Extracorporeal Life Support for Neonatal Respiratory Failure

ANNALS OF SURGERYVol. 220, No. 3. 269-282cc) 1994 J. B. Lippincott Company

Extracorporeal Life Support forNeonatal Respiratory FailureA 20-Year Experience

Charles J. Shanley, M.D.,* Ronald B. Hirschl, M.D.,* Robert E. Schumacher, M.D.JtMichael C. Overbeck, B.S.,* Thomas N. Delosh,t Robin A. Chapman, R.N.,*Arnold G. Coran, M.D.,* and Robert H. Bartlett, M.D.*

From the Departments of Surgery* and Pediatrics,t University of Michigan Medical Center, andthe Extracorporeal Life Support Organization,t Ann Arbor, Michigan

ObjectiveThe authors reviewed their experience with extracorporeal life support (ECLS) in neonatalrespiratory failure; they define changes in patient population, technique, and outcomes.

Summary Background DataExtracorporeal life support has progressed from laboratory research to initial clinical trials in 1972.Following a decade of clinical research, ECLS is now standard treatment for neonatal respiratoryfailure refractory to conventional pulmonary support techniques. Our group has the longest andlargest experience with this technique.

MethodsBetween 1973 and 1993, 460 neonates with severe respiratory failure were treated using ECLS.The records of all patients were reviewed.

ResultsOverall survival was 87%. Primary diagnoses were meconium aspiration syndrome (MAS; 169cases [96% survival]), respiratory distress syndrome/hyaline membrane disease (91 cases [88%survival]), persistent pulmonary hypertension of the newborn (37 cases [92%]), pneumonia/sepsis (75 cases [84% survival]), congenital diaphragmatic hernia (CDH; 67 cases [67%survival]), and other diagnoses (21 cases [71 % survival]). Common mechanical complicationsincluded clots in the circuit (136; 85% survival); air in the circuit (67; 82% survival); cannulaproblems (65; 83% survival) and oxygenator failure (34; 65% survival). Patient-relatedcomplications included intracranial infarct or bleed (54 cases; 61% survival), major bleeding (48cases; 81 % survival), seizures (88 cases; 76% survival), metabolic abnormalities (158 cases; 71 %survival) and infection (21 cases; 48% survival). Since 1989, treatment groups have beenexpanded to include premature infants (13 cases; 62% survival), infants with grade intracranialhemorrhage (28 cases; 54% survival) and 'non-honeymoon" CDH patients (15 cases; 27%survival). Since 1990, single-catheter venovenous access has been used in 131 patients (97%survival) and currently is the preferred mode of access. Follow-up ranges from 1 to 19 years; 80%of patients are growing and developing normally.

ConclusionsExtracorporeal life support has become standard treatment for severe neonatal respiratory failurein our center (460 cases; 87% survival), and worldwide (8913 cases; 81% survival). The availability

269

270 Shanley and Others

of ECLS makes the evaluation of other innovative methods of treatment, such as late electiverepair of diaphragmatic hernia and new pulmonary vasodilators, possible. The application of ECLSis now being extended to premature and low-birth weight infants as well as older children andadults.

Extracorporeal life support (ECLS) refers to the use ofprolonged extracorporeal circulation for temporary sup-port ofthe failing heart or lungs. The most common andsuccessful clinical application of ECLS has been in themanagement of term or near-term neonates with respi-ratory failure refractory to conventional ventilator ther-apy."2 Persistent pulmonary hypertension is the primarypathophysiologic mechanism ofrespiratory failure in thenewborn, regardless of the underlying disease process.3Increased pulmonary vascular resistance leads to a vi-cious cycle of right-to-left shunt with progressive hypox-emia and acidosis. By providing for adequate gas ex-change, ECLS allows time for reversal of pulmonary ar-terial hypertension while simultaneously avoiding theinjurious effects of elevated airway pressure and inspired

2oxygen concentration.

After a series of laboratory investigations, 4-8 we beganclinical trials of ECLS in 1972 and reported the first suc-cessful clinical application for neonatal respiratory fail-ure in 1976.9 Subsequently, neonatal ECLS was shownto be feasible, then safe and effective in the treatment ofneonatal respiratory failure. '0"' Between 1982 and 1984,we conducted a prospective, randomized trial that dem-onstrated that ECLS was superior to conventional venti-lator management.'2 We reported our first 100 consecu-tive cases for neonatal respiratory failure in 1986.1 3 Fortyof these patients were treated at the University of Cali-fornia, Irvine, and 60 of these patients were treated atthe University of Michigan. Since that report, ECLS hasprogressed from a clinical research project to a standardof care for neonatal respiratory failure.'4"5 Additionalcases in our series have been reported at regular intervalsas part of cost effectiveness16 and follow-up 7 studies andto introduce technical advances, such as single-cathetervenovenous access. 18 Recently, we expanded our treat-ment groups to include traditionally high-risk patients,such as "non-honeymoon" CDH patients, premature in-fants, and those with grade I intracranial hemorrhage

Presented at the I I 5th Annual Meeting ofthe American Surgical Asso-ciation; April 7, 1994; San Antonio, Texas.

Supported in part by grants from the National Institutes of Health andthe William Randolph Hearst Foundation.

Address reprint requests to Robert H. Bartlett, M.D., 1500 E. MedicalCenter Drive, 2918 Taubman Center, Box 0331, Ann Arbor, MI48109-0331.

Accepted for publication April II, 1994.

(ICH). This report summarizes our entire 20-year expe-rience with an emphasis on changing indications, tech-niques, and results. This project has been supported con-tinuously by the National Institutes of Health since1972.

PATIENTS AND METHODS

Data were abstracted from patient records and bedsideECLS flow sheets using standardized data capture formsthat are available through the Neonatal ExtracorporealMembrane Oxygenation Registry of the ExtracorporealLife Support Organization (ELSO). Although all patientshad some degree of pulmonary hypertension, a primarydiagnosis (i.e., MAS, respiratory distress syndrome, etc.)was assigned to each patient, and only those in whom theetiology ofpulmonary hypertension was truly idiopathicwere assigned a diagnosis ofpersistent pulmonary hyper-tension of the newborn.

Selection criteria have evolved over time; however,since our last report; we generally have used the oxygen-ation index (OI) based on arterial oxygenation and meanairway pressure and computed using the following for-mula:

01 = MAP X (FiO2 X 100)/PaO2

In our neonatal intensive care unit, an 01 value consis-tently greater than 25 defines a mortality risk of50%, andan 01 value of more than 40 defines an 80% mortalityrisk. Extracorporeal life support was considered for in-fants with an 01 that was consistently greater than 25,and ECLS was used if improvement did not occur or ifthe 01 reached 40. Other indications included an[Aa]DO2 > 600 for 4 to 6 hours, acute deterioration, se-vere barotrauma, cardiac arrest, failure to respond tomaximal medical therapy, and other indications basedon the particular clinical circumstances.From 1983 to 1989, relative contraindications to

ECLS were a gestational age of less than 35 weeks andevidence of intracranial hemorrhage detected by cranialultrasound. Recently, some premature infants (i.e., those< 35 weeks) and infants with grade I intracranial hemor-rhage were treated as part of clinical research protocols.Mechanical ventilation for more than 7 days was consid-ered a relative contraindication, and ventilation for morethan 10 days was considered an absolute contraindica-tion because ofthe high incidence ofbronchopulmonary

Ann. Surg. * September 1994

ECLS for Neonatal Respiratory Failure 271

dysplasia associated with prolonged high-pressure venti-lation. ForCDH patients, lack ofa "honeymoon period"(i.e., a postductal P02 > 50 mm Hg) generally was con-sidered evidence of irreversible hypoplasia and a relativecontraindication; however, for the past 5 years, all CDHpatients were treated as part of a clinical research proto-col. Absolute contraindications included profound neu-rologic impairment, congenital anomalies or conditionsnot compatible with a meaningful life, and irreversiblelung disease, such as severe bronchopulmonary dyspla-sia. In the early years ofour ECLS experience, neurologicassessment was limited to physical examination, and,undoubtedly, some infants with pre-existing ICH wereplaced on ECLS; later, ultrasound and computed tomog-raphy scan were added. For the last several years, ourpolicy has been to place moribund infants on ECLS, thenevaluate neurologic status 24 to 48 hours later. If there isevidence of severe neurologic impairment, all life sup-port is terminated.

Mechanical complications were compiled on an oc-currence basis and are defined in detail on the registrydata form available through the ELSO. Patient compli-cations were compiled similarly and are characterized ashemorrhagic, neurologic, renal, cardiopulmonary, pul-monary, infectious, and metabolic.Pre-ECLS management was performed in the neona-

tal intensive care unit under the direction of a staff neo-natologist or surgeon. Conventional management hasevolved over the past 20 years from high-pressure hyper-ventilation to pharmacologic alkalosis, to high fre-quency/low pressure ventilation and pulmonary vasodi-lators. The 01 criterion for case selection is suited ideallyfor detecting high mortality, despite changing conven-tional care. Any new treatment that is successful im-proves oxygenation or lowers airway pressure, decreas-ing the 01. General principles of conventional medicalmanagement included intubation and mechanical venti-lation with a standard infant ventilator. Inspired oxygenand positive end-expiratory pressure were adjusted to thelowest levels that would maintain adequate oxygenation.Peak inspiratory pressure, ventilator rate, and flow wereadjusted to the lowest levels that would maintain ade-quate ventilation. Attempts were made to lower pulmo-nary vascular resistance by hyperventilation or pharma-cologic therapy, and inotropic support was used as nec-essary. Echocardiography was used to rule out structuralcongenital heart disease, and cranial ultrasound was usedto detect ICH.

Neonatal ECLS management traditionally has in-volved extrathoracic vascular cannulation under localanesthesia ofthe right internal jugular vein and commoncarotid artery for venoarterial support. However, since1990, single-catheter, double-lumen venovenous access

has been the preferred mode ofaccess in our center. Dur-ing ECLS, venous blood was drained by siphon to a col-lapsible bladder that functioned to servoregulate a rollerpump and then was perfused through a membrane lungand a small heat exchanger. Arterialized blood was re-turned to the aortic arch via the right common carotidartery (venoarterial bypass) or the right atrium (venoven-ous bypass). Continuous intravenous heparin dosage wastitrated based on whole blood activated clotting time.Activated clotting time was maintained initially at 240seconds, then 200, and since 1988, 180 seconds. Plateletsinitially were transfused as necessary to maintain theplatelet count greater than 50,000 and more recently,greater than 80,000. Extracorporeal blood flow was ad-justed to optimize systemic oxygen delivery as reflectedby continuously measured mixed-venous saturation.Sweep gas composition and flow rate were adjusted tomaintain an arterial PCO2 of 35 to 40 mm Hg. Mechan-ical ventilation was reduced to "rest" settings (typicallyFiO2 = 0.30, ventilator rate = 1 0/min, airway pressure =20/4 cm H20). Extracorporeal life support was discon-tinued when native gas exchange was acceptable on"rest" ventilator settings or for other reasons deemednecessary by the attending physicians. Patients usuallywere maintained awake and alert during ECLS. Survivalwas defined as being decannulated from ECLS and extu-bated from all mechanical ventilator support for at least24 hours. Detailed discussions of ECLS techniques andmanagement have been published elsewhere.2

Statistical analyses were performed using a standardstatistical software package on a microcomputer (AppleComputer, Inc., Cupertino, CA).

RESULTSBetween 1973 and 1993, approximately 6000 new-

born infants were treated for severe respiratory failurein our neonatal intensive care units. Extracorporeal lifesupport was used in the treatment of 460 of these pa-tients, the vast majority ofwhom were were referred spe-cifically for ECLS. Characteristics ofthe patients who ul-timately required ECLS are summarized in Table 1.

Primary diagnoses and overall survival are outlined inTable 2. The most common primary diagnosis was MAS(37%), followed by respiratory distress syndrome (20%),pneumonia/sepsis (16%), CDH (15%), persistent pulmo-nary hypertension of newborns (8%), and other diagno-ses (4%). Figure 1 shows the cumulative number of casesand number of cases/year since our last comprehensivereport in 1986. Total number of cases treated fell in1993, reflecting both an increase in the number of re-gional ECLS centers and an overall improvement inperinatal management.

Vol. 220 -f No. 3


Table 1. PATIENT CHARACTERISTICSFOR NEONATAL ECLS

University of InternationalMichigan* Registryt(n = 460) (n = 8913)

Male/female (%)Apgar scores

1 min5 min

Birthweight (kg)Gestational age (wk)Age at ECLS initiation (hr)Duration of ECLS (hr)Last pre-ECLS ABGpO2 (mm Hg)pC02 (mm Hg)pH (mm Hg)

Last pre-ECLS ventilatorsettings

FiO2PIP (cm H20)PEEP (cm H20)MAP (cm H20)

(60/40)

4.88 ± 2.636.72 ± 2.143.21 ±.6838.7 ± 2.79

48.58 ± 53.54132.78 ± 95.36

43.54 ± 30.2839.15 ± 17.297.39 ± 0.17

0.99 ± 0.0642.75 ± 9.694.67 ± 3.8517.56 ± 4.83

(56/44)

5.08 ± 2.556.92 ± 2.063.26 ± 0.60

38.95 ± 2.3148.33 ± 55.22142.80 ± 130.86

41.51 ± 31.8541.19 ± 24.327.39 ± 0.22

1.00 ± 0.0543.77 ± 9.995.09 ± 3.7218.85 ± 5.04

500

400aIo 300-0

A 200-Ez

100

EI*ITotl1-O Anus I

'73-'86 '87 '88 '89 '90 '91 '92 '93

YearFigure 1. Cumulative and annual number of neonatal ECLS casestreated by year from 1973 to 1993. The number of annual cases treatedhas been stable at approximately 50 cases/year. Less cases were treatedin 1993, reflecting both an increase in the number of regional ECLS cen-ters and improved perinatal care.

ABG = arterial blood gas; FiO2 = fraction inspired oxygen; PIP = peak inspiratorypressure; PEEP = positive end-expiratory pressure; MAP = mean airway pressure.* Includes initial 45 cases at treated at University of California, Irvine.t Data from the neonatal ECMO Registry Report of the Extracorporeal Life SupportOrganization as of March 1994.

Data are reported as Mean ± SD.

The number of CDH cases treated per year has in-creased over time, whereas the number of cases treatedfor the other primary diagnoses has remained stable or

Table 2. PERCENT SURVIVAL BYPRIMARY DIAGNOSIS FOR

NEONATAL ECLS

University of InternationalMichigan* Registryt(n = 460) (n = 8913)

MASRDS/HMDPneumonia/sepsisCDHPPHN/PFCOtherOverall

96% (163/169)88% (80/91)84% (63/75)67% (45/67)92% (34/37)71% (15/21)87% (400/460)

93% (3074/3292)84% (864/1033)76% (1040/1364)58% (1008/1730)83% (960/1150)78% (267/344)81% (7213/8913)

decreased slightly. Figure 2 shows the number of casestreated per year for MAS (the most common primarydiagnosis), CDH, and for the entire series. Congenital di-aphragmatic hernia and overall survival have decreased,whereas survival for most other diagnoses has remainedstable. Figure 3 shows the outcome by year for MAS,CDH, and the entire series. Since 1988, the number ofhigh-risk cases has increased, including 15 "non-honey-moon" CDH patients, 13 premature patients, and 28grade I ICH patients. As the number ofhigh-risk patientshas increased, overall survival has decreased.Mode of access related to survival is outlined in Table

e0-

0

S

0

aa

60

50-

40

30-

20-

10-

*-r CDH-G MAS

'87 '88 '89 '90 '91 '92 '93

MAS = meconium aspiration syndrome; RDS = respiratory distress syndrome; HMD= hyaline membrane disease; CDH = congenital diaphramatic hernia; PPHN = per-sistant pulmonary hypertension of the newborn; PFC = persistant fetal circulation.* Includes initial 45 cases at treated at University of California, Irvine.t Data from the neonatal ECMO Registry Report of the Extracorporeal Life SupportOrganization as of March 1994.

Year

Figure 2. Number of annual cases by diagnosis since 1987. The numberof CDH cases as a proportion of the total number of cases treated hasincreased since ECLS indications were expanded. Annual MAS cases, themost common entry diagnosis, are included for comparison.


ECLS for Neonatal Respiratory Failure

401

£

0@

1-*- CDH a

MAS _

.0Ez

30-

20

10-

0 VA

-*- WDLw

'87 '88 '89 '90 '91 '92 '93

Year

Figure 3. Annual per cent survival by diagnosis since 1987. The annualsurvival for CDH cases dropped markedly in 1989 after the entry criteriawere broadened to include "non-honeymoon" cases. Annual percent sur-

vival for MAS by comparison remained stable until 1993. Overall survivalhas decreased, reflecting an increase in the number of complex cases

treated.

3. Preferred mode of access by year is shown in Figure4. Venovenous double lumen (VVDL) has become thepreferred mode of access at our institution for primaryneonatal respiratory failure.

Indication for ECLS and overall survival are shown inTable 4. The 01 was the most common indication forECLS. Characteristics ofsurvivors and those who did notsurvive are outlined in Table 5. Duration of ECLS bydiagnosis and year is plotted in Figure 5. Note that timeon bypass basically has remained stable for most diagno-ses, except CDH. As the number and complexity ofCDHcases has increased over time, so has the duration on

ECLS.There were a total of 1209 complications (2.63 ± 2.71

per case), ofwhich 446 were mechanical (0.97 1.17 per

patient) and 764 were patient related (1.66 2.06 per

patient). Common mechanical complications includedclots in the circuit (136; 85% survival), air in the circuit

Table 3. MODE OF ACCESSFOR NEONATAL ECLS

n Survival

Venoarterial 288 83Venovenous double-lumen 131 97Venovenous 18 94Venoarterial (+venous) 3 67Venovenous changed to venoarterial 16 95Venoarterial changed to venovenous 1 100Unknown 3 33

'87 '88 '89 '90 '91 '92 '93

YearFigure 4. Mode of access by year since the introduction of VVDL in 1988.The number of VVDL cases have increased each year. VVDL currently isthe most common and preferred mode of access for neonatal respiratoryfailure at our institution. Other refers primarily to conventional jugular tofemoral venovenous access.

(67; 82% survival), cannula problems (65; 83% survival),and oxygenator failure (34; 65% survival). Patient-re-lated complications included intracranial infarct or

bleeding (54 cases; 61% survival), major bleeding (48cases; 81% survival), seizures (88 cases; 76% survival),metabolic abnormalities (158 cases; 71% survival) andinfection (21; 48% survival). Incidence and per cent sur-

vival for all reported mechanical and patient complica-tions are outlined in Tables 6 and 7, respectively. Figure6 shows the number of total, mechanical, and patient-related complications per patient by year. Figure 7 dem-onstrates an association between the increase in thenumber of total complications per patient and the de-cline in overall survival over time. Figure 8 shows thatnumber of major complications has remained stable,whereas minor complications (i.e. any clot noted withinthe circuit) have been reported more frequently since1989.

Table 4. INDICATIONS FORNEONATAL ECLS

n Survival (%)

Oxygenation index 188 91Failure to respond 146 89Acute deterioration 88 74AaDO2 5 100Barotrauma 13 85Cardiac arrest 6 83Others 14 86

AaDO2 = alveolar-arterial oxygen content difference.

100-

90-

_ 80

co 70

(0 60-

50

273Vol. 220 - No. 3


Common reported causes of early death were pro-found neurologic injury (14 cases), pulmonary hypopla-sia/respiratory failure (5 cases), and sepsis/multiple or-gan failure (9 cases). There were 5 late deaths; reportedcauses of late death included sepsis (1), pulmonary hy-poplasia (1), and sudden infant death syndrome (1). Atthe time of discharge, 16 patients (4%) had evidence ofbronchopulmonary dysplasia, and 22 patients (5%) re-quired home oxygen.

Follow-up ranged from 1 to 19 years. Neurodevelop-mental outcome has been normal in approximately 80%of patients. Twenty per cent have some form ofcognitiveor neurologic impairment. Approximately 25% of pa-tients are hospitalized again within the first year, second-ary to respiratory illness and an additional 30% requireoutpatient treatment for lower respiratory illness. Pa-tients on supplemental oxygen at the time of dischargegenerally do not require long-term oxygen therapy.Common causes of chronic morbidity included someform of early developmental delay (26%) and sensori-neural hearing loss (4%).

DISCUSSIONThe first clinical trials of extracorporeal support for

neonatal respiratory failure were reported by Rash-kind,'9 Dorson,20 and White.2' Although these reportsdemonstrated that prolonged extracorporeal circulationin newborn infants was possible, all ofthese patients diedof their primary disease. After our first successful case in1975,9 we reported the results of a Phase I trial demon-strating safety and efficacy ofECLS as rescue therapy for

Table 5. CHARACTERISTICS OFSURVIVORS VERSUS NONSURVIVORS FOR

NEONATAL ECLS

Survivors Nonsurvivors(n = 400) (n = 60)

Birthweight (kg) 3.27 ± 0.64 2.84 ± 0.76Gestational age (wk) 38.87 ± 2.63 37.51 ±3.50Pre-ECLS

01 52.45 ± 35.47 56.17 37.24pO2 42.63 ± 22.91 49.69 ± 59.41pC02 38.35 ± 17.08 44.60 17.69pH 7.40±0.17 7.30±0.18

Duration of ECLS (hr) 122 ± 69.61 194.63 ± 174.57Average no. of mechanical

complications/patient 0.91 ± 1.12 1.38 ± 1.39Average no. of patient

complications/patient 1.37 ± 1.68 3.58 ± 3.07

01 = oxygen index score.

4001

0

-

0

CEFi

300

200

100

'73-'86 '87 '88 '89 '90 .91 '92 '93

Year

Figure 5. Duration of time on ECLS by diagnosis since 1973. Bypasstime has averaged approximately 120 hours during the past 20 years formost diagnoses except CDH. Time on ECLS for CDH has increased mark-edly since 1989, at which time the entry criteria were broadened to include'non-honeymoon" cases.

lethal respiratory failure (i.e., 100% mortality risk)," aPhase II prospective, randomized, trial demonstratingsuperiority to conventional treatment for infants at ahigh risk for mortality (i.e., 80 to 100% mortality risk),'2and finally, a Phase III prospective, randomized, trialdemonstrating cost effectiveness and reduced morbidityin infants at moderate risk for mortality (i.e., 50 to 80%mortality risk).'6 Additional large series from our insti-tution'3 and other institutions, 13,22-29 including a secondprospective randomized trial,30 have corroborated theseresults, and ECLS is now widely accepted as a standardof care for neonatal respiratory failure.'4"5

Table 6. MECHANICAL COMPLICATIONSDURING NEONATAL ECLS*

n Prevalence (%) Survival (%)

Oxytenator failureRaceway ruptureTubing rupturePump malfunctionHeat exchangerClots in circuitAir in circuitCannula problemsRestrictive suturesHemofilterKinking in cannulaOther

342

11914

1366765931483

70223

30151421318

65100828979858283786710078

* Data are recorded on an occurrence basis and there may be more than one occur-rence per patient.

Ann. Surg. - September 1994

ECLS for Neonatal Respiratory Failure

Neurologicbrain deathSeizuresInfarct/bleed HUSInfarct/bleed CT/MRIOther

HemorrhagicGastrointestinalcannula siteSurgical SiteHemolysisOther

CardiopulmonaryPulmonary

hemorrhageCPR requiredMyocardial stunArrythmiaSymptomatic PDAHypertensionPneumothoraxOther pulmonary

RenalCr> 1.5 mg%Dialysis/hemofilterOther

InfectiousInfectionWBC suspectOther infectious

MetabolicK > 6.0K < 2.5Na> 150Na < 125Ca> 12Ca <6Blood sugar > 240Blood sugar < 40pH> 7.6pH < 7.2HyperbilirubinemiaOther metabolic

588421221

19935

12

22146136

353138

7

235125102617

61

-W

Fival (%) 00

76 >57 "

7 a.

76 a

8395577578

25131254

50

719

8665609280608888

1 1

152

1542

310

149924341923124217

3220

1

1

45394

HUS = head ultrasound; CT = computed tomography; Cr = creatinine; CPR = car-

diopulmonary rescusitation; PDA = patent ductus arteriosus.* Data are recorded on an occurrence basis and there may be more than one occur-

rence per patient.

Currently, ECLS is practiced routinely in 110 centersworldwide. Global interest in the expanding clinical roleof ECLS led to the establishment of an internationalstudy group, the Extracorporeal Life Support Organiza-tion, which was chartered in 1989 to promote researchand foster communication. One of the unique functions

5

4-

3

2

* TotMechanical

-01- Pailent

'73-'85 '86 '87 '88 '89 '90 '91 '92 '93

Year

Figure 6. Average number of total, mechanical, and patient complica-tions per case reported annually from 1973 to 1993. Complications haveincreased since 1988, reflecting an increase in the number of complica-tions reported and in the complexity of cases treated.

of this organization is the maintenance of an interna-tional data registry that records case activity, indications,survival, and complications for virtually every ECLS pa-

tient. Registry data are reported routinely at the annualmeetings of the American Society for Artificial InternalOrgans (ASAIO) and ELSO, as well as in peer-reviewedjournals. 13' -36The growth of neonatal ECLS has been documented

very well.'4 In 1982, we reported our initial series of 45cases with 25 survivors treated at the University of Cali-fornia, Irvine." By the end of 1986, 715 cases had beentreated in 18 neonatal centers, with an overall survivalrate of 81%.33 These numbers increased to more than3500 cases in 65 centers by 198932 and subsequently, tonearly 8000 cases in more than 100 centers by 1993.34 Asof January 1994, 8913 cases have been reported to theinternational registry, with an overall survival rate of 80to 85% for infants expected to have at least an 80% mor-

tality risk (data from the Neonatal Extracorporeal Mem-brane Oxygenation Registry of the ELSO, Ann Arbor,MI). Survival varies with primary diagnosis and is bestfor MAS, which has an overall survival of 93% in 3292reported cases, whereas CDH is consistently lower, withan overall survival of 58% in 1730 reported cases. As ex-

pected, the results of the current series, which representsthe largest single-institution experience in the world,compare favorably with the results being reportedworldwide (Table 2).

Since our last report in 1986,'3 survival has improvedfor most diagnoses, with the exception ofCDH, in whichsurvival actually has decreased from 87% in 198737 to67% in 1993 (Fig. 3). Indications for ECLS forCDH were

broadened in 1988 to include patients without a "honey-

Table 7. PATIENT COMPLICATIONSDURING NEONATAL ECLS*

n Prevalence (%) Survi

275Vol. 220 - No. 3


6-

5-

4-

3-

2-

I1-

'73.'85 '86 '87 '88 '89 '90 '91 '92 '93

YearFigure 7. Average number of total complications reported per year inrelation to overall survival. An association between total number of com-

plications and decreased survival is demonstrated, reflecting the in-creased complexity of cases treated since 1988 and increased reportingof minor complications.

moon" (i.e. a post-ductal pO2 > 50 mm Hg), which hasincreased the actual number of survivors, but decreasedthe survival rate (Fig. 2). Recently, we reviewed our ex-

perience with ECLS in the management of infants withCDH.38 Since 1981, both the number of CDH patientsand the severity of associated respiratory failure have in-creased at our institution. From 1981 to 1987, we treated36 patients with CDH (6% "non-honeymoon"). Overallsurvival was 75%, and ECLS survival was 80% for thiscohort. Conversely, from 1988 to 1993, we treated 75

50-Ox FaIlur

* arcua lottC 40 Punp alur

-a-ss sai7 8 9

C. 30-E0

0

200

E 10-

z

0

'73-'85 '86 '87 '88 '89 9'91 9'92 '93

Year

Figure 8. Number of specific complications reported per year from 1973to 1993. The number of major complications has remained stable; how-ever, the frequency with which more minor complications are being re-

ported has increased. Note that the increase in the number of circuit clotshas increased with the introduction of minimal anticoagulation techniques;nonetheless, macroembolic complications remain exceedingly rare in our

experience. Ox = oxygenator; ICH = intracranial hemorrhage.

additional patients (28% "non-honeymoon") with anoverall survival of 59% and an ECLS survival of 59%.These differences in overall and ECLS survival were sta-tistically significant. However, ifone excludes "non-hon-eymoon" patients from the analysis, the differences insurvival were not significant suggesting that the inclusionof "non-honeymoon" CDH patients has had a signifi-cant impact on ECLS survival. Therefore, the decline inCDH survival since 1988 appears to be related both toan increase in the number of CDH patients with moresevere respiratory failure as well a broadened applicationECLS to patients without a honeymoon period. In addi-tion, survival for "non-honeymoon" CDH patients (pre-viously not considered salvageable) has improved mod-estly from 0% to 27%, suggesting continued improve-ments of ECLS management since 1987. As with anytreatment modality for high-risk patients, we must askourselves if survival in 27% justifies futile treatment in73% of patients.

Additional factors that might have contributed to thereduction in overall ECLS survival since 1987 includethe use of ECLS in increased numbers of premature in-fants and those with grade I intracranial hemorrhage.Based on our early experience (. 1986), we documenteddecreased survival and an increased incidence of ICH innewborns with an estimated gestational age of c 35weeks and birth weight < 2.0 kg.39 Thus, prematurityand low birth weight were considered relative contrain-dications to ECLS. However, more recent data on pre-mature and low birth-weight infants have demonstratedimproved survival and decreased rate of ICH in prema-ture infants.35 Furthermore, this analysis suggested thatlow birth weight itself does not appear to be an indepen-dent predictor of intracranial hemorrhage or outcome.Improved techniques in modern ECLS management,

including minimal anticoagulation techniques and sin-gle-catheter venovenous access, have allowed a return tothe treatment of these traditionally high-risk patients.40Prior to 1985, we treated 26 premature infants with just6 survivors (23% ECLS survival), two of which went onto late deaths. Since 1989, we have treated 13 prematureinfants with 11 survivors (85% ECLS survival rate).Among the ECLS survivors there were two early deathsand one late death, resulting in an overall survival rate of62% in this cohort. These results suggest that by usingmodern ECLS techniques, acceptable survival can be ex-pected in selected premature and low birth-weight in-fants.Both premature and full-term neonates on ECLS are

at increased risk for ICH as reflected by the relativelyhigh incidence of ICH in both groups.4' Because of theneed for systemic anticoagulation and the potential formorbidity and mortality, the presence of ICH generally

-O.- c0

1.45

ZOE --

=* 0.

Co.)

Ann.- Surg. * September 1994

-0- ConpiWavorm--O- Survlval


has been considered an absolute contraindication toECLS.39 Results for patients with ICH are difficult to pre-dict with certainty; however, since 1987, there have been28 patients with documented ICH by ultrasound, yield-ing 15 survivors (54%). Perhaps more important thanoverall survival is the fact that the annual survival ratefor patients with ICH appears to have increased from 0%in 1988 to approximately 60% in 1993. This data sug-gests that the presence of ICH should not be consideredan absolute contraindication to ECLS. Finally, the pres-ence ofICH does not preclude a normal neurologic out-come. In one study, 84% ofpremature infants with gradeI to II ICH were neurologically normal at 5 years ofage.42In the future, the routine use of heparin-bonded circuitcomponents and high-flow recirculation techniques willfurther reduce the risk ofICH during ECLS.

Complications also have increased since 1986, reflect-ing an increase in the complexity of cases treated andmore detailed data collection, which has increased re-porting of minor complications. The increase in thenumber of complications is associated with decreasedper cent survival, but it is not clear which is cause andeffect. Zwishenberger recently reported on the complica-tions of neonatal ECLS from the Neonatal Extracorpo-real Membrane Oxygenation Registry ofELSO;36 our re-sults compare favorably with those reported worldwide.

Recent advances in perinatal pulmonary care, includ-ing the use of exogenous surfactant,43-46 high-frequencyoscillatory ventilation4547-49 and nitric oxide50-56 mayimprove overall survival, but probably contributed to anincrease in ECLS mortality. Patients who respond tothese treatment modalities do not require ECLS, butthose who do not respond will, of necessity, be referredlater in their clinical course, potentially contributing toreduced overall ECLS survival. It is hoped that these ad-vances ultimately will result in improved overall survivalfor neonatal respiratory failure with reduced morbidity,mortality, and expense. The best result of the neonatalECLS project would be that better prevention and treat-ment leads to uniform survival of healthy infants, thus,eliminating any need for ECLS.A major technical advance has been the routine use

of single-catheter, double-lumen, venovenous access(VVDL) as the preferred mode of access at our institu-tion. (Fig. 4, Table 3). Potential disadvantages of con-ventional venoarterial access include the need to ligatethe right common carotid artery and the potential forsystemic micro- and macroembolization. Although con-ventional venovenous ECLS provides adequate gas ex-change, it has traditionally involved reinfusion of oxy-genated blood through a femoral venous cannula. Fem-oral cannulation in the neonate is more complex andtime consuming and is associated with increased mor-

bidity, owing to the extra dissection involved and thesmall size of the femoral vein.57 '58 The development ofa safe and effective double-lumen internal jugular veincannula avoided the need for ligation of the carotid ar-tery and the potential for systemic embolization withoutthe increased time and morbidity offemoral vein cannu-lation in the neonate. In addition, single-catheter jugularvein access greatly simplifies both cannulation and dec-annulation thus increasing overall safety. A study fromour institution'8 as well as a multicenter ELSO study3'compared venovenous and venoarterial access in neo-nates. The venovenous patients did better in all catego-ries; however, because venoarterial is required for hemo-dynamically unstable patients, the best risk patients arein the venovenous category.

Extracorporeal life support is beneficial for patientswith respiratory failure at high risk for mortality; never-theless, it is an expensive, labor intensive, and highly in-vasive technology. We conducted a prospective, ran-domized trial comparing the early use of ECLS inpatients at moderate mortality risk (50%) with conven-tional management including ECLS for patients at high-mortality risk (.80%). 16 This study demonstrated thatearly ECLS does not increase hospital costs or resourceuse and a trend toward reduced neurologic and pulmo-nary morbidity in the ECLS group. Pearson reportedsimilar results in a retrospective economic analysis ofECLS for respiratory failure in newborns at the Chil-dren's Hospital National Medical Center in Washington,DC.59 These studies evaluated conventional ve-noarterial ECLS and should be repeated, comparing thecost effectiveness of newer treatments (i.e., high-fre-quency oscillatory ventilation, NO, etc.) to venovenous,low-heparin ECLS.Shumacher reported detailed neurodevelopmental

outcome on a cohort of92 infants treated with ECLS forneonatal respiratory failure at the University of Michi-gan during an 8-year period between 1981 and 1987.'7Follow-up ranged from 1 to 7 years. At last follow-up,20% of the children exhibited some handicap. This issimilar to the 18.6% handicap rate reported in the litera-ture for infants treated conventionally with persistentpulmonary hypertension of the newborn.'7 A fair groupfor comparison would have been newborns who had an80% mortality rate; however, these patients were notavailable for comparison. On the other hand, if one as-sumes an 80% mortality rate, there currently are 65 pa-tients from this cohort alone who are alive but wouldhave died with conventional therapy. Forty-nine ofthesechildren are alive without a handicap, and 13 are alivewith a handicap. If one carries out a similar arithmeticexercise on the 9000 infants worldwide who have been

Vol. 220 - No. 3


treated using ECLS, the impact of ECLS on infant mor-tality over the past 20 years is demonstrated.The ECLS experience has led to an improved under-

standing of pulmonary pathophysiology. Important ad-vances in our understanding of respiratory disease in-clude the identification of pulmonary hypertension as amajor pathophysiologic abnormality in all forms of neo-natal respiratory failure3 and the iatrogenic and immi-nently preventable nature ofbronchopulmonary dyspla-sia. In addition, the use of ECLS allowed for the identi-fication of progressive irreversible fibrosis as the finalcommon pathway in adult acute interstitial lung dis-ease60 and provided the impetus to two decades of re-search into the basic pathophysiologic mechanisms ofthe adult respiratory distress syndrome. Clinical applica-tion of ECLS has led to an improved understanding ofthe role of elevated airway pressures and volumes as themajor culprits in ventilator-induced lung injury and toan increased emphasis on pressure-limited mechanicalventilation in modern ICU practice. The study of ECLShas brought proper emphasis to the separation of oxy-genation from CO2 removal in all forms of pulmonarysupport and has led to the concept of permissive hyper-capnia and the central importance of optimizing sys-temic oxygen content and delivery. The study of sys-temic oxygen kinetics during ECLS also has resulted inan improved understanding ofthe importance of mixed-venous oxygen saturation monitoring and led to routineapplication ofthis physiology in the management of crit-ical illness. Finally, an improved understanding of therole of extravascular lung water in the pathophysiologyofacute lung injury has led to more liberal use ofdiuresisand hemofiltration as adjuncts in the management ofrespiratory failure.Many technological advances from the ECLS experi-

ence have been found to have application in everydaysurgical practice. Servoregulation, mixed-venous satura-tion monitoring, membrane lungs, and standardized de-scriptors of vascular access catheters currently are ap-plied routinely during cardiopulmonary bypass foropen-heart surgery. Venovenous ECLS techniques areused routinely during the anhepatic phase of orthotopicliver transplantation. Venoarterial ECLS techniques alsoare used in short-term cardiopulmonary support (CPS)systems. Extracorporeal life support technology also hasmade possible the bedside use of continuous arteriove-nous and pumped venovenous hemofiltration. TheECLS experience has demonstrated that it is both possi-ble and safe to perform even major surgical procedures(i.e., patent ductus arteriosus ligation,6' repair of CDH,etc.) in the intensive care unit, necessary. Finally, therapid growth of ECLS in the last several years has led tothe development of a new health care professional. Ex-

tracorporeal life support clinical specialists are highlytrained individuals from diverse backgrounds in medi-cine, nursing, respiratory therapy, and perfusion whocurrently provide most of the continuous monitoringand management skills necessary to allow routine appli-cation ofECLS.The development of safe and reliable heparin-bonded,

nonthrombogenic, surfaces has ushered in an entirelynew era in prolonged extracorporeal circulation.62-65 Theavailability of heparin-bonded circuit components pro-vides the opportunity to study ECLS with minimal or nosystemic heparin administration. This may allow saferapplication of ECLS to patients with conditions cur-rently considered contraindicated, such as very lowbirth-weight, premature infants or patients with activebleeding, coagulopathy, or the need for major operationswhile on ECLS. The Milan group demonstrated a de-creased incidence of bleeding complications using hepa-rin-bonded circuits.62 The clinical availability of hepa-rin-bonded systems may have other advantages in addi-tion to decreased heparin requirements. Decreasedplatelet, leukocyte, complement, and kinin system acti-vation may occur, making the use of heparin-bondedsystems desirable for both short- and long-term ECLSapplications.66 Finally, nonthrombogenic surfaces mayfind major application for other types of blood-surfacecontact artificial organs, including hemodialysis, hemo-filtration, and plasmapheresis.

In 1990, the National Institutes ofHealth held a work-shop on development and diffusion of high-technologyintensive care using the neonatal ECLS project as theprototypic example of how the process should work.'4 Amajor medical problem was taken first to the laboratory.Over a period of 10 years, basic research in bioengineer-ing, physiology, and hematology led to successful animaltrials, then to careful Phase I clinical trials. Two Phase IIprospective, randomized trials demonstrated the valueof this technique. The adaptive designs used for thesestudies addressed the ethical and logistic dilemmas ofrandomized studies of life support in a lethal disease pro-cess. A Phase III study analyzed cost effectiveness. Thisresearch has been supported by the National Institutes ofHealth from 1972 to the present. Laboratory and clinicalinvestigators shared new information freely and fre-quently and published their results in peer-reviewedjournals. Sensational journalism was avoided. Details ofevery patient were kept in a central registry, and guide-lines for referral, training, and qualifications were setforth by the study group of active centers. The technologywas used as a safety net to permit the evaluation of new,simple, but potentially risky treatments. The net result isthousands of healthy children and happy families.


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CONCLUSIONSThe goal of neonatal ECLS research continues to be

the elimination of primary respiratory failure as a causeof infant morbidity and mortality. During the past 20years, ECLS has become a standard of care for severeneonatal respiratory failure and has led to routine sur-vival from what had been a uniformly lethal problem.Lessons learned from ECLS research have led to an im-proved understanding of this disease and have provideda mechanism by which neonatal pulmonary care contin-ues to be optimized. Extracorporeal life support has be-come standard treatment for severe neonatal respiratoryfailure in our center (460 cases; 87% survival), andworldwide (8913 cases; 81% survival). Eighty per cent ofsurvivors are healthy children; 20% have some degree ofpulmonary or neurologic impairment. Death or disabil-ity is caused by perinatal neurologic injury or pulmonaryhypoplasia. Extracorporeal life support techniques haveimproved, and risks have been reduced, allowing appli-cation to ever-expanding groups of patients. In the fu-ture, it is hoped that continued advances in respiratorycare will reduce or eliminate the need for ECLS. How-ever, experience with ECLS has taught us to predict notthe limitations, but the possibilities.

References

1. Custer JR, Bartlett RH. Recent research in extracorporeal life sup-port for respiratory failure. ASAIO Trans 1992; 38:754-771.

2. Bartlett RH. Extracorporeal life support for cardiopulmonary fail-ure. Curr Probl Surg 1990; 27:621-705.

3. Lyrenne RK, Phillips JB. Control ofpulmonary vascular resistancein the fetus and newborn. Clin Perinatol 1984; 11:561-584.

4. Bartlett RH, Fong SW, Burns NE, Gazzaniga AB. Prolonged par-tial venoarterial bypass: physiologic, biochemical, and hemato-logic responses. Ann Surg 1974; 180:850-856.

5. Bartlett RH, Kittredge D, Noyes BS Jr, et al. Development of amembrane oxygenator: overcoming blood diffusiolimitation. JThorac Cardiovasc Surg 1969; 58:795-800.

6. Bartlett RH, Isherwood J, Moss RA, et al. A toroidal flow mem-brane oxygenator: four day partial bypass in dogs. Surg Forum1969; 20:152-153.

7. Fong SW, Burns NE, Williams G, et al. Changes in coagulationand platelet function during prolonged extracorporeal circulation(ECC) in sheep and man. Trans Am Soc Artif Intern Organs 1974;20A:239-247.

8. Bartlett RH, Drinker PA, Burns NE, et al. The toroidal membraneoxygenator: design, performance, and prolonged bypass testing ofa clinical model. Trans Am Soc Artif Intern Organs 1972; 18:369-374.

9. Bartlett RH, Gazzaniga AB, Jefferies MR, et al. Extracorporealmembrane oxygenation (ECMO) cardiopulmonary support in in-fancy. Trans Am Soc Artif Intern Organs 1976; 22:80-93.

10. Bartlett RH, Gazzaniga AB, Huxtable RF, et al. Extracorporealcirculation (ECMO) in neonatal respiratory failure. J ThoracCardiovasc Surg 1977; 74:826-833.

11. Bartlett RH, Andrews AF, Toomasian JM, et al. Extracorporeal


membrane oxygenation for newborn respiratory failure: forty-fivecases. Surgery 1982; 92:425-433.

12. Bartlett RH, Roloff DW, Cornell RG, et al. Extracorporeal circu-lation in neonatal respiratory failure: a prospective randomizedstudy. Pediatrics 1985; 76:479-487.

13. Bartlett RH, Gazzaniga AB, Toomasian J, et al. Extracorporealmembrane oxygenation (ECMO) in neonatal respiratory failure.100 cases [published erratum appears in Ann Surg 1987 Jan;205(l):l lA]. Ann Surg 1986; 204:236-245.

14. Wright L. NIH Workshop on Diffusion of High-Tech Care (Neo-natal ECMO). Bethesda, MD: National Institutes of Health; 1993.National Institutes of Health Publication No. 93-3399:25-41.

15. Committee on Fetus and Newborn (American Academy of Pedi-atrics). Recommendations on extracorporeal membrane oxygena-tion. Pediatrics 1990; 85:618-619.

16. Schumacher RE, Roloff DW, Chapman R, et al. Extracorporealmembrane oxygenation in term newborns: a prospective cost-ben-efit analysis. ASAIO J 1993; 39:873-879.

17. Schumacher RE, Palmer TW, Roloff DW, et al. Follow-up of in-fants treated with extracorporeal membrane oxygenation for new-born respiratory failure. Pediatrics 1991; 87:451-457.

18. Delius R, Anderson H, Schumacher R, et al. Venovenous com-pares favorably with venoarterial access for extracorporeal mem-brane oxygenation in neonatal respiratory failure. J ThoracCardiovasc Surg 1993; 106:329-338.

19. Rashkind WJ, Freeman A, Klein D, Toft RW. Evaluation of a dis-posable plastic, low volume, pumpless oxygenator as a lung substi-tute. J Pediatr 1965; 66:94-102.

20. Dorson W Jr, Meyer B, Baker E, et al. Response of distressed in-fants to partial bypass lung assist. Trans Am Soc Artif Intern Or-gans 1970; 16:345-35 1.

21. White JJ, Andrews HG, Risemberg H, et al. Prolonged respiratorysupport in newborn infants with a membrane oxygenator. Surgery1971; 70:288-296.

22. Weber TR, Pennington DG, Connors R, et al. Extracorporealmembrane oxygenation for newborn respiratory failure. AnnThorac Surg 1986; 42:529-535.

23. Short BL, Miller MK, Anderson KD. Extracorporeal membraneoxygenation in the management of respiratory failure in the new-born. Clin Perinatol 1987; 14:737-748.

24. Loe WA Jr, Graves ED, Ochsner JL, et al. Extracorporeal mem-brane oxygenation for newborn respiratory failure. J Pediatr Surg1985; 20:684-688.

25. Lillehei CW, O'Rourke PP, Vacanti JP, Crone RK. Role of extra-corporeal membrane oxygenation in selected pediatric respiratoryproblems. J Thorac Cardiovasc Surg 1989; 98:968-970 (discus-sion).

26. Moront MG, Katz NM, Keszler M, et al. Extracorporeal mem-brane oxygenation for neonatal respiratory failure: a report of 50cases. J Thorac Cardiovasc Surg 1989; 97:706-714.

27. Kirkpatrick BV, Krummel TM, Mueller DG, et al. Use of extra-corporeal membrane oxygenation for respiratory failure in terminfants. Pediatrics 1983; 72:872-876.

28. Arnold D, Kachel W, Rettwitz W, et al. Clinical application ofextracorporeal membrane oxygenation (ECMO) in neonatal respi-ratory failure. Thorac Cardiovasc Surg 1987; 35:321-325.

29. Krummel TM, Greenfield U, Kirkpatrick BV, et al. Extracorpo-real membrane oxygenation in neonatal pulmonary failure. Pedi-atr Ann 1982; 11:905-908.

30. O'Rourke PP, Crone RK, Vacanti JP, et al. Extracorporeal mem-brane oxygenation and conventional medical therapy in neonateswith persistent pulmonary hypertension of the newborn: a pros-


pective randomized study [see comments]. Pediatrics 1989; 84:957-963.

31. Anderson HL, Snedecor SM, Otsu T, Bartlett RH. Multicentercomparison ofconventional venoarterial access versus venovenousdouble-lumen catheter access in newborn infants undergoing ex-tracorporeal membrane oxygenation. J Pediatr Surg 1993; 28:530-534 (discussion).

32. Stolar CJ, Snedecor SM, Bartlett RH. Extracorporeal membraneoxygenation and neonatal respiratory failure: experience from theextracorporeal life support organization. J Pediatr Surg 1991; 26:563-571.

33. Toomasian JM, Snedecor SM, Cornell RG, et al. National experi-ence with extracorporeal membrane oxygenation for newborn re-spiratory failure: data from 715 cases. ASAIO Trans 1988; 34:140-147.

34. Stolar CJH, Delosh T, Bartlett RH. Extracorporeal life support or-ganization 1993: registry report. ASAIO J 1993; 39:976-979.

35. Hirschl RB, Schumacher RE, Snedecor SN, et al. The efficacy ofextracorporeal life support in premature and low birth weight in-fants. J Pediatr Surg 1993; 28:1336-1341.

36. Zwishenberger JB, Nguyen TT, Upp R, et al. Complications ofneonatal extracorporeal membrane oxygenation. J Thorac Cardio-vasc Surg 1994; 107:838-849.

37. Heiss K, Manning P, Oldham KT, et al. Reversal of mortality forcongenital diaphragmatic hernia with ECMO. Ann Surg 1988;209:225-230.

38. Steimle CN, Meric F, Hirschl RB, et al. The effect ofextracorporeallife support on survival when applied to all patients with congenitaldiaphragmatic hernia. J Pediatr Surg 1994 (in press).

39. Cilley RE, Zwishenberger JB, Andrews AF, et al. Intracranial hem-orrhage during extracorporeal membrane oxygenation in the neo-nate. Pediatrics 1986; 78:699-704.

40. Bui KC, LaClair P, Vanderkerkhove J, Bartlett RH. ECMO in pre-mature infants: review of factors associated with mortality. TransAm Soc Artif Intern Organs 1991; 37:54-59.

41. Taylor GA, Short BA, Fitz CR. Imaging of cerebrovascular injuryin 207 infants treated with ECMO. J Pediatr 1989; 114:635-639.

42. Vohr B, Coll CG, Flanagan P. Effects of intraventricular hemor-rhage and socioeconomic status on perceptual, cognitive, and neu-rologic status of low birth weight infants at 5 years of age. J Pediatr1992; 121:280-285.

43. Bui KC, Walther FJ, David-Cu R, Garg M, Warburton D. Phos-pholipid and surfactant protein A concentrations in tracheal aspi-rates from infants requiring extracorporeal membrane oxygena-tion. J Pediatr 1992; 121:271-274.

44. Lotze A, Knight GR, Martin GR, et al. Improved pulmonary out-come after exogenous surfactant therapy for respiratory failure interm infants requiring extracorporeal membrane oxygenation. JPediatr 1993; 122:261-268.

45. Davis JM, Richter SE, Kendig JW, Notter RH. High-frequencyjet ventilation and surfactant treatment of newborns with severerespiratory failure. Pediatr Pulmonol 1992; 13:108-112.

46. Auten RL, Notter RH, Kendig JW, et al. Surfactant treatment offull-term newborns with respiratory failure. Pediatrics 199 1; 87:101-107.

47. Schwendeman CA, Clark RH, Yoder BA, et al. Frequency ofchronic lung disease in infants with severe respiratory failuretreated with high-frequency ventilation and/or extracorporealmembrane oxygenation. Crit Care Med 1992; 20:372-377.

48. DeLemos R, Yoder B, McCurnin D, et al. The use of high-fre-quency oscillatory ventilation (HFOV) and extracorporeal mem-brane oxygenation (ECMO) in the management of the term/near


term infant with respiratory failure. Early Hum Dev 1992; 29:299-303.

49. Carter JM, Gerstmann DR, Clark RH, et al. High-frequency oscil-latory ventilation and extracorporeal membrane oxygenation forthe treatment ofacute neonatal respiratory failure. Pediatrics 1990;85:159-164.

50. Kinsella JP, McQueston JA, Rosenberg AA, Abman SH. Hemo-dynamic effects ofexogenous nitric oxide in ovine transitional pul-monary circulation. Am J Physiol 1992; 263:H875-H880.

51. Finer NN, Etches PC, Kamstra B, et al. Inhaled nitric oxide ininfants referred for extracorporeal membrane oxygenation: doseresponse. J Pediatr 1994; 124:302-308.

52. Kinsella JP, Neish SR, Ivy DD, Shaffer E, Abman SH. Clinicalresponses to prolonged treatment of persistent pulmonary hyper-tension of the newborn with low doses of inhaled nitric oxide [seecomments]. J Pediatr 1993; 123:103-108.

53. Kinsella JP, Toews WH, Henry D, Abman SH. Selective and sus-tained pulmonary vasodilation with inhalational nitric oxide ther-apy in a child with idiopathic pulmonary hypertension. J Pediatr1993; 122:803-806.

54. Kinsella JP, Neish SR, Shaffer E, Abman SH. Low-dose inhalationnitric oxide in persistent pulmonary hypertension of the newborn.Lancet 1992; 340:819-820.

55. Abman SH, Kinsella JP, Schaffer MS, Wilkening RB. Inhaled ni-tric oxide in the management of a premature newborn with severerespiratory distress and pulmonary hypertension. Pediatrics 1993;92:606-609.

56. Kinsella JP, Abman SH. Inhalational nitric oxide therapy for per-sistent pulmonary hypertension of the newborn. Pediatrics 1993;91:997-998.

57. Andrews AF, Klein MD, Toomasian JM, et al. Venovenous extra-corporeal membrane oxygenation in neonates with respiratory fail-ure. J Pediatr Surg 1983; 18:339-346.

58. Klein MD, Andrews AF, Wesley JR, et al. Venovenous perfusionin ECMO for newborn respiratory insufficiency. Ann Surg 1985;201:520-526.

59. Pearson GD, Short BL. An economic analysis of extracorporealmembrane oxygenation. J Intensive Care Med 1987; 2:116-120.

60. Pratt PC, Vollmer RT, Shelburne JD, Crapo JD. Pulmonary mor-phology in a multihospital collaborative extracorporeal membraneoxygenation project. I. Light microscopy. Am J Pathol 1979; 95:191-214.

61. Hubbard C, Rucker RW, Realyvasquez F, et al. Ligation of thepatent ductus arteriosus in newborn respiratory failure. J PediatrSurg 1986; 21:3-5.

62. Pesenti A, Gattinoni L, Bombino M. Long term extracorporealrespiratory support: 20 years ofprogress. Intensive Crit Care Digest1993; 12:15-18.

63. Lazzara RR, Magovern JA, Benckart DH, et al. Extracorporealmembrane oxygenation for adult post cardiotomy cardiogenicshock using a heparin bonded system. ASAIO J 1993; 39:M444-M447.

64. Shanley CJ, Hultquist KA, Rosenberg DM, et al. Prolonged extra-corporeal circulation without heparin. Evaluation of the Med-tronic Minimax oxygenator. ASAIO J 1992; 38:M31 I-M316.

65. Tsuno K, Terasaki H, Otsu T, et al. Newborn extracorporeal lungassist using a novel double lumen catheter and a heparin-bondedmembrane lung. Intensive Care Med 1993; 19:70-72.

66. Plotz FB, van Oeveren W, Bartlett RH, Wildevuur CR. Blood ac-tivation during neonatal extracorporeal life support. J ThoracCardiovasc Surg 1993; 105:823-832.

Extracorporeal Life Support for Neonatal Respiratory Failure

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