Published online March 5, 2007
PEDIATRICS Vol. 119 No. 4 April 2007, pp. e860-e865 (doi:10.1542/peds.2006-2082)
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ARTICLE

Neuromotor Outcome at 2 Years of Very Preterm Infants Who Were Treated With High-Frequency Oscillatory Ventilation or Conventional Ventilation for Neonatal Respiratory Distress Syndrome

Patrick Truffert, MD, PhDa,b, Josefa Paris-Llado, PhDb, Benoît Escande, MDc, Jean-François Magny, MDd, Gilles Cambonie, MDe, Elie Saliba, MDf, Gérard Thiriez, MDg, Véronique Zupan-Simunekh, Thierry Blanc, MDi, Jean-Christophe Rozé, MDj, Gérard Bréart, MD, MSCb and Guy Moriette, MDk

a Department of Neonatology, Lille University Hospital, Lille, France
b INSERM U 149, Paris, France
c Department of Neonatology, Strasbourg University Hospital, Strasbourg, France
d Department of Neonatology, Institut de Puériculture, Paris, France
e Department of Neonatology, Montpellier University Hospital, Montpellier, France
f Department of Neonatology, Tours University Hospital, Tours, France
g Department of Neonatology, Besançon University Hospital, Besançon, France
h Department of Neonatology, Antoine Béclère University Hospital, Clamart, France
i Department of Neonatology, Rouen University Hospital, Rouen, France
j Department of Neonatology, Nantes University Hospital, Nantes, France
k Department of Neonatology, Cochin Port-Royal University Hospital, Paris, France


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. In a previous multicenter, randomized trial, elective use of high-frequency oscillatory ventilation was compared with the use of conventional ventilation in the management of respiratory distress syndrome in preterm infants <30 weeks. No difference in terms of respiratory outcome was observed, but concerns were raised about an increased rate of severe intraventricular hemorrhage in the high-frequency ventilation group. To evaluate outcome, a follow-up study was conducted until a corrected age of 2 years. We report the results concerning neuromotor outcome.

METHODS. Outcome was able to be evaluated in 192 of the 212 infants who survived until discharge from the neonatal unit: 97 of 105 infants of the high-frequency group and 95 of 104 infants of the conventional ventilation group.

RESULTS. In the infants reviewed, mean birth weight and gestational age were similar in the 2 ventilation groups. As in the overall study population, the following differences were observed between the high-frequency ventilation group and the conventional ventilation group: lower 5-minute Apgar score, fewer surfactant instillations, and a higher incidence of severe intraventricular hemorrhage. At a corrected age of 2 years, 93 of the 97 infants of the high-frequency group and 79 of the 95 infants of the conventional ventilation group did not present any neuromotor disability, whereas 4 infants of the high-frequency group and 16 infants of the conventional ventilation group had cerebral palsy.

CONCLUSIONS. Contrary to our initial concern about the increased rate of severe intraventricular hemorrhage in the high-frequency ventilation group, these data suggest that early use of high-frequency ventilation, compared with conventional ventilation, may be associated with a better neuromotor outcome. Because of the small number of patients studied and the absence of any explanation for this finding, we can conclude only that high-frequency oscillatory ventilation is not associated with a poorer neuromotor outcome.

Key Words: prematurity • high-frequency ventilation • outcome • chronic lung disease • multicenter trial • intraventricular hemorrhage

Abbreviations: HFOV—high-frequency oscillatory ventilation • IVH—intraventricular hemorrhage • OR—odds ratio • CI—confidence interval • PVL—periventricular leukomalacia • CP—cerebral palsy

In a previous multicenter, randomized trial, we tested the hypothesis that the early use of high-frequency oscillatory ventilation (HFOV) with a lung volume recruitment strategy compared with the use of conventional ventilation in the management of respiratory distress syndrome in preterm infants <30 weeks could improve pulmonary outcome, without altering the incidence of severe intraventricular hemorrhage (IVH). We found that HFOV was associated with a nonsignificant decrease in chronic lung disease rate and an increase in the severe IVH rate, which no longer was significant after adjustment.1

Results that were published subsequently suggested that the elective use of HFOV rather than conventional ventilation may result at best in a slight reduction of the incidence of chronic lung disease. They did not show any increase of IVH rate with HFOV.2–4

A slight benefit of HFOV would not justify high risks. Because concerns were raised in our trial about an increased rate of severe IVH in the HFOV group, a follow-up study was conducted to evaluate outcome until a corrected age of 2 years. The development of IVH indeed has an impact on outcome,5,6 but variations in IVH incidence may not be reflected accurately by outcome, as previously reported.7 Follow-up data therefore are necessary to provide an adequate prognostic evaluation.

Few data have been reported on the neurodevelopmental outcome of infants who were randomly assigned to receive HFOV or conventional ventilation.2,8–11 The present follow-up study assessed the neuromotor outcome at 2 years of age in infants who were included in our trial.1


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Initial Study
The study protocol and results were reported previously in detail.1 Briefly, infants were eligible when their postmenstrual age at birth was between 24 and 29 weeks and when they required mechanical ventilation as a result of respiratory distress syndrome. Eligible patients were randomly assigned to HFOV with lung volume recruitment strategy or conventional ventilation. A first dose of surfactant was given in both groups after randomization. A total of 273 patients were analyzed: 139 in the HFOV group and 134 in the conventional ventilation group. In the HFOV group, compared with the conventional group, a nonsignificantly smaller proportion of infants developed chronic lung disease at 36 weeks (adjusted odds ratio [OR]: 0.53; 95% confidence interval [CI]: 0.24–1.14]), and a nonsignificantly greater proportion of infants developed grade 3 or 4 IVH after randomization (24% vs 14%; adjusted OR: 1.50; 95% CI: 0.68–1.30). Because previous studies reported increased rates of severe IVH in infants who were randomly assigned to HFOV,12–14 accurate grading was ascertained by review of all ultrasound examinations indicating the presence of grades 2 to 4 IVH at the coordinating center, by a radiologist who was not informed about the group assignment. Cystic periventricular leukomalacia (PVL) rates were similar in the HFOV group (10%) and the conventional group (13%).

Follow-up Study
Data on outcome at a corrected age of 2 years were collected by the questionnaires that were used in the EPIPAGE study, as previously reported.15 Briefly, physicians (pediatric neurologists, pediatricians, neonatologists, or general practitioners) who followed the infants and examined them at 2 years of corrected age were asked to complete a standardized precoded questionnaire. Completing the standardized questionnaire, which was designed to minimize the risk for ambiguous answers, required a detailed physical and neurologic examination that assessed tone, reflexes, posture, and movements. Cerebral palsy (CP) was defined according to the definitions of the European Collaborative study group.15,16 The diagnosis of spastic CP was based on the observation of at least 2 of the following 3 findings: abnormal posture and/or movement, increased tone, and abnormal reflexes. Correct classification of our CP cases was checked by an investigator of the EPIPAGE study who was not informed about the ventilation group allocation.15

Data were analyzed by SAS software (SAS Institute, Cary, NC). Rate comparisons and crude and adjusted ORs are presented with corresponding 95% CIs. The adjusted ORs were computed by multiple logistic regression.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Of the 273 infants analyzed in the initial trial, 212 survived to discharge from the neonatal unit. A total of 192 infants (90% of discharged infants) were included in the present study: 97 from the HFOV group and 95 from the conventional ventilation group (Fig 1).


Figure 1
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  		FIGURE 1 Patients: from randomization in the initial trial to follow-up at 2 years of corrected age.

 
Data on the follow-up of these 192 infants were derived from specialized institutions in 69% of cases (follow-up at the initial neonatal center, a hospital pediatric clinic, or an institution that specializes in the detection and care of developmental abnormalities). The remaining infants were followed in less specialized institutions or by private pediatricians or general practitioners. The proportions of infants who were followed in specialized institutions and of infants who were followed according to the latter description were not different between the HFOV and conventional ventilation groups. Forty-two percent of the infants followed belonged to the EPIPAGE cohort.15

In the 192 infants assessed at 2 years of age, compared with the 20 infants who died after discharge or who were lost to follow-up, the mean birth weight was lower (999 ± 242 vs 1109 ± 165 g; P = .05) and the proportion of infants with birth weight ≤1000 g was higher (49.5% vs 25%; P = .04). There also was a trend for a higher rate of chronic lung disease (supplemental oxygen required at 36 weeks; 26% vs 10%; P = .11).

Perinatal and neonatal data by treatment group for the infants evaluated are summarized in Table 1. Similar significant differences were observed as in the total population of the initial trial. In the HFOV group, compared with the conventional ventilation group, lower incidences of preeclampsia and high blood pressure were observed during pregnancy, and fewer infants had a 5-minute Apgar score ≥7 or required >1 surfactant instillation. Other perinatal characteristics were comparable between the 2 treatment groups, and the hospital mortality rate was comparable between the 2 treatment groups (23% vs 22%). Neonatal mortality related to ultrasound detection of major cerebral complications (severe IVH or cystic PVL) in infants of the 2 treatment groups is described in Table 2. No significant difference was demonstrated.


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  		TABLE 1 Characteristics of Infants Who Were Reviewed According to the Initial Treatment Group

 

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  		TABLE 2 Neonatal Mortality Adjusted for Presence of Major Cranial Ultrasound Abnormalities, by Treatment Group (Initial Trial)

 
The neuromotor outcome at a corrected age of 2 years is shown in Table 3. The corrected age at examination was comparable in the 2 groups (median [interquartile]: 25 months [5] in both groups). Spastic CP was diagnosed in 4 (4%) infants of the HFOV group and 16 (17%) infants of the conventional ventilation group; this difference was significant (OR: 0.87; 95% CI: 0.79–0.96). Survival without CP also was more frequent in the HFOV group (OR: 1.89; 95% CI: 1.04–3.44). Most perinatal characteristics of the infants were similar, regardless of whether they developed CP, including severe IVH. Only the presence of cystic PVL during the neonatal period was significantly associated with the development of CP at the age of 2 years. Cystic PVL was detected in 11 (6%) infants without CP compared with 7 (35%) infants with CP (P < .001).


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  		TABLE 3 Neuromotor Outcome at Corrected Age of 2 Years

 
The occurrence of CP in infants with neonatal cerebral complications is assessed in Table 4. Among the infants who were assessed at 2 years, there were significantly more cases of severe IVH in the HFOV group than in the conventional ventilation group (13 [13%] vs 3 [3%] cases; OR: 4.7; 95% CI: 1.2–21.8), in agreement with the results that were observed for the total population included in the initial trial. The proportion of infants who were followed at 2 years and developed cystic PVL during the neonatal period was similar in the 2 groups.


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  		TABLE 4 Neonatal Cerebral Complications and CP at 2 Years

 
The relationship between CP at 2 years and the use of HFOV or conventional ventilation during the neonatal period was assessed by multiple logistic regression with adjustment for gestational age, birth weight, antenatal steroids, preeclampsia, high blood pressure during pregnancy, IVH grades 3 to 4, leukomalacia, and 5-minute Apgar score <7. After adjustment, CP was significantly less frequent in the HFOV group than in the conventional ventilation group (adjusted OR: 0.3; 95% CI: 0.1–0.6).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
The neurologic outcome of infants who were included in a randomized trial that compared HFOV and conventional ventilation in the treatment of neonatal respiratory distress syndrome was evaluated at a corrected age of 2 years. Data that were collected on the sensorial and cognitive outcome were not sufficiently accurate or comprehensive to allow adequate evaluation. We therefore limited our analysis to neuromotor outcome.

Despite a nonsignificant increase in the severe IVH rate in the HFOV group compared with the conventional ventilation group, the neuromotor outcome actually seemed better in the HFOV group, because CP rates and the combined rates of mortality or CP were lower in the HFOV group compared with the conventional ventilation group. CP and mortality or CP rates remained lower in the HFOV group after adjustment for multiple factors.

Lung immaturity continues to be a major cause of mortality and morbidity in very preterm infants. The objective of HFOV is to reduce acute lung injury. Pulmonary benefits have been demonstrated in animal experiments when HFOV rather than conventional ventilation was used17–21 but often were not confirmed in newborn infants.1,4,22 In 1 large-scale trial, a beneficial effect was shown, but, despite the inclusion of 500 infants, it was too small to result in a significant reduction of the chronic lung disease rate in survivors.3 Our initial observation of a nonsignificantly increased severe IVH rate in infants who received HFOV and the limited follow-up data2 justified the present follow-up study.

The follow-up rate was satisfactory. Infants who were followed at 3 years presented higher rates of extremely low birth weight and chronic lung disease than infants who died before 2 years of age or who were lost to follow-up. The rate of infants who were lost to follow-up was similar in the 2 treatment groups. The HFOV group required fewer surfactant instillations. Among the infants reviewed, severe IVH rates remained higher in the HFOV group, whereas cystic leukomalacia rates were similar in the 2 treatment groups.

Severe IVH has been reported to be predictive of the subsequent development of CP.5,6,23 However, this predictive value may be only limited; Schmidt et al7 reported identical CP rates in 2 groups of infants despite different neonatal IVH rates (9% and 13%). Only 4 of our 13 infants in the HFOV group with severe IVH developed CP, a proportion almost identical to that observed in the EPIPAGE study in infants with grade 3 IVH.15 In the conventional group, only 3 cases of severe IVH were observed, in contrast with 16 cases of CP, a highly unexpected finding. Because all head ultrasounds that showed cerebral bleeding were reviewed centrally, incorrect classification of IVH is very unlikely. A higher hospital mortality of infants with severe cerebral lesions, which could have improved the outcome in the HFOV group, was not observed.

Of the other factors that contribute to CP, the most important probably is PVL,23,24 as confirmed by our observation of a significant correlation between cystic PVL and CP. However, the presence of cystic PVL allowed identification of only 7 (35%) of our 20 cases of CP. The same prediction rate was reported in the EPIPAGE study, when unilateral lesions were considered.15 The sensitivity of cerebral ultrasound for the detection of white matter injury is considered to be relatively low.24 CP prediction rates that are based on ultrasound could be increased by performing a greater number of ultrasound examinations, which should not be limited to the first 4 weeks after birth, and by using high-quality techniques, as suggested by De Vries et al.25 The design of our initial trial focused on ventilatory aspects, and cerebral ultrasound examinations were designed only to detect IVH accurately. These examinations therefore were included in our protocol before randomization, during the first week, between days 7 and 10 and at day 28. No other guidelines concerning the number of examinations or technical issues were given, and the diagnosis of cystic PVL was established at each participating center using local protocols. No evaluation was required at term equivalent. Detection of PVL in our trial therefore was far from optimal.

A total of 34 infants experienced severe IVH or cystic PVL. Twenty-six (76%) of them did not develop CP. Using an optimal ultrasound protocol, De Vries et al25 reported that 52% of infants with major ultrasound abnormalities did not develop CP.

Neurologic assessment was similar in the 2 treatment groups. More than two thirds of assessments, distributed equally between the 2 groups, were performed in specialized institutions. All questionnaires were reviewed carefully, as previously described, suggesting the reliability of the information collected. The definition of CP was based on the EPIPAGE study criteria and examination modalities.15 Infants were evaluated blindly as to treatment groups.

Very few data are available concerning the neurologic outcome of infants who were randomly assigned to receive HFOV or conventional ventilation in the age of surfactant. Two studies reported similar IVH rates and similar neurologic outcomes with either technique.9,10 Both of these studies concerned more mature infants, and 1 study reported data from only 1 of 3 centers.10

The difference in CP rates, although significant, was based on small numbers of patients (4 and 16) and therefore should be interpreted cautiously. The explanation for the higher CP rate in the conventional ventilation group remains highly speculative. Infants may have been more effectively stabilized in the HFOV group, with more limited variations of PCO2 and blood pressure, but this was not detected in our initial study. However, more infants switched from conventional ventilation to HFOV,1 thereby identifying a subset of patients who were randomly assigned to conventional ventilation and who had a particularly severe respiratory outcome, possibly increasing the risk for CP.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Our trial raised concerns about the safety of HFOV compared with conventional ventilation, on the basis of an increased severe IVH rate in the group of infants who were randomly assigned to HFOV. Surprisingly, neuromotor assessment at a corrected age of 2 years showed a higher CP rate among infants who were randomly assigned to receive conventional ventilation. Cerebral ultrasound examinations during the neonatal period had a low predictive value for CP, highlighting the importance of follow-up. Because of the various limitations of our study, these findings must be interpreted cautiously. Nevertheless, the neuromotor prognosis of infants who are treated early after birth by HFOV seems to be at least as good as that of infants who are treated by conventional ventilation.


   ACKNOWLEDGMENTS
 
This study was supported by Programme Hospitalier de Recherche Clinique and Assistance-Publique-Hôpitaux de Paris.

We gratefully acknowledge the contribution of investigators of the initial trial: Hervé Walti, MD (Sherbrook University, Canada); Thierry Lacaze-Masmonteil, MD, PhD (University of Edmonton, Canada); Sylvain Cantagrel, MD (University of Tours, France); and Laurent Storme, MD (University of Lille, France). We thank Pierre-Yves Ancel, MD, PhD, investigator of the EPIPAGE study, who checked the CP classification; all of the professionals who took part in the follow-up study; and Anthony Saul, MBBS, for stylistic review of the manuscript.


   FOOTNOTES
 
Accepted Oct 13, 2006.

Address correspondence to Guy Moriette, MD, Service de Médecine Néonatale de Port-Royal, Groupe Hospitalier Cochin-Saint Vincent de Paul, 123, Bd de Port-Royal, 75014 Paris, France. E-mail: guy.moriette{at}cch.ap-hop-paris.fr

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics




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