How Do We Safely Use Inhaled Nitric Oxide?

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COMMENTARIES

Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.

How Do We Safely Use Inhaled

Nitric Oxide?

ABBREVIATIONS. iNO, inhaled nitric oxide; ECMO, extracorpo-real membrane oxygenation.

T

he physiologic effects of inhaled nitric oxide (iNO) were first presented in 1992.1,2_Although

the neonatal community has embraced iNO as a selective pulmonary vasodilator that reduces the use of (not need for) extracorporeal membrane oxy-genation (ECMO), the drug (at the time that this commentary was written) is not approved for clinical use. Why?

To approve a therapy, the Food and Drug Admin-istration usually requires that two separate clinical trials show that it improves a specific outcome with-out increasing the risk for adverse with-outcomes. In ad-dition, the improved outcome should impact health, not just physiology. Improvements in physiology (improved oxygenation) do not always translate to improvements in health (eg, increased Pao2 in pre-mature neonates increases the risk for retinopathy).

Studies establish that iNO improves oxygen-ation3–5 _{and reduces the use of ECMO.}4,6

Unfortu-nately, these outcome measures are not surrogate markers for improved health. If avoiding ECMO is associated with an increased risk for poor outcome, the safety of iNO must be questioned.

There are no data that demonstrate any health benefit from the use of iNO. In the NINOS study, the length of hospitalization was longer for neonates treated with iNO (36 days vs 30 days; P 5 .17).6_In

addition, Davidson et al7_{reported a higher mortality}

in neonates treated with iNO than in patients as-signed to placebo (8% vs 2%;P5.22). Although it is tempting to dismiss these trends as not statistically different, these results must be carefully understood and explained.

If iNO prevents the evolution of pulmonary hy-pertension and progressive hypoxemia that necessi-tates the use of ECMO, why does it not promote better health? One possible explanation is that ECMO is an effective rescue tool. ECMO saves lives and improves survival without neurodevelopmental problems.8,9 _{In addition, studies show that ECMO}

candidates who are managed with alternate

thera-pies may do worse than neonates who are treated with ECMO.10,11_{If ECMO is an effective rescue tool,}

it may erase the health benefits of iNO by saving patients in whom iNO fails.

Another potential and opposite explanation is that we apply iNO only after injury is irrecoverable. If we use iNO only after all else (alkalosis, hyperventila-tion, paralysis, surfactant, and high-frequency venti-lation) has failed, then we may not see the benefit of iNO because we acted too late. Ongoing studies hope to determine if early use of iNO improves its safety profile.

In this month’s issue ofPediatrics, Davidson et al12

give us another possible explanation. Stopping iNO can be associated with the development of severe hypoxemia. The hypoxemia associated with with-drawal of iNO is dose-dependent and occurs in pa-tients classified as treatment successesand in patients considered treatment failures. Both observations are im-portant and can improve our ability to use iNO safely.

The dose-dependent nature of the severity of the deterioration in oxygenation offers us a practice guideline. The data suggest that iNO should be de-creased to 1 ppm before stopping it. The authors also suggest that oxygen support should be increased when iNO is stopped even in patients in whom iNO has failed.

Davidson et al also describe an avoidable cause of mortality. Four of the iNO treatment failures died after iNO was stopped. One death occurred soon after stopping iNO. The authors suggest that abruptly stopping iNO in patients meeting ECMO criteria may be fatal. Weaning of iNO in ECMO candidates should be done only when ECMO is readily available and iNO should be continued until ECMO support is established.

It may be argued that withdrawal of iNO is not to blame. Instead, the hypoxemia may be caused by the progression of the underlying pathophysiology. However, the dose-dependent nature of the degree of hypoxemia and the failure to describe rebound hypoxemia in patients treated with placebo gas sug-gest that iNO is playing an active, not a passive, role. Looking to the future, much remains to be learned. Are we using the correct dose of iNO for the right duration? Are we selecting the best patients for treat-ment? Does iNO delay the initiation of ECMO? Is the delay associated with an increased risk for morbid-ity? In the era of surfactant, high-frequency ventila-tion, and iNO, understanding how to safely avoid ECMO takes on new importance. Only by discover-ing how, when, and in whom we should use iNO will we improve the health of critically ill neonates. Davidson et al are to be applauded for the

collabo-Received for publication Feb 9, 1999; accepted Mar 2, 1999.

Address correspondence to Reese H. Clark, MD, Pediatrix Medical Group, 1455 North Park Dr, Fort Lauderdale, FL 33326. E-mail: reese_clark@ mail.pediatrix.com

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rative efforts in moving our understanding forward. Their observations have made iNO safer to use.

Reese H. Clark, MD

Pediatrix Medical Group Fort Lauderdale, FL 33326

REFERENCES

1. Kinsella JP, Neish SR, Shaffer E, Abman SH. Low-dose inhalation nitric oxide in persistent pulmonary hypertension of the newborn.Lancet.

1992;340:819 – 820. See comments

2. Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn.Lancet.1992;340: 818 – 819. See comments

3. Barefield ES, Karle VA, Phillips JB III, Carlo WA. Inhaled nitric oxide in term infants with hypoxemic respiratory failure.J Pediatr.1996;129: 279 –286

4. Roberts JD Jr, Fineman JR, Morin FC III, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group.N Engl J Med.1997;336:605– 610

5. Wessel DL, Adatia I, Van Marter LJ, et al. Improved oxygenation in a randomized trial of inhaled nitric oxide for persistent pulmonary hy-pertension of the newborn. Pediatrics. 1997;100(5). URL: http:// www.pediatrics.org/cgi/content/full/100/5/e7

6. Anonymous. Inhaled nitric oxide in full-term and nearly full-term in-fants with hypoxic respiratory failure. The Neonatal Inhaled Nitric Oxide Study Group.N Engl J Med.1997;336:597– 604

7. Davidson D, Barefield ES, Kattwinkel J, et al. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study. The I-NO/PPHN Study Group.Pediatrics.

1998;101:325–334

8. Anonymous. UK collaborative randomised trial of neonatal extracorpo-real membrane oxygenation. UK Collaborative ECMO Trail Group.

Lancet.1996;348:75– 82. See comments

9. O’Rourke PP, Crone RK, Vacanti JP, et al. Extracorporeal membrane oxygenation and conventional medical therapy in neonates with per-sistent pulmonary hypertension of the newborn: a prospective random-ized study.Pediatrics.1989;84:957–963. See comments

10. Walsh-Sukys MC, Bauer RE, Cornell DJ, Friedman HG, Stork EK, Hack M. Severe respiratory failure in neonates: mortality and morbidity rates and neurodevelopmental outcomes.J Pediatr.1994;125:104 –110 11. Vaucher YE, Dudell GG, Bejar R, Gist K. Predictors of early childhood

outcome in candidates for extracorporeal membrane oxygenation.J Pe-diatr.1996;128:109 –117

12. Davidson D, Barefield ES, Kattwinkel J, et al. Safety of withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn.Pediatrics.1999;104:231–236

Apnea of Prematurity and Risk for

Sudden Infant Death Syndrome

W

e found Dr Hodgman’s commentary1_that

appeared in the October 1998 issue of Pe-diatricsvery interesting.

Dr Hodgman acknowledges the fact that “the pre-mature infant is at increased risk to die of SIDS” and points out that in Los Angeles County in 1996, the risk in babies born before 37 weeks’ gestation was approximately five times higher than the overall population. She also comments that “this increased risk has been recognized for many years, yet the

reasons remain obscure.” Although we may not know thecauseof SIDS, there have been a number of death recordings published that have revealed that bradycardia almost always precedes central apnea as the terminal event.2,3_{These recordings are especially}

germane to her commentary because they are re-stricted to premature infants who died of SIDS or with bronchopulmonary dysplasia. In addition, al-though no death recordings have contained data on oxygenation, Poets4 _{has published data on}

hypox-emia preceding many bradycardias and apneas. These data may be relevant for preterm SIDS deaths also. A recent advance in oxygen saturation monitor-ing, signal extraction technology, has reduced the number of alarms compared with conventional oximetry by 93% and yet detects hypoxemia and bradycardia reliably.5,6_{Hence, it now may be}

possi-ble routinely to follow oxygen saturation in the home. Therefore, a new generation of home monitors might alarm for desaturations and arrhythmias, rather than for apnea.

Dr Hodgman refers to the preliminary data re-cently presented by investigators involved with the Collaborative Home Infant Monitoring Evaluation (CHIME) study that “apparently normal” prema-tures have prolonged apnea with obstruction and oxygen desaturation in the home.7_{One of the infants}

had an apnea 72 seconds long. No explanation is furnished in the abstract to which she referred as to why there was no intervention to terminate this ap-nea earlier. But, in any case, if home monitoring could lead to earlier termination of such an event, most reasonable people would be supportive of such an action. Although such an event may not be fatal, few would argue that it could be beneficial for the brain.

Dr Hodgman tells us that there is “no evidence that monitoring is effective.” It is true that there are no controlled studies on the efficacy of home moni-toring, either pro or con. Such a randomized, pro-spective study has never been done and it is unlikely that it ever will be as institutional review boards would be loathe to approve such a study in today’s legal climate. There is, however, much anecdotal evidence from clinicians that shouldn’t be totally ignored. In addition, when case studies showing monitor effectiveness (ie, cardiopulmonary resusci-tation started as a result of a monitor alarming) are submitted for publication they are uniformly not published. If home cardiorespiratory monitors should not be used because there are no controlled studies showing their effectiveness, would Dr Hodg-man have us discard the monitors we use in the neonatal intensive care unit or the pediatric intensive care unit? There are no controlled studies showing their effectiveness either.

We do agree with Dr Hodgman that it is “past time to discontinue the practice of obtaining cardiorespi-ratory recordings to identify risk for SIDS . . . ”. But we do believe that, for now, home cardiorespiratory monitoring, in conjunction with a complete medical management program, has a place in the care of the

Received for publication Dec 15, 1998; accepted Mar 16, 1999.

Reprint requests to (G.E.F.) Emory Egleston Apnea Center, 1405 Clifton Rd, NE, Atlanta, GA 30322. E-mail: gfreed@emory.edu

COMMENTARIES 297

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high-risk infant. In the future, home monitors might detect and alarm for desaturations and arrhythmias and only record chest movements.

Home monitoring is used not only as an alarm system, but can be used as a diagnostic tool. We have diagnosed cardiac arrhythmias such as heart blocks, and prolonged asystoles (up to 16 seconds long) that were totally unsuspected by the neonatologist and/or primary care physician. In addition, the home monitor can be used to determine if various therapeutic regimens are effective and when medi-cations (such as theophylline) can be stopped safely. Clearly, there is enough data in the literature that demonstrates that we cannot rely on parental obser-vations to tell us how a child is doing.8_{There is no}

argument that apnea of prematurity is not a risk factor for SIDS, but, to negate the role of home car-diorespiratory monitoring in the continuum of care of the high-risk infant is not justified.

Gary E. Freed, DO, FAAP

Department of Pediatrics Emory Egleston Apnea Center Atlanta, GA 30322

Robert G. Meny, MD

SIDS and Pediatric Sleep Disorder Unit

N5W67 University Hospital University of Maryland

School of Medicine Baltimore, MD 21201

REFERENCES

1. Hodgman JE. Apnea of prematurity and risk for SIDS.Pediatrics.1998; 102:969 –971

2. Kelly DH, Pathak A, Meny R. Sudden severe bradycardia in infancy.

Pediatr Pulmonol.1991;10:199 –204

3. Meny R, Carroll JL, Carbone MT, Kelly DH. Cardiorespiratory record-ings from infants dying suddenly and unexpectedly at home.Pediatrics.

1994;93:44 – 49

4. Poets CF, Samuels MP, Noyes JP, Jones KA, Southall DP. Home mon-itoring of transcutaneous oxygen tension in the early detection of hy-poxemia in infants and young children.Arch Dis Child.1991;66:676 – 682 5. Bohnhorst B, Poets CF. Alarm rate evaluation of a new technology

oximeter.Pediatr Pulmonol.1997;24:450A

6. Bohnhorst B, Peter C, Poets CF. Pulse oximeters’ reliability in detecting hypoxemia and bradycardia: comparison between Nellcor N-200, Nell-cor N-3000 and Masimo SET.Pediatr Pulmonol.1998;26:444A 7. Ramanathan R, Corwin M, Hunt CE, et al. Preterm infants have

pro-longed apnea with obstruction and associated oxygen desaturation at home.Pediatr Res.1997;41:171. Abstract

8. Krongrad E, O’Neil L. Near miss sudden infant death syndrome epi-sodes? A clinical and electrocardiographic correlation.Pediatrics.1986; 77:811– 815

NEW YORK HOSPITALS DROPPING OUT OF PROGRAM TO TRAIN FEWER DOCTORS

Two years ago, dozens of teaching hospitals across New York State embraced an unusual pilot program to ease the nationwide glut of physicians. The federal government would pay bonuses to the hospitals if they trained fewer doctors, just as it once paid corn farmers not to grow corn.

But half those hospitals have now dropped out of the plan after finding that they cannot function without the low-cost labor provided by doctors-in-training, known as residents.

The development, which comes even as the government is planning to expand the New York pilot program nationwide, raises doubts about federal efforts to curb the number of doctors in the nation, and it illustrates a conundrum of health care today. While society at large can ill afford to have an oversupply of doctors, which experts say drives up the cost of health care, hospital officials cannot afford to run their institutions without the trainees who will add to that oversupply.

Foderaro LW.New York Times, April 1, 1999

Noted by JFL, MD

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DOI: 10.1542/peds.104.2.296

1999;104;296

Pediatrics

Reese H. Clark

How Do We Safely Use Inhaled Nitric Oxide?

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DOI: 10.1542/peds.104.2.296

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