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Background/Purpose: Congenital diaphragmatic hernia (CDH), occurring approximately once in every 2,400 live births, remains a significant cause of perinatal death and morbidity. Risk assessment tools for congenital diaphragmatic hernia derived at single institutions fail to predict outcome at other institutions. Without a generally applicable risk assessment tool it is impossible to determine whether the current variation in outcomes is caused by differences in treatment or to variations in the types of patients treated. The authors report a broadly applicable risk assessment tool for newborns with CDH derived from multiinstitutional data. Methods: Survival data on 322 consecutive liveborn infants with CDH were collected using data from 71 institutions. Demographic and early treatment results were evaluated by univariate analysis. Items useful in an early stratification system were examined using a multivariate logistic regression analysis. The predictive equation developed was applied to the next series of evaluable patients. Results: A total of 1,054 patients with CDH were evaluated from 1995 to 1999 with an overall survival rate of 64%. For the first 322 patients, factors associated with outcome included birth weight, Apgar scores, gestational age, race, immediate distress, presence of a cardiac anomaly, and prenatal diagnosis. Multivariate analysis showed that birth weight and 5-minute Apgar scores were most useful in a predictive equation. A logistic equation using these 2 variables could separate the next 673 patients into high, intermediate, and low risk of death, and this correlated closely with the actual outcome. Conclusion: Stratifying neonates with CDH into broad risk groups should allow better comparison of outcomes data from different centers, reserving novel and high-risk strategies for patients with a high likelihood of dying.

Background. Growth curves described in the 1960s are used to classify neonate intrauterine growth as normal or abnormal. Our objective was to determine whether continued use of these curves is appropriate. Methods. From 1996 to 1998, we collected birth weight, length, head circumference, estimated gestational age (EGA), gender, race, and place of birth ( Results. Gestational age had the largest influence on each growth parameter. Race and gender both had effects on birth weight. Female neonates were smaller than male neonates, and black neonates were smaller than Hispanic and white neonates at each EGA. For neonates with an EGA 36 weeks, the variance was similar, but our curves showed that neonates in our sample were larger and heavier. Use of the older growth curves to classify neonates as SGA, LGA, and appropriate for gestational age (AGA) led to significantly different rates of each by gender and race. Conclusions. Intrauterine growth patterns previously described and commonly used to classify neonates as AGA are inaccurate for use in current populations and lead to gender- and race-specific diagnoses of SGA and LGA that are misleading. neonates, growth, race, gender.

Background. Extracorporeal membrane oxygenation (ECMO) is an important treatment tool in the management of near-term and term neonates with severe hypoxemic respiratory failure. To better understand how health care for patients treated with ECMO has changed, we studied the demographic and treatment data reported to the Extracorporeal Life Support Organization (ELSO) registry from January 1, 1988, through January 1, 1998. Methods. We used data stored in the ELSO registry and evaluated the changes in demographics, use of alternate therapies before ECMO, severity of illness, duration of ECMO therapy, and mortality over a 10-year period. All data on neonates reported between January 1, 1988, and January 1, 1998 were used. Verification checks were performed on all fields to eliminate nonsense outliers. We separated the neonates into 2 groups—those with and those without a congenital diaphragmatic hernia (CDH). All analyses were performed on the total group and each subgroup separately. Changes in continuous data were analyzed by year using analysis of variance. Year differences in categorical data were evaluated with χ2 analysis. We also used the linear trend test and the Cochran-Armitage trend test to evaluate time-related changes. Results. We reviewed 12 175 neonates. Over the decade, there were no changes in mean gestational age, gender, age at which ECMO was started, pH, or Paco2 just before ECMO. The proportion of neonates with CDH increased from 18% to 26%, while the proportion with respiratory distress syndrome decreased from 15% to 4%. Other diagnostic categories remained constant. The use of surfactant, high-frequency ventilation, and inhaled nitric oxide increased from 0% in 1988 to 36%, 46%, and 24%, respectively, in 1997. The mean peak pressure being used just before ECMO decreased (47 ± 10 in 1988 to 39 ± 12 in 1997), and the mean Pao2/Fio2 ratio increased (38 ± 23 in 1988 to 48 ± 36 in 1997). The primary mode of ECMO remains venoarterial; however, the use of venovenous ECMO increased from 1% to 32% over the decade. Duration of ECMO treatment increased overall, and this trend was seen for patients with and without CDH (124 ± 67 to 141 ± 104 hours for the non-CDH group, 161 ± 99 to 238 ± 141 hours for the CDH group). The number of centers reporting neonatal data to the ELSO registry increased from 52 in 1988 to a peak of 100 in 1993. In 1997, 96 centers reported data to ELSO. The average number of neonatal patients reported from each site decreased from a peak of 18 in 1991 to 9 in 1997. Mortality increased from 18% to 22%; however, when corrected for the relative increase in neonates with CDH, this trend disappeared. Diagnoses-specific mortality rates remained constant. The occurrence of intracranial hemorrhage and/or infarct also stayed constant at 16%. Conclusions. The population of neonates treated with ECMO in 1997 was very different from patients treated in the 1980s and early 1990s. They were exposed to an ever-expanding group of new therapies, appeared to be healthier based on indices of gas exchange, and were cared for at centers that reported fewer cases per year.

It is with deep respect that we write this response to Dr Bell1 who has inspired generations of physicians to do research on acquired neonatal intestinal diseases, most notably NEC. We are also pleased to read his agreement that spontaneous intestinal perforation (SIP) and necrotizing enterocolitis (NEC) are distinct and separate disease entities. We hope that this editorial exchange will encourage others to consider how best to approach these disparate diseases and the populations they affect.

We greatly appreciate the letter from Drs Skerritt, Modi and Clarke, because the most important goal of our review1 was to stimulate dialogue across disciplines. It is obvious that two pediatric surgeons and a neonatologist did exactly that in drafting their letter. We are also gratified to learn that our arguments favoring the necessity of an alternative to Bell's staging was well received. Hopefully this exchange is the beginning of a cordial and constructive debate that will reverberate throughout the neonatal and pediatric surgery communities over the next couple of years.

Extracorporeal membrane oxygenation (ECMO) is used in the treatment of reversible pulmonary disease in the newborn. The ECMO program at Wilford Hall USAF Medical Center began in 1985 and to date, 57 patients have been placed on bypass for a mean of 125 hours. The indications for ECMO are severe, prolonged hypoxemia in patients with an estimated mortality of greater than 90% using conventional ventilator support. The major diagnoses in the patients placed on ECMO were meconium aspiration, congenital diaphragmatic hernia, and neonatal sepsis or pneumonia. Overall survival was 79%, or 45 out of 57. The most frequent complications were intracranial hemorrhage as well as hemorrhage from the surgical site. We have found ECMO to be an extremely valuable adjunct in the care of the critically ill newborn and believe it can significantly improve survival in infants with reversible pulmonary disease.

Background: Repair of congenital diaphragmatic hernia (CDH) has changed from an emergent procedure to a delayed procedure in the last decade. Many other aspects of management have also evolved since the first successful repair. However, most reports are from single institutions. The lack of a large multicenter database has hampered progress in the management of congenital diaphragmatic hernia (CDH) and makes determination of the current standard difficult. Methods: The CDH study group was formed in 1995 to collect data from multiple institutions in North America, Europe, and Australia. Participating centers completed a registry form on all live-born infants with CDH during 1995 and 1996. Demographic information, data about surgical management, and outcome were collected for all patients. Results: Sixty-two centers participated, with 461 patients entered. Overall survival was 280 of 442 patients (63%) where survival was recorded. The defect was left-sided in 78%, right-sided in 21%, and bilateral in 1%. A subcostal approach was used in 91% of patients, with pleural drainage used in 76%. A patch of some kind was used in just over half (51%) of the patients, with polytetrafluoroethylene being the most commonly used material (81%) in those patients with a patch. The mean surgical time was 102 minutes, with an average blood loss of 14 mL (range, 0 to 500 mL). The overwhelming majority of patients underwent repair between 6:00 am and 6:00 pm (289 of 329, 88%). Ninteen percent of patients has surgical repair on extracorporeal membrane oxygenation (ECMO) at a mean time of 170 hours into the ECMO course (range, 10 to 593 hours). The mean age at surgery in patients not treated with ECMO was 73 hours (range, 1 to 445 hours). Conclusions: The multicenter nature of this report makes it a snapshot of current management. The data would indicate that prosthetic patching of the defect has become common, that after-hours repair is infrequent, and that delayed surgical repair has become the preferred approach in many centers. Furthermore, the mean survival rate of 63% indicates that despite decades of individual effort, the CDH problem is far from solved. This highlights the need for a centralized database and cooperative multicenter studies in the future.

In Reply .— We appreciate the comments by Dr Lee. We discussed in our article1 and agree that unmeasured confounding processes of care or unmeasured variables may ultimately be found to explain our results. In the following we try to address Dr Lee's specific concerns. We combined the reports of cerebrospinal fluid (CSF) and blood cultures to increase our statistical power to detect meaningful differences between the 2 treatment approaches in neonates who had documented infection. That is, were neonates who were treated with ampicillin/cefotaxime infected more often than neonates who were treated with ampicillin/gentamicin? Positive CSF cultures were …

Objectives To compare proportions of infants at different gestational ages discharged from the neonatal intensive care unit (NICU) on home oxygen, to determine how many were classified with chronic lung disease based on timing of discharge on home oxygen, and to determine the percentage discharged on home oxygen who received mechanical ventilation. Study design We evaluated a retrospective cohort of infants of 23-43 weeks' gestational age discharged from 228 NICUs in 2009, using the Pediatrix Clinical Data Warehouse. Multilevel logistic regression analysis identified predictors of home oxygen use among extremely preterm, early-moderate preterm, late preterm, and term infants. Duration of mechanical ventilation and median length of stay were calculated for infants discharged on home oxygen. Results For the 48 877 infants studied, the rate of home oxygen use ranged from 28% (722 of 2621) in extremely preterm infants to 0.7% (246 of 34 934) in late preterm and term infants. Extremely preterm infants composed 56% (722 of 1286) of the infants discharged on home oxygen; late preterm and term infants, 19% (246 of 1286). After gestational age, mechanical ventilation was the main predictor of home oxygen use; however, 61% of the late preterm and term infants discharged on home oxygen did not receive ventilation. The median length of hospital stay was 95 days (IQR, 76-114 days) for extremely preterm infants discharged on home oxygen, but only 15 days (IQR, 10-22 days) for late preterm and term ventilated infants discharged on home oxygen. Conclusion Although home oxygen use is uncommon in later-gestation infants, the greater overall numbers of later-gestation infants contribute significantly to the increased need for home oxygen for infants at NICU discharge. Neither respiratory failure nor lengthy hospitalization is a prerequisite for home oxygen use at later gestational age.

Objective : To determine if data collected by the Extracorporeal Life Support Organization Registry could be used to identify neonates with congenital diaphragmatic hernia who had a >90% mortality rate, despite the use of extracorporeal membrane oxygenation (ECMO) support. Design : We retrospectively reviewed data reported to the Extracorporeal Life Support Organization Registry on neonates with congenital diaphragmatic hernia. Patients : Data regarding 1,089 neonates with congenital diaphragmatic hernia reported to the Extracorporeal Life Support Organization Registry between 1980 and 1992 formed the basis of this study. All of the neonates studied had been treated with ECMO. This patient population includes neonates with right- and left-sided diaphragmatic hernia. This registry does not include neonates with congenital diaphragmatic hernia who were not treated with ECMO. Measurements and Main Results : Of 1,089 neonates with congenital diaphragmatic hernia, 679 (62%) survived. There were no differences between the two groups in gender or in the year they were treated. Survival rate did not significantly increase over the years between 1980 and 1992. When compared with survivors, nonsurvivors were more immature (38 ± 2 vs. 39 ± 2 wks ; p =.01), had lower birth weights (3.0 ± 0.5 vs. 3.21 ± 0.53 kg ; p =.001), were more often prenatally diagnosed (42% vs. 32% ; p =.03), were cannulated at a younger age (31 ± 54 vs. 40 ± 50 hrs ; p =.01), and had more severe respiratory compromise (higher peak pressures and Paco 2 , lower Pao 2 values). Multivariate analysis showed that arterial pH and Pao 2 just before ECMO, and birth weight, had the highest discriminant coefficients. By using these variables in a discriminant function (D[fx] = 0.68 x pH + 0.62 x birth weight + 0.29 x Pao 2 ; using standardized coefficients and variables), we could identify neonates who died with a sensitivity of 62%, a specificity of 63%, a positive-predictive value of 50%, and a negative-predictive value of 74%. No single variable or combination of variables yielded better results. Conclusions : Although a number of factors identify neonates with diaphragmatic hernia as being at higher risk of dying despite ECMO support, data currently collected by the neonatal Extracorporeal Life Support Organization Registry do not allow clinicians to effectively discriminate nonsurvivors from survivors.

Acute respiratory failure (ARF) secondary to congenital diaphragmatic hernia (CDH), unresponsive to maximal medical management, has traditionally been treated with venoarterial (VA) extracorporeal membrane oxygenation (ECMO). Venovenous (VV) ECMO offers several benefits over VA ECMO including preserved pulmonary blood flow, preservation of the carotid artery, and pulsatile flow. However, use of the VV modality has not been widespread because of concerns of cardiac instability during bypass, and because only one double-lumen (DL) catheter size is available in the United States. The authors hypothesize that VV ECMO is a safe and effective treatment for CDH, symptomatic at birth, and report a single institution experience of preferential VV use for CDH. Over an 18-month period, 14 patients with CDH were placed on ECMO after maximal medical management failed, including high-frequency ventilation and nitric oxide in some cases. Ability to place the 14 Fr DL catheter was the sole criteria for VA or VV selection. Nine patients were successfully placed on VV and 5 on VA; no VV patient required conversion to VA. The two groups of patients were similar with respect to degree of illness, birth weight, EGA, time on and age at start of ECMO. Overall survival for this series was 64%: 66% in the VV group and 60% in the VA group. Two patients in the VV group were found to have congenital heart disease incompatible with life, were withdrawn from therapy and allowed to die, and are listed as treatment failures. The authors conclude that CDH patients receive adequate oxygenation and show hemodynamic stability on VV ECMO. This experience suggests that VV ECMO is a safe and acceptable method of respiratory support for neonatal CDH. The advantages of VV ECMO should make this modality the preferred method of ECMO support in CDH.

restricted extremely low gestational age newborns with absent or reverse Doppler flow in the umbilical artery Jill Lee, Andrew Wilt, Reese Clark, Amy Picklesimer Greenville Hospital System University Medical Center, Obstetrics and Gynecology, Greenville, SC, University of South Carolina School of Medicine, Obstetrics and Gynecology, Columbia, SC, Greenville Hospital System University Medical Center, Neonatology, Greenville, SC OBJECTIVE: Gestational age and birth weight are the primary determinants of neonatal outcomes, and are widely used in the counseling of parents expecting a preterm infant. Fetal Doppler parameters are not widely incorporated into this counseling. Our objective was to determine if absent or reverse Doppler flow in the umbilical artery (A/ REDF) was associated with an increased risk of morbidity or mortality in extremely premature growth restricted infants. STUDY DESIGN: Retrospective chart review identified all neonates born between 23 0/7 and 29 6/7 weeks gestational age at a single institution between January 2008 and June 2011. Those with ultrasound estimate of fetal weight 15% percentile and Doppler evaluation within the 7 days prior to delivery were included for evaluation. Neonatal outcomes for fetuses with forward flow in the umbilical artery (FF) during diastole were compared with fetuses demonstrating A/REDF using Fishers exact test and Students T-test. RESULTS: During the study period, 38 infants met enrollment criteria; 21 had FF, 17 had A/REDF. There was no difference in average gestational age or incidence of major morbities between the groups, but those with A/REDF were smaller and had longer neonatal admissions (Table). CONCLUSION: In the setting of fetal growth restriction at early gestational ages, the finding of A/REDF confers an increased risk for significant growth restriction and prolonged neonatal admission. This is important to include in prenatal counseling of expectant parents.

Objective : To compare the safety and efficacy of high-frequency oscillation (HFO) with conventional ventilation in the treatment of neonates with respiratory failure. Design : We conducted a multicenter, prospective, randomized trial. Patients were stratified according to pulmonary diagnosis and then were randomly selected for conventional ventilation or HFO. A balanced crossover design offered patients who met criteria of treatment failure a trial of the alternative mode of ventilation. Setting : Four tertiary, level 3 neonatal intensive care units accepting regional referrals for extracorporeal membrane oxygenation. Patients : Neonates were eligible for enrollment if their gestational age was >34 weeks, their birth weight was ≥2 kg, they were 0.50 and a mean airway pressure >0.98 kPa (10 cm H 2 O) to support adequate oxygenation, and they required a peak inspiratory pressure >2.9 kPa (30 cm H 2 O) and a rate >40 breaths per minute to support adequate ventilation. Exclusion criteria were lethal congenital anomalies, profound shock, need for cardiopulmonary resuscitation, and failure to obtain consent. Main results : Of 79 patients studied, 40 were assigned to conventional ventilation and 39 to HFO. Neonates randomly assigned to HFO required higher peak pressure (3.8 ± 0.5 vs 3.3 ± 0.8 kPa, 39 ± 5 vs 34 ± 8 cm H 2 O; p = 0.004) and more often met extracorporeal membrane oxygenation criteria (67% vs 40%; p = 0.03) at study entry than did those given conventional ventilation. Twenty- four patients (60%) assigned to conventional ventilation met treatment failure criteria compared with 17 (44%) of those assigned to HFO (not significant). Of the 24 patients in whom conventional ventilation failed, 15 (63%) responded to HFO; 4 (23%) of the 17 in whom HFO failed responded to conventional ventilation ( p = 0.03). There were no differences between the two groups with respect to outcome, need for extracorporeal membrane oxygenation, or complications. Conclusions : We conclude that HFO is a safe and effective rescue technique in the treatment of neonates with respiratory failure in whom conventional ventilation fails. (J Pediatr 1994;124:447-54)

HIE is not a single disease from a single cause, and is characterized by great diversity in the timing and magnitude of brain injury. It is therefore unreasonable to expect any single intervention to provide uniformly favorable outcome. The known heterogeneity in neuropathological changes after perinatal HIE combined with potential regional heterogeneity of treatment effects will lead to marked differential effects on outcomes among survivors of HIE (e.g. physical disability versus cognitive deficits). This underscores the need for longer term follow up of all infants with HIE undergoing any treatment. In spite of rapidly accumulating clinical and laboratory data related to hypothermia as a neuroprotective strategy for HIE, the speakers and discussants at the workshop underscored numerous gaps in knowledge in this field summarized in the Table, which compares the gaps identified at the 2005 NICHD workshop8 with current gaps. The participants noted that with only six completed studies1-6 providing information on follow-up for up to 18 months of age, the longer-term neurodevelopmental impact of hypothermia for HIE are pending.23,24 This, they concluded, should lead to an overall measure of caution in applying the new therapy of hypothermia indiscriminately for all cases of HIE. Table 1 Comparison of Categories of Gaps in Knowledge and Change from 2005 to 2010 Based on the available data and large knowledge gaps, the expert panel suggested that although hypothermia is unequivocally a promising therapy for HIE, a substantial proportion of infants still suffer from death or disability despite treatment. Further analysis of existing trial data, development of adjuvant therapies to hypothermia, development of biomarkers and further refinements of hypothermia therapy for use in infants suffering from HIE and clinical trials of therapeutic hypothermia in mid resource settings with different risk factors but adequate facilities and infrastructure are all urgently needed and were identified as areas of high priority for study.

We evaluated the effects of venovenous extracorporeal membrane oxygenation (ECMO) on cardiac performance by echocardiographic measurements in 15 infants. Heart rate and blood pressure were also recorded. Echocardiographic measurements included aortic and pulmonary peak blood flow velocities, pulmonary time to peak velocity, left ventricular shortening fraction, velocity of circumferential fiber shortening corrected for heart rate, and peak systolic wall stress before, during, and after venovenous ECMO. Pre-ECMO echocardiograms showed borderline or normal indexes of cardiac function. After initiation of venovenous ECMO, all infants had normalization and no infant had deterioration of cardiac performance. The inotropic agents dopamine and dobutamine were decreased from average doses of 12 and 3.6 micrograms/kg per minute, respectively, to 3.7 and 1.3 micrograms/kg per minute, respectively, within 8.8 hours of the institution of venovenous ECMO. During this time the mean arterial pressure remained stable, and the heart rate decreased (169 +/- 21 vs 136 +/- 15 beats/min; p0.001). During the course of ECMO there were no changes in left ventricular shortening fraction, velocity of circumferential fiber shortening corrected for heart rate, or aortic peak blood flow velocities. Pulmonary artery peak blood flow velocity (69 +/- 22 vs 92 +/- 28 cm/sec; p = 0.04) and pulmonary time to peak velocity improved (47 +/- 11 vs 65 +/- 16 msec; p = 0.026). We conclude that venovenous ECMO does not have deleterious effects on cardiac performance.

OBJECTIVE To assess the frequency of chronic lung disease and factors associated with its development in term infants with severe respiratory failure who receive high-frequency oscillatory ventilation, or high-frequency oscillatory ventilation, and extracorporeal membrane oxygenation (ECMO). DESIGN Retrospective review of pulmonary outcome of all ECMO candidates admitted to Wilford Hall USAF Medical Center between July 1985 and September 1989. SETTING A tertiary, level III, neonatal ICU accepting regional referrals for high-frequency ventilation and ECMO. PATIENTS Ninety-four patients who were candidates for ECMO were studied. High-frequency oscillatory ventilation alone was used in 48 infants. Forty-six infants were treated with high-frequency oscillatory ventilation and ECMO. MAIN RESULTS Twenty (24%) of 84 survivors developed chronic lung disease. There were no differences in gestational age, birth weight, or gender between those infants who developed chronic lung disease and those infants who did not. Arterial blood gas and ventilatory settings at initiation of high-frequency oscillatory ventilation were similar between those infants who did and those who did not develop chronic disease. Patients who developed chronic lung disease more often had lung hypoplasia (40% vs. 5%) and more often required ECMO (75% vs. 39%) than those patients who did not. In patients without lung hypoplasia, those patients who developed chronic lung disease were older at initiation of high-frequency oscillatory ventilation rescue than those patients who did not develop chronic lung disease (median 91 vs. 46 hrs). CONCLUSIONS The frequency of chronic lung disease in ECMO candidates is clinically important. Factors associated with chronic lung disease in ECMO candidates are: the presence of lung hypoplasia, delayed referral, and the need for ECMO to support gas exchange.

We tested the hypothesis that high-frequency oscillatory ventilation can be efficacious in hyaline membrane disease (HMD) even after lung injury is established. We compared high frequency oscillatory ventilation (HFOV) rescue (n = 8; 15 Hz; I:E = 1:2) after 8 hours of positive pressure ventilation (PPV) with positive end-expiratory pressure, to continued PPV (control, n = 7) in premature baboons with HMD over a 24 hour period. Ventilator settings and physiologic parameters were recorded hourly. At necropsy (24 hours), lung status pressure-volume curves, alveolar phospholipids (PL), platelet activating factor-like activity (PAF), and lung water were determined. Roentgenographic and morphologic differences in lung inflation were quantified by standard techniques. No intergroup differences were found in heart rate, blood pressures, ventilator settings, FiO2, blood gases, or chest radiographs during the first 8 hours. Both groups had progressive physiologic disease. At 8 hours, HFOV-rescue animals, in contrast to controls, had immediate significant time-related improvements in Pa/AO2 (at the same Paw) and in oxygenation index (Pa/AO2/Paw) lasting for 16 hours. No significant intergroup differences in lung/body weight, lung water, lung mechanics, PL, PAF, or frequency of moderate to severe roentgenographic changes existed at 24 hours. Although all animals had morphologic evidence of HMD, saccular aeration was more uniform and airway dilatation less evident in HFOV rescue (P < 0.0001). Based on the improved gas exchange, we conclude that HFOV rescue was efficacious in the “late” treatment of HMD, presumably because of the more uniform saccular aeration. Though HFOV rescue did not appear to reverse lung injury incurred during the first 8 hours of PPV, it may have interrupted the progression of injury, as seen in the PPV control group.

We studied the hemodynamic consequences during the first 24 h of life in premature baboons (140 d) with hyaline membrane disease that were treated with high-frequency oscillatory ventilation (HFOV) or conventional intermittent mandatory ventilation (IMV). Cardiac output and organ blood flow were measured at three time-points using the radiolabeled microsphere technique. Seven of seven HFOV and six of eight IMV animals survived the 24-h period. By design, initial mean airway pressure (Paw) was higher in the HFOV group (p less than 0.01). HFOV Paw was progressively reduced during the study period because of improving oxygenation as measured by the arterial to alveolar oxygen ratio. In contrast, it was necessary to increase Paw in the IMV animals to maintain the arterial to alveolar oxygen ratio. By 23 h, the IMV group required higher Paw than the HFOV group (p less than 0.05) and had a lower arterial to alveolar oxygen ratio (p less than 0.05). We found no significant differences in left ventricular output, effective systemic flow, organ blood flow, or central venous pressure between the two groups at 3, 8, or 23 h. The HFOV strategy used in our study resulted in significant improvement in oxygenation during the initial 24 h of treatment without adverse effect on left ventricular output, cerebral blood flow, or central venous pressure. We conclude that when appropriate changes in Paw are made during HFOV in response to improvement in arterial oxygenation and changes in lung inflation as assessed by chest radiographs HFOV can be achieved without depressing cardiovascular dynamics more than during conventional therapy with IMV.

ROSEMARY D. HIGGINS, MD, TONSE N.K. RAJU, MD, JEFFREY PERLMAN, MD, DENIS VICTOR AZZOPARDI, MD, LILLIAN R. BLACKMON, MD, REESE H. CLARK, MD, A. DAVID EDWARDS, F MED SCI, DONNA M. FERRIERO, MD, PETER D. GLUCKMAN, MBCHB, FRS, ALISTAIR J. GUNN, MBCHB, PHD, SUSAN E. JACOBS, MD, DOROTHEA JENKINS EICHER, MD, ALAN H. JOBE, MD, PHD, ABBOT R. LAPTOOK, MD, MICHAEL H. LEBLANC, MD, CHARLES PALMER , MBCHB, SEETHA SHANKARAN, MD, ROGER F. SOLL, MD, ANN R. STARK, MD, MARIANNE THORESEN, MD, JOHN WYATT, MD, THE NICHD HYPOTHERMIA WORKSHOP SPEAKERS AND DISCUSSANTS*

We appreciate the observation reported by Cheung et al, and agree with their findings. We reported similar results on survival in premature infants with pulmonary interstitial emphysema in 1986. These data show that high-frequency oscillatory ventilation (HFOV) response delineates two groups of infants with different outcomes. It is important to note that most neonates treated with HFOV have improved ventilation, but that a smaller proportion of neonates have improved oxygenation. In our experience improved oxygenation is a better predictor of outcome than improved ventilation.

* Abbreviations: iNO = : inhaled nitric oxide • ECMO = : extracorporeal membrane oxygenation The 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 oxygenation (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 Administration usually requires that two separate clinical trials show that it improves a specific outcome without increasing the risk for adverse outcomes. In addition, the improved outcome should impact health, not just physiology. Improvements in physiology (improved oxygenation) do not always translate to improvements in health (eg, increased Pao 2 in premature neonates increases the risk for retinopathy). Studies establish that iNO improves oxygenation3–5 and reduces the use of ECMO.4 ,6 Unfortunately, these outcome measures are not surrogate markers for improved health. If avoiding ECMO … Address correspondence to Reese H. Clark, MD, Pediatrix Medical Group, 1455 North Park Dr, Fort Lauderdale, FL 33326. E-mail:reese_clark{at}mail.pediatrix.com

To the Editor.— We read with interest the recent article by Dworetz et al.1 We agree with the authors' conclusions that controlled studies to assess the merits of alternative strategies for the management of critically ill neonates are necessary. The authors have carefully presented the limitations of their report including the retrospective nature of the study, the restrictive selection criteria used, and the small number of patients. However, the authors did not include the number of inborn vs outborn infants, the age of patients at the time of entry into the "study," and the specific diagnoses of the patients meeting ECMO criteria.

Inhaled Nitric Oxide Reduces Cardiopulmonary Bypass-Induced Pulmonary Vascular Injury in Neonatal Swine • 202

Purpose: To evaluate the effect of chronic lung disease (CLD) on length of stay (LOS) and days of ventilator support (Vent days) in neonates discharged home from our neonatal intensive care unit. Setting: All neonates with a gestational age

Background: When used during extracorporeal membrane oxygenation (ECMO), jugular venous bulb catheters, known as cephalad cannulae, increase venous drainage, augment circuit flow and decompress cerebral venous pressure. Optimized cerebral oxygen delivery during ECMO may contribute to a reduction in neurological morbidity. This study describes the use of cephalad cannulae and identifies rudimentary data for jugular venous oxygen saturation (JVO2) and arterial to jugular venous oxygen saturation difference (AVDO2) in this patient population. Results: Patients on venoarterial (VA) ECMO displayed higher JVO2 (P 7.4 (P = 0.01). During VA ECMO, similar differences in AVDO2 but not in JVO2 were observed at different pH levels (P = 0.01). Conclusions: Jugular venous saturation and AVDO2 were influenced by systemic pH, ECMO type and patient age. These data provide the foundation for normative values of JVO2 and AVDO2 in neonates and children treated with ECMO. extracorporeal membrane oxygenation venovenous ECMO, venoarterial ECMO, cephalad cannulae, jugular venous oxygen content

RANDOMIZED, MULTICENTER TRIAL OF INHALED NITRIC OXIDE AND HIGH FREQUENCY OSCILLATORY VENTILATION IN SEVERE PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN (PPHN). • 1315

We compared airway histopathologic findings in premature baboons given standard positive pressure ventilation with those seen after high-frequency oscillatory ventilation. Six animals received standard frequency conventional ventilation for a mean of 9.2 days; seven received high-frequency oscillatory ventilation at 10 Hz using a piston oscillator for a mean of 10.2 days; five baboons served as controls, and were killed immediately after birth. A semiquantitative histopathologic scoring system was used to grade tissue changes in the trachea, carina, and both mainstem bronchi. Compared with the nonventilated control animals, injury was produced with both forms of mechanical ventilation (P less than 0.01 for both instruments); however, the degree of damage was mild, with no significant difference in the extent of injury between the two treatment groups. High-frequency oscillatory ventilation appears to result in no greater degree of airway damage than conventional positive pressure ventilation.

We compared the histopathologic changes in the airways of premature baboons treated with conventional positive-pressure ventilation (PPV) with those seen after high-frequency oscillatory ventilation (HFOV) and high-frequency flow interruption (HFFI). Twenty-six animals were treated with ventilation for 24 hours (five PPV, 10 HFOV, 11 HFFI), and 18 were treated with ventilation for 96 hours (six PPV, six HFOV, six HFFI). A semiquantitative scoring system was used to grade tissue changes in the trachea, carina, and both main-stem bronchi. Alterations were produced by all forms of mechanical ventilation. The degree of injury was similar and relatively mild for the PPV- and HFOV-treated animals at both 24 and 96 hours. Eleven of 17 baboons treated with HFFI ventilation (8/11 at 24 hours; 3/6 at 96 hours) had severe airway damage characterized by diffuse submucosal necrosis, extensive hemorrhage, dense polymorphonuclear leukocyte infiltration, sloughed epithelium, focal basophilia, and intraluminal debris. HFOV resulted in no greater degree of airway damage than did PPV. The use of HFFI, with the particular strategy we employed, resulted in a far greater degree of damage than either PPV (P less than 0.01) or HFOV.

To assess the influence of ventilatory technique on pulmonary baroinjury in experimental hyaline membrane disease, we randomized 24 premature baboons to six treatment groups according to ventilator (PPV, positive pressure ventilator; HFO, high frequency oscillator; HFI, high frequency flow interrupter) and O2 therapy FIO2 as clinically indicated, or FIO2 1.0). PaCO2 was adjusted by varying pressure amplitude, and for PPV, also by rate (less than 60/min). HFO and HFI were set at a frequency of 10 Hz. Animals were cared for with standard NICU techniques until death or sacrifice at 11 days. One animal died at delivery and was excluded from data analysis. There were no intergroup differences in Paw, Pa/AO2, PaCO2 or oxygenation index (IO2 = [Pa/AO2]/Paw) prior to death of the first study animal at 13 h. Animals who subsequently developed airleak had higher Paw, lower Pa/AO2 and lower IO2 during this period. The degree of airleak was significantly less with HFO compared to PPV or HFI. The effect of O2 exposure did not appear different with respect to the degree of airleak or the frequency of severe tracheal injury, although survival was shortened. Severe tracheal injury was more frequent with HFI compared to PPV or HFO. BPD was found only in 100% O2 exposed animals surviving greater than 1 wk. Management of premature baboons with HFO and appropriate O2 resulted in less severe airleak, 100% survival, and no evidence of severe tracheal injury or BPD. These outcomes were not achieved with clinically similar strategies using PPV or HFI.

Twenty-seven low birth weight infants who developed pulmonary interstitial emphysema (PIE) and respiratory failure while on conventional ventilation were treated with high-frequency oscillatory ventilation (HFOV). The mean birth weight was 1.2 kg (range 0.55 to 2) with gestational age of 28 wk (range 25 to 34). Ten patients died, six of whom had documented sepsis with shock and were therefore excluded from analysis. All patients showed initial improvement on HFOV. Surviving patients showed continued improvement in oxygenation and ventilation at increasingly lower fraction of inspired oxygen and proximal airway pressure with resolution of PIE, while nonsurvivors progressively developed chronic respiratory insufficiency with continued PIE from which recovery was not possible. Overall survival in nonseptic patients was 80% (16 of 20). We found HFOV to be effective in the treatment of PIE and hypothesize that interstitial airleak is decreased during HFOV because adequate ventilation is provided at lower peak distal airway pressures.

The case of a patient with ecchymosis, hepatomegaly, leukocytosis, thrombocytopenia, and anemia at birth is presented. Throughout his course, thrombocytopenia, anemia, and leukocytosis without a marked increase in the number of blast forms in either peripheral blood or bone marrow persisted until the patient developed a blast crisis shortly before his death at age 4 months. This patient is the youngest reported to have the juvenile form of chronic myelogenous leukemia and the first that in the present era can be considered congenital in origin.