SD) versus Flinders Sensitive Line (FSL) rats.

SD and FSL rats were divided into pre-pubertal and pubertal groups, whereafter 14-day saline or SIL treatment was initiated. Pre-pubertal and pubertal rats were treated from postnatal day 21 (PND21) and PND35, respectively. The open field and forced swim tests (FST) were performed on PND60, followed by hippocampal BDNF level analysis 1 day later.

FSL rats displayed greater immobility in the FST compared to SD rats (p < 0.0001), which was reduced by SIL (p < 0.0001), regardless of treatment period. Hippocampal BDNF levels were unaltered by SIL in all treatment groups (p > 0.05).

Juvenile sub-chronic SIL treatment reduces the risk of depressive-like behaviour manifesting during young adulthood in genetically susceptible rats.

Efficacy of sildenafil in treating paediatric pulmonary arterial hypertension is controversial. This systematic review aimed to explore the safety and effect of sildenafil on treating paediatric pulmonary arterial hypertension (PAH) through meta-analysis.

In this study, the electronic databases, including the Cochran Library database, EMBASE, and MEDLINE were systemically retrieved to identify the related randomised controlled trials (RCTs). Two reviewers had independently completed study selection, data collection, and assessment of the bias risk. Amongst 938 articles researched according to our retrieval strategy, 15 papers that involved 673 cases had been screened. Relative to control group, the sildenafil group had markedly reduced mortality (RR = 0.25, 95% CI: 0.12–0.51; p < 0.0001), but difference within the mortality was not statistically significant between high- and low-dose sildenafil groups (p = 0.152). Nonetheless, difference of the mean pulmonary arterial pressure between sildenafil as well as control group was of no statistical significance. Differences in the length of hospital stay and the incidences of pulmonary hypertensive crisis between children with PAH and controls were of no statistical significance. However, the summary estimate favoured that sildenafil reduced the duration of mechanical ventilation time, as well as the length of ICU stay and inotropic support.

Sildenafil therapy reduces the mortality of PAH patients, but its effects on the haemodynamic outcomes and other clinical outcomes are still unclear.

Enteral sildenafil may be used in the intensive care unit for treatment of pulmonary arterial hypertension. We aimed to determine if initial enteral sildenafil dosing is safe in children receiving concurrent vasoactive infusions.

We performed a single-centre retrospective chart review that included patients less than 2 years of age in paediatric and cardiovascular intensive care units at an academic medical centre from 1 January, 2010 to 30 November, 2016. Included patients received concomitant enteral sildenafil and a continuously infused vasoactive agent. Exclusion criteria consisted of mechanical circulatory support, any form of dialysis, or a suspicion of septic shock at the time of sildenafil initiation. We sought to identify patients who developed worsening hemodynamic instability after initiation of enteral sildenafil defined as one or more of the following observations within 24 hours of sildenafil initiation: sildenafil discontinuation, total fluid bolus receipt >10 ml/kg, increased vasoactive support, epinephrine intravenous push administration, and/or the initiation of mechanical circulatory support.

Worsening hemodynamic instability was identified in 35% of the 130-patient cohort. Patients younger than 4 months were at increased risk of further hemodynamic instability compared with older patients (56% versus 44%, p = 0.0003) despite receiving lower median doses (1.28 mg/kg/day versus 1.78 mg/kg/day, p = 0.01).

Critically ill children receiving vasoactive infusions may be at increased risk for further hemodynamic instability after initiation of enteral sildenafil, particularly in younger patients. This population may benefit from lower starting enteral sildenafil doses of 0.25 mg/kg/dose or less every 8 hours to avoid further hemodynamic compromise.

The relationship between sildenafil dosing, exposure, and systemic hypotension in infants is incompletely understood.

The aim of this study was to characterise the relationship between predicted sildenafil exposure and hypotension in hospitalised infants.

We extracted information on sildenafil dosing and clinical characteristics from electronic health records of 348 neonatal ICUs from 1997 to 2013, and we predicted drug exposure using a population pharmacokinetic model.

We identified 232 infants receiving sildenafil at a median dose of 3.2 mg/kg/day (2.0, 6.0). The median steady-state area under the concentration–time curve over 24 hours (AUC24,SS) and maximum concentration of sildenafil (Cmax,SS,SIL) were 712 ng×hour/ml (401, 1561) and 129 ng/ml (69, 293), respectively. Systemic hypotension occurred in 9% of the cohort. In multivariable analysis, neither dosing nor exposure were associated with systemic hypotension: odds ratio=0.96 (95% confidence interval: 0.81, 1.14) for sildenafil dose; 0.87 (0.59, 1.28) for AUC24,SS; 1.19 (0.78, 1.82) for Cmax,SS,SIL.

We found no association between sildenafil dosing or exposure with systemic hypotension. Continued assessment of sildenafil’s safety profile in infants is warranted.

The Fontan circulation is the optimal treatment for patients with univentricular hearts. These patients are at high risk of circulatory failure. There is no consensus on the optimal drug treatment for the prevention of failure of the Fontan circulation. The aim of this systematic review was to provide an overview of evidence for drug therapy used in the prevention of Fontan circulatory failure.

We searched the Embase database for articles that reported drug therapy in Fontan patients. Studies published between 1997 and 2014 were included if efficacy or safety of medication was assessed, drug therapy aimed to prevent or treat failure of the Fontan circulation, and if the full text was available. Case reports were excluded.

A total of nine studies were included with a total of 267 Fontan patients; four studies evaluated the medication sildenafil, one iloprost, three bosentan, and one enalapril. Among all, two sildenafil studies reported improvement in exercise capacity, one in exercise haemodynamics, and one in ventricular performance. In the largest study of bosentan, an increase in exercise capacity was found. Enalapril did not result in improvements.

The studies analysed in this review suggest that bosentan, sildenafil, and iloprost may improve exercise capacity at the short term. Given the limitations of the studies, more, larger, placebo-controlled studies with longer follow-up periods are needed to better understand which drug therapies are effective in the prevention of failure of the Fontan circulation.

Sildenafil is frequently prescribed to children with single ventricle heart defects. These children have unique hepatic physiology with elevated hepatic pressures, which may alter drug pharmacokinetics. We sought to determine the impact of hepatic pressure on sildenafil pharmacokinetics in children with single ventricle heart defects.

A population pharmacokinetic model was developed using data from 20 single ventricle children receiving single-dose intravenous sildenafil during cardiac catheterisation. Non-linear mixed effect modelling was used for model development, and covariate effects were evaluated based on estimated precision and clinical significance.

The analysis included a median (range) of 4 (2–5) pharmacokinetic samples per child. The final structural model was a two-compartment model for sildenafil with a one-compartment model for des-methyl-sildenafil (active metabolite), with assumed 100% sildenafil to des-methyl-sildenafil conversion. Sildenafil clearance was unaffected by hepatic pressure (clearance=0.62 L/hour/kg); however, clearance of des-methyl-sildenafil (1.94×(hepatic pressure/9)−1.33 L/hour/kg) was predicted to decrease ~7-fold as hepatic pressure increased from 4 to 18 mmHg. Predicted drug exposure was increased by ~1.5-fold in subjects with hepatic pressures ⩾10 versus <10 mmHg (median area under the curve=533 versus 792 µg*h/L).

Elevated hepatic pressure delays clearance of the sildenafil metabolite – des-methyl-sildenafil – and increases drug exposure. We speculate that this results from impaired biliary clearance. Hepatic pressure should be considered when prescribing sildenafil to children. These data demonstrate the importance of pharmacokinetic assessments in patients with unique cardiovascular physiology that may affect drug metabolism.

We hypothesised that sildenafil would improve hemodynamics in children with pulmonary hypertension and attenuate rebound pulmonary hypertension after inhaled nitric oxide withdrawal.

We undertook an open-label, single-drug study of sildenafil in patients under 5 years of age with either symptomatic or rebound pulmonary hypertension following inhaled nitric oxide withdrawal.

We recruited 25 patients (median age 180 days, 10–1790) to receive sildenafil. The median right ventricular to systemic systolic blood pressure ratio before sildenafil therapy was 1.0 (0.5–1.4) and decreased to 0.5 (with a range from 0.3 to 1.3; p = 0.0002). In five patients the baseline pulmonary vascular resistance index was 10 (7.1–13.6) Wood units metre square and decreased to 5.8 (2.7–15.6) Wood units metre square (p = 0.04) at 6 months. Ten patients were treated with sildenafil for a median of 34 days (9–499) until resolution of pulmonary artery hypertension and continue to do well. Six patients continued sildenafil therapy for a median of 1002 days (384–1574) with improvement but without resolution of pulmonary hypertension. There was no change in serum creatinine, urea, liver function tests, or platelet count. In 15 patients sildenafil abolished rebound pulmonary artery hypertension following withdrawal of inhaled nitric oxide. Median right ventricular pressure to systemic systolic pressure ratio decreased from 1.0 (0.8–1.4) during nitric oxide withdrawal to 0.4 (0.3–0.8) p = 0.006 after pre-treatment with sildenafil.

In children under 5 years of age with severe pulmonary hypertension, sildenafil therapy resulted in prolonged hemodynamic improvements without adverse effects. Sildenafil attenuated rebound pulmonary hypertension after withdrawal of inhaled nitric oxide.