Share this article on:

Adversity in Neonates and Children with Pulmonary Artery Hypertension: The Role of ECMO

Wearden, Peter D.; Maul, Timothy M.

doi: 10.1097/MAT.0000000000000459
Invited Commentary

From the *Cardiac Center, Nemours Children’s Hospital, Orlando, Florida; Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennysylvania; and Department of Biomedical Engineering, University of Pittsburgh, Pittsburgh, Pennysylvania.

Submitted for consideration September 2016; accepted for publication in revised form October 2016.

Disclosures: The authors have no conflicts of interest to report.

Correspondence: Peter. D. Wearden, Cardiac Center, Cardiovascular Services, Nemours Children’s Hospital, 13535 Nemours Parkway, Orlando, FL 32827. Email: Peter.Wearden@nemours.org.

In a study in this issue by Nasr et al.,1 the authors found a striking mortality rate in pediatric patients with pulmonary artery hypertension (PAH) from noncongenital cardiac disease who were treated with extracorporeal membrane oxygenation (ECMO) compared with a propensity-matched cohort of patients who were not treated with ECMO. This study, remarkable for its utilization of a large-scale database of administrative and hospital admission data collected from a broad variety of sizes and types of hospitals in a large cross-section of the United States, provides some insight into a relatively rare disease (1.4% of the database) and one of the most extreme methods available to clinicians to combat its effects, the use of which is also exceedingly rare (0.15%). From the outset, before propensity matching, we are introduced to a patient population that is younger (54% <12 months in age), less likely to be electively admitted (91%), admitted for longer periods of time, and who have a significantly higher likelihood for comorbidity (per Elixhauser scale) compared with those who do not require ECMO. This population profile discrepancy is reminiscent of the makeup of pediatric cardiac ECMO and ventricular assist device population versus those that do not require this support, or pediatric respiratory ECMO versus conventional therapy, which also tend to be younger, emergently admitted, and sicker as demonstrated through a variety of comorbidity scales.2,3 While the results of this study are somewhat disheartening from an outcomes standpoint (39% mortality vs. 8% mortality in matched cohorts), given that ECMO is generally utilized in the most extreme cases and as a last resort, it is hopefully apparent to the reader that clinicians in deciding to implement ECMO are faced with a significantly refractory patient population with few if any remaining options. In other words, despite the propensity matching, it is likely that there was a certain clinical “je ne sais quoi” certainly not captured by such an administrative database that required the utilization of ECMO. More bluntly, even if one picks the ripest apples from the bunch to compare with, they still are not oranges.

While ECMO is not a tool that is taken lightly by those who practice it, and is employed in the face of exhaustion of nearly all other medical therapies, there is significant debate in the clinical community over the timing and utilization of this therapy in a variety of disease states, with recognition that the earlier implementation of therapy, the fewer complications and the better the patient outcome.4,5 Some of the debate has been driven by the fact that the risks of complications from ECMO utilization have been dramatically reduced over the past decade thanks in large part to newer and better equipment: Polymethylpentene oxygenators that last for weeks, centrifugal pumps that cause little hemolysis, and a better understanding of pediatric anticoagulation and anticoagulation testing.6–10 However, the utilization of ECMO still is not without risks, and in this PAH population, Nasr et al.1 reported higher incidences of kidney failure, neurologic injury, thrombotic complications, and sepsis in their ECMO population compared with those who did not require ECMO with the same caveats as noted above.

A few key challenges are hopefully apparent when viewing this study in the larger context of outcomes, resource utilization, and healthcare costs. The first is that because this is a large retrospective dataset which primarily relied on administrative coding and inpatient reports, there is no chance to distinguish the events leading up to the utilization of ECMO. In fact, this study points to the need for a concerted effort to study the progression of apparently similar patients from the outset (i.e., prospective matching on age, elective admission, and the Elixhauser score) down two very different paths. One would expect that those that require ECMO might take a slow progressive march toward multiple organ failure as the strain on the right ventricle and limited oxygen supply leads to a chronic and progressive organ ischemia; or it might be a sudden onset of cardiac failure due to cardiac strain, or even adverse reactions to the medical therapy being received.11 For instance, how many of these patients saw the implementation of ECMO urgently, or even emergently following cardiac arrest? It is our hypothesis that these two scenarios represent a portion of the root cause for the increased kidney, neurologic, and septic injury that were found by Nasr et al.1 in the ECMO population of this study, and we would further hypothesize that these complications provided a significant contribution to the increased mortality of these patients as has been demonstrated in other studies,9,12–15 particularly with reference to neurologic14,16 and renal failure.17,18 Furthermore, viewed from the perspective of the non ECMO group, how many of these patients, if they had been placed on ECMO, might have survived? One might make the suggestion that fully 61% of these patients may have survived given the outcomes of the propensity-matched ECMO group.

Another question which must be asked is what were the circumstances that led to the termination of ECMO, and therefore death in these patients? In recent years, the decision to end ECMO in the face of futility has increasingly become controversial.19 We are experiencing longer, and more complication-free ECMO runs, and as a result may be finding that diseases which we thought were futile can be reversed with sufficient time and proper ECMO management. To wit, we have previously employed a pumpless lung technology in a pediatric patient with PAH following cardiac arrest onto ECMO. After 30 days on a central shunt and oxygenator with no pump and the initiation of pharmacologic therapy for pulmonary hypertension, the patient was weaned from the device and discharged to home.20 Similar results have also been published, both experimentally21 and clinically.22,23

In conclusion, we commend Nasr et al.1 for their study on the outcomes of ECMO utilization in PAH, and recognize the complexities and challenges of utilizing, and propensity matching, an unaudited, administrative database in a retrospective fashion. It is our hope that the questions raised by this article do not spur the “knee-jerk” reaction that ECMO is an inferior therapy in pulmonary arterial hypertension. Instead, we believe that thoughtful consideration will lead to the recognition of the need for further investigation into the underlying causes of this disparity in outcomes so that more targeted and effective therapies can be developed and utilized, perhaps even in conjunction with more timely implementation of ECMO, to effect a reduction in the mortality related to this disease.

Back to Top | Article Outline

References

1. Nasr VG, Faraoni D, DiNardo JA, Thiagarajan RR: Adverse outcomes in neonates and children with pulmonary artery hypertension supported with ECMO. ASAIO J 2016.62: 728–731.
2. Ibrahim AE, Duncan BW, Blume ED, Jonas RA: Long-term follow-up of pediatric cardiac patients requiring mechanical circulatory support. Ann Thorac Surg 2000.69: 186–192.
3. Hervey-Jumper SL, Annich GM, Yancon AR, Garton HJ, Muraszko KM, Maher CO: Neurological complications of extracorporeal membrane oxygenation in children. J Neurosurg Pediatr 2011.7: 338–344.
4. Chrysostomou C, Maul T, Callahan PM, et al: Neurodevelopmental outcomes after pediatric cardiac ECMO support. Front Pediatr 2013.1: 47.
5. Zabrocki LA, Brogan TV, Statler KD, Poss WB, Rollins MD, Bratton SL: Extracorporeal membrane oxygenation for pediatric respiratory failure: Survival and predictors of mortality. Crit Care Med 2011.39: 364–370.
6. Cornelius AM, Riley JB, Schears GJ, Burkhart HM: Plasma-free hemoglobin levels in advanced vs. conventional infant and pediatric extracorporeal life support circuits. J Extra Corpor Technol 2013.45: 21–25.
7. Northrop MS, Sidonio RF, Phillips SE, et al: The use of an extracorporeal membrane oxygenation anticoagulation laboratory protocol is associated with decreased blood product use, decreased hemorrhagic complications, and increased circuit life. Pediatr Crit Care Med 2015.16: 66–74.
8. Kessel AD, Kline M, Zinger M, McLaughlin D, Silver P, Sweberg TM. The impact and statistical analysis of a multifaceted anticoagulation strategy in children supported on ECMO: Performance and pitfalls. J Intensive Care Med 2015 [Epub ahead of print].
9. Maul TM, Wolff EL, Kuch BA, Rosendorff A, Morell VO, Wearden PD: Activated partial thromboplastin time is a better trending tool in pediatric extracorporeal membrane oxygenation. Pediatr Crit Care Med 2012.13: e363–e371.
10. Robak O, Lakatos PK, Bojic A, et al: Influence of different oxygenator types on changing frequency, infection incidence, and mortality in ARDS patients on veno-venous ECMO. Int J Artif Organs 2014.37: 839–846.
11. O’Byrne ML, Glatz AC, Hanna BD, et al: Predictors of catastrophic adverse outcomes in children with pulmonary hypertension undergoing cardiac catheterization: A multi-institutional analysis from the pediatric health information systems database. J Am Coll Cardiol 2015.66: 1261–1269.
12. Maul TM, Kuch BA, Wearden PD: Development of risk indices for neonatal respiratory extracorporeal membrane oxygenation. ASAIO J 2016.62: 584–590.
13. Ruth A, McCracken CE, Fortenberry JD, Hebbar KB: Extracorporeal therapies in pediatric severe sepsis: Findings from the pediatric health-care information system. Crit Care 2015.19: 397.
14. Barrett CS, Bratton SL, Salvin JW, Laussen PC, Rycus PT, Thiagarajan RR: Neurological injury after extracorporeal membrane oxygenation use to aid pediatric cardiopulmonary resuscitation. Pediatr Crit Care Med 2009.10: 445–451.
15. Alsoufi B, Al-Radi OO, Gruenwald C, et al: Extra-corporeal life support following cardiac surgery in children: analysis of risk factors and survival in a single institution. Eur J Cardiothorac Surg 2009.35: 1004–11; discussion 1011.
16. Graziani LJ, Gringlas M, Baumgart S: Cerebrovascular complications and neurodevelopmental sequelae of neonatal ECMO. Clin Perinatol 1997.24: 655–675.
17. Morris MC, Ittenbach RF, Godinez RI, et al: Risk factors for mortality in 137 pediatric cardiac intensive care unit patients managed with extracorporeal membrane oxygenation. Crit Care Med 2004.32: 1061–1069.
18. Rajagopal SK, Almond CS, Laussen PC, Rycus PT, Wypij D, Thiagarajan RR: Extracorporeal membrane oxygenation for the support of infants, children, and young adults with acute myocarditis: A review of the Extracorporeal Life Support Organization registry. Crit Care Med 2010.38: 382–387.
19. Gadepalli SK, Hirschl RB: Extracorporeal life support: Updates and controversies. Semin Pediatr Surg 2015.24: 8–11.
20. Kuch BA, Maul TM, O’Malley E, et al. Novalung as a bridge to recovery in a six year old with undiagnosed pulmonary hypertension with right-heart failure requiring ECMO: A case report. in 27th Annual Children’s National Medical Center Symposium ECMO & Advanced Therapies for Respiratory Failure 2011. Keystone, CO.
21. El-Ferzli GT, Philips JB 3rd, Bulger A, Ambalavanan N: Evaluation of a pumpless lung assist device in hypoxia-induced pulmonary hypertension in juvenile piglets. Pediatr Res 2009.66: 677–681.
22. Mayes J, Niranjan G, Dark J, Clark S: Bridging to lung transplantation for severe pulmonary hypertension using dual central Novalung lung assist devices. Interact Cardiovasc Thorac Surg 2016.22: 677–678.
23. Hoganson DM, Gazit AZ, Boston US, et al: Paracorporeal lung assist devices as a bridge to recovery or lung transplantation in neonates and young children. J Thorac Cardiovasc Surg 2014.147: 420–426.
Copyright © 2016 by the American Society for Artificial Internal Organs