Management of pulmonary hypertension with cardiac arrest in infants and children in the hospital setting: PLS ScR

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: none applicable.

The following Task Force members Kee-Chong Ng, Hiroshi Kurosawa, Anne-Marie Guerguerian (Pediatric Life Support (PLS) Taskforce); Georg Schmolzer (Neonatal Life Support (NLS) Taskforce nodal lead); and other experts Dyan Zhang, Leandra Rech, Joel Lim, Jessie Cunningham, and other authors declared no conflict of interest, and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees.

Task Force Synthesis Citation

Insert citation for ILCOR.org posting of a Task Force Synthesis of a Scoping Review
The following Task Force members Kee-Chong Ng, Hiroshi Kurosawa, Anne-Marie Guerguerian (PLS Taskforce) and Georg Schmoelzer (NLS nodal lead); other content experts Dyan Zhang, Leandra Rech, Joel Lim, and Jessie Cunningham Information Specialists -on behalf of the International Liaison Committee on Resuscitation (ILCOR) Life Support Task Force(s).

Methodological Preamble and Link to Published Scoping Review

The continuous evidence evaluation process began by reviewing the previous PICOSTs used by the PLS Task Force for the pulmonary hypertension crisis related topic.

In 2019, Evidence Updates were prepared for the following PICOSTs: (1) Prevention and Management of Postoperative Pulmonary Hypertensive Crises in Infants and Children; (2) Opioids, Sedatives, and Neuromuscular Blocking Drugs for Pulmonary Hypertension; and (3) Therapy With Inhaled Nitric Oxide or Prostaglandins for Pulmonary Hypertensive Crisis and Right Heart Failure.

In 2022, to focus on the management of pediatric patients with pulmonary hypertension who suffer from a cardiac arrest, we formulated a new 2022 PICOST. Using this new 2022 PICOST, we undertook a scoping review of the literature. Evidence for pediatric literature was sought and considered by the PLS and by the NLS Task Forces.

Scoping Review

Webmaster to insert the Scoping Review citation and link to Pubmed using this format when/if it is available.

PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Infants and children with pulmonary hypertension at high risk of pulmonary hypertensive crises with a cardiac arrest in the in-hospital setting including post-operatively.

Intervention: Specific management strategies included 1) respiratory management and monitoring to avoid hypoxia and acidosis; 2) use of opioids, sedatives & neuromuscular blocking agents; and 3) pulmonary arterial hypertension (PAH)-specific targeted therapy, like a) phosphodiesterase-5 inhibitors, endothelin receptor antagonists, inhaled pulmonary vasodilators (e.g., inhaled nitric oxide or prostaglandin) or : b) drugs that enhance the nitric oxide–cyclic guanosine monophosphate biological pathway (e.g., sildenafil, tadalafil, or riociguat), prostacyclin pathway agonists (e.g., epoprostenol or treprostinil), or endothelin pathway antagonists (e.g., bosentan or ambrisentan).

Comparators: Standard care without specific management strategies for pulmonary hypertensive crisis.

Outcomes: All including survival to hospital discharge with good neurological outcome and survival to hospital discharge.

Study Designs: Randomized controlled trials (RCTs) and nonrandomized studies (non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies) eligible for inclusion. We anticipated there will be insufficient studies from which to draw a conclusion, case series may be included in the initial search. The minimum number of cases for a case series to be included was set at 5 cases. Grey literature and social media and non-peer reviewed studies, unpublished studies, conference abstracts were not included. Trial protocols were eligible if they informed the question. All relevant publications in any language are included as long as there is an English abstract.

Timeframe: The literature search was completed and the selection focused on the most recent decade from 2012 to 2023

Inclusion and Exclusion criteria

Citations obtained from each database (Cochrane, Embase, Pubmed and Medline) were listed and merged, and duplicates were removed with electronic filtering. The final set of citations with title and abstracts were retrieved and imported into https://rayyan.ai/reviews. Two independent reviewers selected among 10525 titles and abstracts. In the event of discordant selection, consensus was achieved with discussion and review with at least a third reviewer. To be included in the full text reading sample, the title and abstract of the citation needed to indicate the population as being ‘pediatric’ with ‘pulmonary hypertension’. The full text articles were retrieved in pdf format. The management of cardiac arrest was discerned with the use of full text reading. We included for full text reading guidelines and review articles to determine if any original studies were over-looked by the database searches.

The set of full text reports retrieved included three main types of literature. Epidemiological studies, either retrospective or prospective studies, reporting outcomes of children with pulmonary hypertension with or without cardiac arrest. Physiologic studies undertaken in the pediatric population with pulmonary hypertension evaluating the hemodynamic effects of a pharmacological intervention. These articles did not include studied groups of children treated for cardiac arrest. A third type included narrative reviews and systematic reviews on pulmonary hypertension management, guidelines and statements published by different organizations on the diagnostic classification of pulmonary hypertension in childhood and its management. Some of these reports included suggestions on the management of the deteriorating pediatric patient, but none included specific evidence to support the management of a cardiac arrest. The approaches suggested avoiding a cardiopulmonary collapse by the application of physiologic principles; no specific comparative studies were available to support the proposed approaches.

Data tables

Figure 1: Flow diagram following PRISMA guidelines. NOT INCLUDED IN PUBLIC POSTING

Table 1: First author and title of published articles grouped as Guidelines, Statements, and Systematic Reviews and Meta-analyses, and Epidemiological Studies that included background information on the acute management of children with pulmonary hypertension retrieved with the search (ordered from the oldest to the most recent). NOT INCLUDED IN PUBLIC POSTING

Table 2: Reports of studies including patient-level data with pulmonary hypertension and cardiac arrests.

PH: Pulmonary Hypertension; PAH: Pulmonary Arterial Hypertension; RHC: Right Heart Catheterization; CHD: Congenital Heart Disease; CA: Cardiac Arrest.

Task Force Insights

1. Why this topic was reviewed.

This topic with a new PICOST was chosen by the PLS with the NLS Task Force because of the concern that children with pulmonary hypertension who are hospitalized have been reported to be at higher risk of death following a cardiopulmonary arrest.{Morgan, 2021, 52}

In 2015, the American Heart Association (AHA) and the American Thoracic Society (ATS) published a guideline on the management of pediatric pulmonary hypertension.{Abman, 2015b, 2037} In 2018, the AHA published a statement on the management of Cardiopulmonary Resuscitation in Infants and Children With Cardiac Disease that included a chapter on pulmonary hypertension.{Marino, 2018, e691 } In 2018, the AHA published a statement on right sided-heart failure and its management, but this statement focused on adult populations and did not include content for the pediatric population.{Konstam, 2018, e578}

The 2019 ILCOR Evidence updates and the 2015 AHA Guideline provided guidance on the acute treatment of pulmonary hypertension {Abman, 2015b, 2037} These included general principles to support management, the use of specific therapies such as inhaled nitric oxide (iNO), and in the event of failing medical management, the use of ECMO. For the post operative strategies, they also included general recommendations on therapeutic approaches such as the avoidance of hypoxia, acidosis, and agitation induction of alkalosis; administration of opiates, sedatives, and neuromuscular blockade to reduce the risk for or severity pulmonary hypertensive crisis. In addition to conventional postoperative care, iNO and/or inhaled prostaglandin E2 could be used for pulmonary hypertensive crisis and failing of the right side of the heart; sildenafil may be prescribed to prevent rebound pulmonary hypertension in patients who have evidence of a sustained increase in pulmonary artery pressures on withdrawal of iNO and require reinstitution of iNO despite gradual weaning off. In patients with pulmonary hypertensive crisis, inotropic and or pressor therapy may be used to avoid right ventricle ischemia caused by systemic hypotension. Mechanical cardiopulmonary support could be considered in refractory cases. In patients with right ventricle failure, recurrent syncope or pulmonary hypertensive crisis that persist despite optimal management, a referral to an experienced pulmonary hypertension center should be considered for consideration of atrial septostomy.

Faced with this pediatric population at high-risk of cardiopulmonary arrest, we formulated the new PICOST and conducted a scoping review to better understand if new specific therapies had been published to treat cardiopulmonary arrest. This work would inform the task forces as to whether we should proceed to a systematic review for specific interventions.

2. Narrative summary of evidence identified

Of the initial 10525 abstracts, 10289 were excluded. 236 abstracts were included for full text review. Of these 208 of the 236 published were retrievable in full text. The great majority (n=205) did not report patient-level data within pediatric patients with pulmonary hypertension and cardiac arrest. We list in Table 1, 17 foundational background articles which includes 10 guidelines and statements,{Abman, 2015a, 2037; Abman, 2016, 898; Ball, 2022; Dabbagh, 2014, S113; Durongpisitkul, 2021, 679; Olsson, 2018, 46} 2 systematic reviews,{Kuang, 2019, 393; Mulligan and Beghetti, 2012, 472} and five epidemiological studies reporting the risk of cardiac arrest in pediatric pulmonary hypertension. {Morell, 2021, 454; Morgan, 2021, 52; Morgan, 2023, 1; Morgan, 2020, 305; Nasr, 2016, 728} These articles collectively highlight the elevated risk of mortality in children with pulmonary hypertension and the results of recent international efforts in establishing a pediatric pulmonary hypertension classification to support future international and multisite research and general therapeutic management.

Definition and classification of Pediatric Pulmonary Hypertension

Over the last decade, the field has published guidelines to better characterize and classify clinical conditions associated with pulmonary hypertension in pediatrics.{Abman, 2016, 597; Abman, 2015b, 2037; Abman, 2016, 898; Ball, 2022; Barbera, 2018a, 205; Barbera, 2018b, 205; Durongpisitkul, 2021, 679; Hansmann, 2016, ii86; Hansmann, 2019, 879; Idrees, 2014, S79; Johnson, 2012, e134; Lau, 2015, 879; Olschewski and Kovacs, 2015, 1055; Opitz, 2016, 1764; Simonneau, 2019, 1; Trisvetova and Gubkin, 2016, 79; Wilkes, 2016, 609} During the 6th World Symposia on Pulmonary Hypertension, the hemodynamic definition for pulmonary hypertension in children was aligned with the adult definition as a mean pulmonary artery pressure (mPAP) of > 20 mm Hg {Galiè, 2019; Rosenzweig, 2019, 1; Simonneau, 2019, 1} from being previously set at >=25 mmHg.{Abman, 2015b, 2037} Five large clinical groups were updated: (1) pulmonary arterial hypertension (PAH) which includes pulmonary hypertension associated with congenital heart disease and PPHN syndrome (which is the most frequent cause of transient pulmonary hypertension);{Rosenzweig, 2019, 1} (2) pulmonary hypertension due to left heart disease; (3) pulmonary hypertension owing to lung diseases and or hypoxia; (4) pulmonary hypertension due to pulmonary artery obstructions; and (5) pulmonary hypertension with unclear multifactorial mechanism. These classifications are very useful as distinct phenotypes and related outcomes are emerging across groups reported in registries.{Abman, 2021, 1}

Epidemiology of Pediatric Pulmonary Hypertension

As pulmonary hypertension is a relatively rare condition, it has been studied with the use of national and international registries.{Abman and Raj, 2009, 3; Berger, 2012, 537; Fraisse, 2010, 66; McGoon, 2013, D51; Moledina, 2010, 1401; Swinnen, 2019, 1} The estimated incidence of sustained pulmonary hypertension was reported at 4–10 cases per million children per year with a prevalence of 20–40 cases per million in Europe {del Cerro Marín, 2014, 1421; Kwiatkowska, 2020; Van Loon, 2011, 1755} and 5–8 cases per million children per year and 26–33 per million children in the USA.{Li, 2017, 126} Importantly using the strength of a longitudinal national registry, the great majority of children present with pulmonary artery hypertension, as infants with either PPHN or repairable cardiac shunt defects.{Van Loon, 2011, 1755} The remaining children with sustained pulmonary hypertension had other forms of pulmonary artery hypertension (idiopathic, associated with congenital heart disease, or with connective tissue disease and pulmonary veno-occlusive disease) while a significant proportion had pulmonary hypertension associated with developmental lung disease, including BPD, CDH and congenital pulmonary vascular abnormalities. Overall pulmonary hypertension associated with congenital heart disease is the most frequent in children.

Focusing on pediatric pulmonary hypertension hospitalizations, a retrospective cohort study from the Kids’ Inpatient Database in the United States estimated that children with pulmonary hypertension accounted for 0.13% of the 43 million pediatric hospitalizations nationally between 1997 and 2012 with an increasing trend over the study period.{Maxwell, 2015, 241}

In the prospective multicenter ICU-RESUS study comprising of 18 pediatric intensive care units and pediatric cardiac intensive care units in the United States with 1276 IHCA patients during the study period, 16% of children had pre-existing pulmonary hypertension.{Morgan, 2023, 1}

Pediatric In-Hospital Pulmonary Hypertension Survival Data

In a review of the Registry to Evaluate Early and Long-Term Pulmonary Artery Hypertension Disease Management (REVEAL) database, the 5-year survival for patients below 18 years old was 74 +/-6 %, with no significant difference between the idiopathic pulmonary hypertension/familial pulmonary hypertension and pulmonary hypertension associated with congenital heart disease.{Barst, 2012, 113} Older age at diagnosis was a feature associated with worse prognosis.

In another multi-national study, children with pulmonary hypertension associated with congenital heart disease showed favorable survival compared to idiopathic and hereditary pulmonary arterial hypertension patients. In this study, mean pulmonary-to-systemic arterial pressure ratio and pulmonary vascular resistance index were independent predictors of survival.{Zijlstra, 2014, 2159}

Risk of death and intensive care hospitalizations

To promote the study of children with pulmonary hypertension, the term ‘Clinical Worsening’ is emerging as a meaningful composite endpoint for interventional trials. One of the clinical worsening endpoints associated with the risk of death or lung transplantation includes non-elective pulmonary artery hypertension-related hospitalizations (including hospitalizations for atrial septostomies, initiation of intravenous prostanoids and functional deterioration). Non-elective hospitalizations are a relevant patient-oriented outcome in pediatric pulmonary hypertension.{Ploegstra, 2015, 655}

From a large in-patient national database studied (from 2000 to 2009) in the United States, we learn that hospitalization rates of pediatric patients with pulmonary hypertension have increased; the risk of mortality in hospitalized patients with pulmonary hypertension is greater than patients without pulmonary hypertension; however, the risk of mortality decreased over the studied period. This study also evaluated hospital charges and suggests these changes increased in patients with pulmonary hypertension over the studied period.{Frank, 2015, 339}

In a recent multicenter study from the Pediatric Cardiac Critical Care Consortium (PC4) (from 2014 to 2019), the risk of mortality for children with pulmonary hypertension was higher compared to all other medical cardiac admissions (10% vs 3.9%). Importantly 6.1% of these admissions with pulmonary hypertension experienced a CPR event. Among this cohort, the receipt of mechanical ventilation and vasoactive therapies within the first two days of intensive care admission were associated with a significantly increased odds of mortality.{Morell, 2021, 454}

A study using the Virtual Pediatric Intensive Care (VPICUs) database that includes over 160 intensive care units, focused on children with an in-hospital cardiac arrest and compared patients with and without pulmonary hypertension. Using a propensity matching method, it showed that patients with pulmonary hypertension were less likely to survive to hospital discharge (aOR 0.83 (95%CI: 0.72–0.95; p=0.01)). The pulmonary hypertension group with an in-hospital cardiac arrest had a predicted survival rate of 59.1% (56.5–61.8%) compared to 61.6% (60.0–63.2%) in the group without pulmonary hypertension with an in-hospital cardiac arrest. {Morgan, 2021, 52}

More recently, the authors of the analysis of 1129 pediatric IHCA events from the prospective multicenter ICU-RESUS study, concluded that pre-arrest pulmonary hypertension “was not associated with statistically significant differences in survival outcomes or intra-arrest physiologic measures.” {Morgan, 2023, 1}

Extracorporeal life support technologies, extracorporeal membrane oxygenation (ECMO) & Pediatric Pulmonary Hypertension

Before a cardiac arrest, extracorporeal membrane oxygenation (ECMO) may be used to stabilize infants with PPHN or CDH or in the post operative period of congenital heart disease when iNO and mechanical ventilation with general measures are insufficient.{Abman, 2015b, 2037} Other modes of extracorporeal life support technologies than ECMO may be applied for pediatric patients with pulmonary hypertension failing to respond to medical management as a bridge to lung transplantation, but these other modes are not applied during an acute resuscitation from cardiac arrest.{Strueber, 2009, 853} ECMO may also be employed as a back-up plan when undertaking stabilization of patients with advanced severe pulmonary hypertension undergoing high-risk interventions such as atrial septostomy or Potts shunts.{Rosenzweig, 2019, 1}

ECMO may be applied during refractory cardiac arrest in pediatric patients with pulmonary hypertension, however the comparative evidence is limited. Moreover, it is important to note that the risk of survival of pediatric patients with pulmonary hypertension supported with ECMO may be worse than in other disease groups supported with ECMO. Using an ECMO registry, a study in pediatric patients with pulmonary hypertension supported with ECMO suggests they have a risk of survival lower than those supported with ECMO without pulmonary hypertension.{Morell, 2020, 256} In another study, using an in-patient hospitalization database and a comparative study with propensity matching of children supported with pulmonary hypertension with and without ECMO, the incidence of mortality was higher in the ECMO group compared to the control group (OR 6.98, 95% CI 3.43–14.21, p < 0.001). Patients in the ECMO group had higher odds for acute kidney injury (OR: 2.41, 95% CI: 1.30–4.47, p = 0.005), neurologic complications (OR: 7.11, 95% CI: 1.57–32.18, p = 0.011), sepsis (OR: 2.69, 95% CI: 1.46–4.96, p = 0.002), and thrombotic complications (OR: 2.90, 95% CI: 1.10–7.67, p = 0.032).{Nasr, 2016, 728} Several factors may explain these results and we speculate that the efficacy of conventional CPR preceding the cannulation to ECMO may be impaired from the increased pulmonary vascular resistance.

Pulmonary hypertensive specific therapies and interventions for the treatment of cardiac arrest

Only three articles presented data on the management of cardiac arrest in children with pulmonary hypertension (see Table 2).  Two of these studies included ECMO cannulation as intervention.

In a retrospective multicenter registry study using the ELSO database with patients aged from 28 days to 18y with pulmonary hypertension who received ECMO from 2007 – 2018, there were 605 patients (634 ECMO runs). Among these, 30% had a cardiac arrest at some point before being supported by ECMO and 16.7% were classified as ECPR. iNO was in use prior to ECMO in 58.5% of cases and 32% were receiving at least three vasoactive infusions the day before ECMO cannulation. Survival in patients with pulmonary hypertension requiring ECMO was lower compared to those patients who required ECMO and did not have diagnosis of pulmonary hypertension (48.7% vs 55.2%, p=0.001) during the same era. Survival among ECPR group was lowest (27.4%) with an adjusted odds of mortality of

3.8; 95% CI, 2.2–6.3.{Morell, 2020, 256}

In another retrospective study including patients <18y with pulmonary arterial hypertension (PAH) admitted for diagnostic cardiac catheterization in a center in China from 2007 to 2020, there were 147 patients (163 procedures). They defined PAH as pulmonary arterial pressure (PAP) ≥ 25 mmHg, pulmonary artery wedge pressure ≤ 15mmHg, and pulmonary vascular resistance (PVR) index >3 wood units⋅m2 by right heart catheterization. Pulmonary Hypertensive Crisis (PHC) was defined as a quick drop in both systolic blood pressure (<80 mmHg or drop >20%) and pulse oximetry SpO2 <90%, and an acute increase to supra-systemic PAP during right heart catheterization. The incidence of PHC was 11.7% (19 patients) and among these with PHC, five patients required chest compressions. Treatments for PHC included: initiation of high flow oxygen; iloprost inhalation; vasoactive agents (dopamine, dobutamine, epinephrine, norepinephrine); intravenous treprostinil and acidosis correction. One patient died. Immediate survival was 99.4% in patients with a PHC event but long-term survival was lower when compared to patients without a PHC. The study does not compare therapies used to treat PHC or cardiac compression-related events.{Li, 2022, e12067}

In a retrospective case series of six children in France with drug-refractory supra-systemic PAH and deteriorating right ventricle function that underwent transcatheter Potts shunt procedure, the investigators report the detailed physiology and course. Two patients demonstrated reduced left ventricle systolic function resulting in cardiac arrest after establishment of the transcatheter Potts shunt (both unstable since anesthesia induction). Both were cannulated to ECMO but died from irreversible brain injury on 3rd and 10th day after the procedure. This study does not compare interventions used for therapies for cardiac arrest but characterizes children with severe PAH undergoing Potts procedure.{Boudjemline, 2017, 1188}

We conclude from this scoping review, that there are insufficient studies to support a systematic review on specific interventions or management strategies for the resuscitation of children with pulmonary hypertension with cardiac arrest. The next steps should focus on generating primary evidence in key at risk pulmonary hypertension disease groups characterized using contemporary classification systems and definitions. Children hospitalized with pulmonary hypertension are at higher risk of cardiac arrest than other children. However, this disease remains relatively rare which suggests that future research will require multicenter studies or large registry-based comparative studies to better understand the value of one intervention over another for treatment of cardiac arrest.

3. Narrative Reporting of the task force discussions

General approaches to improving cardiopulmonary physiology in the context of a pulmonary hypertension crisis or cardiac arrest remain important. These are included below as ‘Good Practice Statements’. Similarly, these statements are found in the 2015 AHA Statement for Pulmonary Hypertension by Abman et al {Abman, 2015a, 2037} and in the section on pulmonary hypertension in the 2018 AHA Statement by Marino et al {Marino, 2018, e691 } on the management of Cardiopulmonary Resuscitation in Infants and Children With Cardiac Disease.

Moving forward, we propose ILCOR keep this new PICOST to maintain a focus on interventions to treat cardiopulmonary arrest in children with pulmonary hypertension to promote studies and research in this high-risk pediatric disease group.

We suggest that the classification of five groups of conditions and diagnoses detailed in the most recent international guidelines on pediatric pulmonary hypertension be used when studying the risk of cardiopulmonary arrest or interventions to treat cardiopulmonary arrest.{Simonneau, 2019, 1} Better characterizing each infant and child with pulmonary hypertension is the first step in ensuring that their deterioration is anticipated.

We suggest that the definition of pulmonary hypertension in ILCOR be harmonized with the latest international pediatric pulmonary hypertension guidelines{Abman, 2015a, 2037; Abman, 2021, 1; Simonneau, 2019, 1}. ILCOR Treatment recommendations are not made following a scoping review. The PLS/NLS Task Forces considered the review evidence and suggest the following good practice statement.

Good practice statements:

In children including neonates with pulmonary hypertension hospitalized for a clinical worsening event, we suggest avoiding factors that may increase pulmonary vascular resistance while treating the aggravating condition to decrease the risk of cardiac arrest. There is insufficient evidence to suggest using specific interventions over others. Management strategies include avoiding hypoxia, hypercapnia, acidosis, stressors such as pain, agitation, dehydration or fluid overload, anemia, infection, or arrhythmias. Pulmonary hypertension specific treatments e.g., iNO, L-Arginine, phosphodiesterase inhibitors (e.g., Milrinone, Sildenafil) or endothelin-1 inhibitors (e.g., Bosentan) may be considered.

In children who develop signs of pulmonary hypertensive crisis, of low cardiac output or of right ventricular failure despite optimal medical therapy, ECMO may be considered before cardiac arrest or for refractory cardiac arrest, as a bridge to recovery, or as a bridge to the evaluation for organ replacement and transplantation in very selected cases.

Knowledge Gaps

A main gap identified is that despite this pediatric population being at high risk of cardiopulmonary arrest, specific resuscitation management approaches for this disease group has not been the focus of published studies between 2012-2023.

There were no studies identified that evaluated prospectively the management to treat cardiopulmonary arrest in pediatric patients with pulmonary hypertension in the in-hospital setting.

In the newly born, while many animal and human studies have assessed treatment approaches for PPHN in general or for a specific condition associated with pulmonary hypertension, none of these studies specifically addressed treatment for pulmonary hypertension after chest compression.

Future observational studies should build on published diagnostic and severity classification systems to improve our knowledge of pediatric pulmonary hypertension patients who suffer cardiopulmonary arrest. These include broad studies of the epidemiology, risk factors, short term outcomes (functional, cardiopulmonary, neurological and survival) at hospital discharge and long-term outcomes.{Abman, 2021, 1}

The context of hospitalizations that may present higher risk of cardiac arrest in children with pulmonary hypertension deserve further studies: 1) anesthesia (for diagnostic catheterization or for other procedures); or 2) post operative care period; {Morell, 2021, 454} or 3) hospitalizations with deteriorations associated with clinical worsening events.{Ploegstra, 2015, 655} We propose adding ‘cardiopulmonary arrest events’ as a study variable among clinical worsening endpoints in longitudinal epidemiological registries; this would serve as a first step to measure the burden of this problem.

There are no published studies evaluating approaches to mechanical ventilation that could be optimal during the resuscitation of children with pulmonary hypertension such as the timing of the advanced airway insertion, the quantity of oxygen therapy in cyanotic and non-cyanotic heart disease or in the context of an atrial septostomy; the use of positive end expiratory pressure, of peak inspiratory pressure, of minute ventilation (normal ventilation or hyperventilation), or iNO, or of modes of mechanical ventilation during the post cardiac arrest care period to best support the right and left ventricles and minimize harmful cardiopulmonary interactions.

There are no studies on the dose or type of inotrope or vasopressor that could be delivered during a cardiopulmonary arrest event and on the physiologic endpoints to target during the intra-arrest period such as the optimal target in end tidal capnography value.

There are no studies that inform if children with pulmonary hypertension with known right heart catheterization data should receive personalized resuscitation measures over conventional standard measures.

While some may suggest conventional CPR may not be effective in some severe pulmonary hypertension groups (e.g. pulmonary veno-occlusive disease with severe right-sided failure listed for lung transplant) and that ECMO may need to be considered immediately after loss of output (e.g. percutaneously during insertion of an advanced airway),{Taylor and Holtby, 2009, 382} there are no studies that inform the timing of transitioning from high-quality CPR to ECPR in pediatric patients with severe pulmonary hypertension (e.g. pulmonary hypertension listed for lung transplantation, pulmonary hypertension s/p atrial septostomy).

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