Current and emerging pharmacotherapies for the treatment of pulmonary arterial hypertension in infants.

INTRODUCTION: Pulmonary hypertension (PH) is a complex condition that encompasses an array of underlying disease processes and affects a diverse population of infants, including those with congenital heart disease, congenital diaphragmatic hernia, persistent PH of the newborn, and those with lung disease such as bronchopulmonary dysplasia. While there are treatments available to adults with PH, limited data exists for infants, especially for the newer medications. Therapies that target the three main pathophysiologic pathways of pulmonary hypertension appear to benefit infants, but which are best for each individual disease process is unclear. AREAS COVERED: A review of the therapies to treat pulmonary hypertension is covered in this article including the prostacyclin pathway, endothelin pathway, and the nitric oxide pathway. Other adjunctive treatments are also discussed. Findings are based on a PubMed literature search of research papers spanning 1990-2023 and a search of ongoing trials registered with clinicaltrials.gov. EXPERT OPINION: Overall therapies seem to improve outcomes with most infants with PH. However, given the diverse population of infants with PH, it is imperative to understand the basis for the PH in individual patients and understand which therapies can be applicable. Further research into tailored therapy for the specific populations is warranted.

Characteristics and Outcomes of Patients Discharged Directly Home From the Pediatric Intensive Care Unit.

Introduction: Patients admitted to the pediatric intensive care unit (PICU) typically transfer to an acute care floor prior to discharge (ACD). Various circumstances, including rapid clinical improvement, technology dependence, or capacity constraints, may lead to discharge directly to home from a PICU (DDH). This practice has been studied in adult intensive care units, but research is lacking for PICU patients. Methods: We aimed to describe characteristics and outcomes of patients requiring PICU admission who experienced DDH versus ACD. We conducted a retrospective cohort study of patients ≤18 years old admitted to our academic, tertiary care PICU between 1/1/15 and 12/31/20. Patients who died or were transferred to another facility were excluded. Baseline characteristics (including home ventilator dependence) and markers of illness severity, specifically the need for vasoactive infusion or new mechanical ventilation, were compared between groups. Admission diagnoses were categorized using the Pediatric Clinical Classification System (PECCS). Our primary outcome was hospital readmission within 30 days. Results: Of 4042 PICU admissions during the study period, 768 (19%) were DDH. Baseline demographic characteristics were similar, although DDH patients were more likely to have a tracheostomy (30% vs 5%, P < .01) and require a home ventilator at discharge (24% vs 1%, P < .01). DDH was associated with being less likely to have required a vasoactive infusion (7% vs 11%, P < .01), shorter median length of stay (LOS) (2.1 days vs 5.9 days, P < .01) and increased rate of readmission within 30 days of discharge (17% vs 14%, P < .05). However, repeat analysis after removing ventilator-dependent patients at discharge (n = 202) showed no difference in rates of readmission (14% vs 14%, P = .88). Conclusions: Direct discharge home from the PICU is a common practice. DDH and ACD groups had similar 30-day readmission rate when patient admissions with home ventilator dependence were excluded.

Increasing Seizures, Encephalopathy, and Hypothermia in an 18-Year-Old Woman.

ABSTRACT: An 18-year-old woman with a history of focal epilepsy presents with increasingly frequent seizures, encephalopathy, multiple laboratory abnormalities, and hypothermia. During her hospital course, her symptoms waxed and waned. Multiple etiologies of her symptoms were considered, but the spontaneous resolution of her symptoms and an abnormal MRI of the brain revealed the final diagnosis.

Beyond the Syndrome: Extensive Congenital Abnormalities in an Infant With Trisomy 21.

Herein we discuss the clinical course and subsequent autopsy of a female infant with trisomy 21 with balanced Rastelli Type "C" complete atrioventricular septal defect (AVSD), tetralogy of Fallot and right aortic arch with mirror image branching pattern who underwent a palliative right modified Blalock-Taussig-Thomas shunt (mBTTS) for hypoxemia from progressive right ventricular outflow tract obstruction. The baby was found to have multiple concomitant pathologic findings not typically seen with this constellation of cardiac anatomy. Autopsy revealed significant abdominal adhesions with near-complete stenosis of the transverse colon. In addition, the infant was found to have significantly elongated villi within the small and large bowel and a relatively large collagenous polyp in the small bowel. The decedent also had an abnormal tracheal bronchus, characterized by an additional superior right-sided bronchus, which is an extremely rare abnormality. Her clinical course was complicated by severe pulmonary hypertensive arteriolar changes out of proportion to what would be typical for her age, trisomy 21 status, and degree of left to right intracardiac shunting. Furthermore, she had refractory anasarca and recurrent chylous pleural effusions without gross lymphatic abnormalities that may have been secondary to systemic capillary leak syndrome (SCLS) versus severe pulmonary hypertension. Due to the aforementioned findings, the family elected for comfort care and the baby expired shortly after extubation. Overall, the infant had multiple, rare coexisting congenital abnormalities that likely represents an extreme phenotype of trisomy 21 that has not been described in the literature to date.

Cardiac arrest in the paediatric intensive care unit: defining the problem and developing solutions.

Thousands of children experience a cardiac arrest event in the hospital each year, with more than half of these patients not surviving to hospital discharge. Cardiopulmonary resuscitation (CPR) depth, rate, velocity and percentage of high-quality chest compressions are modifiable factors associated with improved survival. Therefore, we created a novel and standardised process to track and analyse cardiac arrests in the Duke paediatric intensive care unit (PICU). Our aim was to identify areas for improved American Heart Association (AHA) compliance and implement education and communication-based initiatives to enhance early recognition of at-risk patients leading to improved outcomes. From January 2017 to December 2018, all cardiac arrests in our PICU were tracked, reviewed and presented at monthly morbidity and mortality conference. We used the data to track compliance with AHA guidelines and identify opportunities for improvement. Through these efforts, we established a multidisciplinary cardiac arrest education and review programme. Over the 2-year period, we tracked 45 cardiac arrests, which comprised 2% of all PICU admissions. In 2017, during the first year of development, 16 of 22 arrests (73%) were not reported to code committee members in time for complete review. Of the six cardiac arrests with complete reviews, only 17% followed AHA guidelines. In 2018, all 23 arrest events were communicated and 76% of resuscitations were found to be compliant with AHA guidelines. Survival of patients to discharge was 47% in 2017 and increased to 63% in 2018 with similar percentage of PICU admissions having a cardiac arrest between the 2 years. The primary aim of this project was to establish a multidisciplinary comprehensive cardiac arrest review process. This programme allowed for comprehensive analysis of individual events, promoted quality improvement initiatives and improved consistent delivery of high-quality CPR.

Gastric antral vascular ectasia in children, rare presentation.

A 14-year-old boy, a known case of perinatal hypoxic cerebral palsy, presented to paediatric emergency with acute melaena and blood staining around feeding gastrostomy site. Physical examination revealed pallor, but no signs of distress with an unremarkable abdominal examination. Routine blood tests revealed normochromic. Abdominal ultrasound scan and Meckel's scan were unremarkable. The patient underwent examination under anaesthesia of the perianal area and joint upper and lower gastrointestinal endoscopy. Streak-like gastritis with no signs of active bleeding lesions were noted and patchy areas of colitis involving the descending and sigmoid colon and the rectum. All clinical findings and evidence-based diagnosis matched gastric antral vascular ectasia. He was successfully managed conservatively with elemental hydrolysed feeding formula.

Idiopathic acute eosinophilic pneumonia.

A 44-year-old asthmatic male patient presented to the health centre with a 3-week history of coryzal symptoms, persistent productive sputum and shortness of breath. The chest X-ray (CXR) revealed symmetrical, perihilar airspace shadowed with peribronchial cuffing and bilateral reticular markings. The patient did not improve despite treatment, and hence a high resolution CT (HRCT) scan of the thorax was recommended. The HRCT showed smooth interlobular septal thickening, central perihilar soft tissue thickening and patches of ground glass changes. Both the CXR and HRCT findings, along with the symptoms and eosinophilia counts, were suggestive of idiopathic acute eosinophilic pneumonia (IAEP) which was confirmed on bronchoalveolar lavage. The patient was successfully treated with steroids. This case highlights the symptoms, diagnosis, management and treatment of IAEP. A rapid diagnosis of this rare disease is essential since it can be completely cured with correct management but can be fatal if left untreated. Once properly treated, this disease does not recur.

Similar Interstage Outcomes for Single Ventricle Infants Palliated With an Aortopulmonary Shunt Compared to the Norwood Procedure.

BACKGROUND: Interstage outcomes for single ventricle infants following Norwood operation have been well studied, showing significant mortality. Other single ventricle infants require only an aortopulmonary shunt. The aim of the study was to describe the interstage outcomes of this group compared to Norwood patients and identify risk factors for mortality. METHODS: A single-center retrospective cohort review was performed in patients who underwent a Norwood operation (Norwood) or aortopulmonary shunt (Shunt) during 2000 to 2011 and survived to discharge. Hybrid or pulmonary artery banding patients were excluded. Univariate comparison was made between Norwood and Shunt patients as well as a Shunt subgroup analysis. RESULTS: A total of 486 patients (368 Norwood and 118 Shunt) were included. Norwood and Shunt patients were similar in terms of preterm birth, surgery weight, and stage 1 complications. Shunt patients were more likely to be female, have an extracardiac or genetic anomaly, and have a shorter hospital length of stay compared to the Norwood patients (all P < .0001). No significant difference in interstage mortality was seen between the Shunt and Norwood patients (6.8% vs 11.1%, respectively; P = .17). Stage 2 mortality was also similar (Shunt 4.6% vs Norwood 7.8%; P = .25). In the Shunt patients, those who died during interstage weighed less at surgery (2.7 [0.7] kg vs 3.3 [0.7] kg, P = .03) and were more likely to have arrhythmias (50% vs 12%, P = .01), compared to survivors. CONCLUSIONS: Shunt patients have an interstage mortality that is not significantly less than Norwood patients. Lower weight at surgery and arrhythmias are risk factors for interstage death in Shunt patients.

Non-Invasive Thrombolysis Using Microtripsy in a Porcine Deep Vein Thrombosis Model.

Histotripsy is a non-invasive therapeutic technique that uses ultrasound generated from outside the body to create controlled cavitation in targeted tissue, and fractionates it into acellular debris. We have developed a new histotripsy approach, termed microtripsy, to improve targeting accuracy and to avoid collateral tissue damage. This in vivo study evaluates the safety and efficacy of microtripsy for non-invasive thrombolysis in a porcine deep vein thrombosis model. Acute thrombi were formed in left femoral veins of pigs (∼35 kg) by occluding the vessel using two balloon catheters and infusing with thrombin. Guided by real-time ultrasound imaging, microtripsy thrombolysis treatment was conducted in 14 pigs; 10 pigs were euthanized on the same day (acute) and 4 at 2 wk (subacute). To evaluate vessel damage, 30-min free-flow treatment in the right femoral vein (no thrombus) was also conducted in 8 acute pigs. Blood flow was successfully restored or significantly increased after treatment in 13 of the 14 pigs. The flow channels re-opened by microtripsy had a diameter up to 64% of the vessel diameter (∼6 mm). The average treatment time was 16 min per centimeter-long thrombus. Only mild intravascular hemolysis was induced during microtripsy thrombolysis. No damage was observed on vessel walls after 2 wk of recovery, venous valves were preserved, and there was no sign of pulmonary embolism. The results of this study indicate that microtripsy has the potential to be a safe and effective treatment for deep vein thrombosis in a porcine model.

Left main coronary artery atresia in an infant with Shone's complex.

A 6-month-old infant with Shone's complex was found to have left main coronary artery atresia during evaluation for recurrent subaortic stenosis with depressed left ventricular function. The ventricular function improved after surgical subaortic resection without coronary re-vascularisation. This case demonstrates first the rare finding of left main coronary artery atresia and second that coronary re-vascularisation is not necessarily required in all cases of left main coronary artery atresia.

Dissociation of hemodynamic and electrocardiographic indexes of myocardial ischemia in pigs with hibernating myocardium and sudden cardiac death.

Many survivors of sudden cardiac death (SCD) have normal global ventricular function and severe coronary artery disease but no evidence of symptomatic ischemia or infarction before the development of lethal ventricular arrhythmias, and the trigger for ventricular tachycardia (VT)/ventricular fibrillation (VF) remains unclear. We sought to identify the role of spontaneous ischemia and temporal hemodynamic factors preceding SCD using continuous telemetry of left ventricular (LV) pressure and the ECG for periods up to 5 mo in swine (n = 37) with hibernating myocardium who experience spontaneous VT/VF in the absence of heart failure or infarction. Hemodynamics and ST deviation at the time of VT/VF were compared with survivors with hibernating myocardium as well as sham controls. All episodes of VT/VF occurred during sympathetic activation and were initiated by single premature ventricular contractions, and the VT degenerated into VF in ∼ 30 s. ECG evidence of ischemia was infrequent and no different from those that survived. Baseline hemodynamics were no different among groups, but LV end-diastolic pressure during sympathetic activation was higher at the time of SCD (37 ± 4 vs. 26 ± 4 mmHg, P < 0.05) and the ECG demonstrated QT shortening (155 ± 4 vs. 173 ± 5 ms, P < 0.05). The week before SCD, both parameters were no different from survivors. These data indicate that there are no differences in the degree of sympathetic activation or hemodynamic stress when VT/VF develops in swine with hibernating myocardium. The transiently elevated LV end-diastolic pressure and QT shortening preceding VT/VF raises the possibility that electrocardiographically silent subendocardial ischemia and/or mechanoelectrical feedback serve as a trigger for the development of SCD in chronic ischemic heart disease.

Brief sympathetic activation precedes the development of ventricular tachycardia and ventricular fibrillation in hibernating myocardium.

BACKGROUND: Hibernating myocardium develops inhomogeneity in myocardial sympathetic innervation with spontaneous sudden cardiac death (SCD) because of ventricular fibrillation (VF). The triggers and prodromal arrhythmias initiating SCD in this substrate are unknown. METHODS: Swine chronically instrumented with a proximal left anterior descending coronary artery stenosis underwent placement of an implantable telemetry unit capable of continuously recording digitized electrocardiogram and left ventricular pressure signals at 1 kHz in conscious unrestrained animals for periods of up to 5 months. RESULTS: Spontaneous SCD (n = 10) was initiated by a close-coupled premature ventricular contraction followed by ventricular tachycardia (VT) that degenerated into VF during brief sympathetic activation. Peak heart rates were similar in animals that developed SCD vs survivors (250 +/- 12 vs 261 +/- 6 bpm). Electrocardiogram evidence of ischemia preceding VT/VF occurred in only 1 animal, and there was no significant infarction. CONCLUSIONS: Spontaneous VT/VF in hibernating myocardium develops during brief sympathetic activation with only rare evidence of acute ischemia. This supports the notion that the regional remodeling accompanying hibernating myocardium may be a novel substrate for the development of SCD in chronic ischemic heart disease.