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PEDIATRICS Vol. 104 No. 5 November 1999, pp. 1082-1088
From the Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.
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ABSTRACT |
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Top
Abstract
Methods
Results
Discussion
References
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Objective. To determine whether a ventilatory strategy of permissive hypercapnia (PHC) reduces the duration of assisted ventilation in surfactant-treated neonates weighing 601 to 1250 g at birth.
Design. Forty-nine surfactant-treated preterm infants (birth weight: 854 ± 163 g; gestational age: 26 ± 1.4 weeks) receiving assisted ventilation were randomized during the first 24 hours of age to a PHC group (PaCO2: 45-55 mm Hg) or to a normocapnia group (NC; PaCO2: 35-45 mm Hg). The primary outcome measure was the total number of days on assisted ventilation. Uniform extubation and reintubation criteria were used for both groups. All patients received aminophylline before extubation.
Results. The total number of days on assisted ventilation expressed as median (25th-75th percentiles) was 2.5 (1.5-11.5) in the PHC group and 9.5 (2.0-22.5) in the NC group (Mann-Whitney U test). The number of patients on assisted ventilation throughout the first 96 hours after randomization was lower in the PHC group (log rank test). During that period, the ventilated patients in the PHC group had a higher PaCO2 and lower peak inspiratory pressure, mean airway pressure, and ventilator rate than did those in the NC group. The percentage of patients requiring reintubation within 24 hours postextubation (PHC 17% vs NC 28%) and supplemental oxygen at 28 days of life (PHC 43% vs NC 64%) and the total days of oxygen supplementation (PHC 15 [4-53] vs NC 32 [17-50]) did not differ between the groups. There were no differences in mortality, air leaks, intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, or patent ductus arteriosus.
Conclusion. A ventilatory strategy of PHC in preterm infants who receive assisted ventilation is feasible, seems safe, and may reduce the duration of assisted ventilation.assisted ventilation, respiratory distress syndrome, gentle ventilation, lung injury.
Despite important advances in respiratory care, lung injury
is still a leading cause of neonatal morbidity in neonates who receive
ventilatory support. Although surfactant administration in neonates is
very effective, it has not decreased the incidence of bronchopulmonary
dysplasia/chronic lung disease (BPD/CLD).1,2 The duration
and intensity of assisted ventilation may be important determinants in
the development of lung injury. Large tidal volumes are considered
particularly harmful to the developing lung.3 Retrospective studies suggest that ventilatory strategies that lead to
relative hypocapnia during the first days after birth may increase
BPD/CLD.4,5 Permissive hypercapnia (PHC) is a strategy for
the management of patients receiving assisted ventilation in which
relatively high levels of PaCO2 are
accepted to avoid high tidal volumes, pulmonary overdistention, and
hypocapnia, thus potentially reducing lung injury.6,7 PHC has been reported to be a safe alternative to conventional normocapnic assisted ventilation in adult patients with acute respiratory distress
syndrome8-10 and may increase survival.11 PHC may be important in the management of preterm infants with respiratory distress syndrome (RDS).12 Data on hypercapnia in ventilated neonates are limited, and none of the reported studies predetermined or controlled the degree of hypercapnia. We performed a
randomized, controlled pilot study to evaluate whether a strategy of
PHC, initiated during the first 24 hours after birth in neonates weighing 601 to 1250 g at birth, decreases the number of days of
assisted ventilation.
Study Outcomes
The primary hypothesis was that a ventilatory strategy of PHC
would reduce the number of days on assisted ventilation by 35%, compared with a normocapnic approach. The primary outcome measure was
the total number of days on assisted ventilation. The secondary outcome
measures included the total number of days on supplemental oxygen, the
incidence of BPD/CLD, postnatal steroid administration, air leaks,
intraventricular hemorrhage, periventricular leukomalacia, retinopathy
of prematurity, patent ductus arteriosus, necrotizing enterocolitis
( Eligibility and Randomization
This study was conducted in the Regional Newborn Intensive Care
Unit at the University of Alabama at Birmingham between November 1, 1995 and December 9, 1996. The study protocol and informed consent form
were approved by the institutional review board.
Infants were eligible for the study if all the following criteria were
met: 1) birth weight of 601 to 1250 g; 2) surfactant-treated RDS
on assisted ventilation; 3) postnatal age <24 hours; and 4) written
parental informed consent. Infants were excluded for any of the
following reasons: 1) 5-minute Apgar score <3; 2) small for
gestational age; 3) congenital anomalies or suspected congenital infection; 4) multiple pregnancy of triplets or more; and 5) infant not
expected to need prolonged ventilatory assistance as judged by the
attending neonatologist. The patients were assigned to either a PHC or
a normocapnia (NC) group using a permuted block randomization procedure
consisting of a random sequence of blocks of 4, 6, 8, and 10. The group
assignments were recorded and sealed within sequentially numbered
opaque envelopes. The odds of assignment to one of the two groups were
not known to the investigators. To ensure a similar birth weight mix,
infants were stratified into the following groups: 601 to 750 g,
751 to 1000 g, and 1001 to 1250 g. Twins who met enrollment
criteria were randomized to the same group according to the
randomization of the first eligible infant of the pair.
Ventilator Management
All infants received initial assisted ventilation with an Infant
Star ventilator (Infrasonics, Inc, San Diego, CA), a time-cycled pressure-limited ventilator. High frequency ventilation was used at the
discretion of the attending physician. Oxygenation was monitored
continuously with a pulse oximeter. Ventilatory management was the
responsibility of the attending physicians, but different algorithms
were provided for infants randomized to each treatment group. The goals
for pH and PaCO2 were different in
the two groups of infants. In the NC group, the goals were to keep
PaCO2 between 35 and 45 mm Hg and pH
To achieve these goals, ventilator setting changes followed a modified
clinical algorithm, developed for the management of pressure-limited
ventilation in infants with RDS.13 The algorithm
incorporates accepted concepts of the effects of neonatal assisted
ventilation on gas exchange. Briefly, CO2
elimination was enhanced by increasing the ventilatory frequency. If
this failed, peak inspiratory pressure was increased. During the
weaning process, priority was given to reduce peak inspiratory
pressure. Oxygenation was improved predominantly by increases in mean
airway pressure when the FIO2 was
>0.70. This was accomplished by increasing positive end expiratory
pressure or inspiratory time. If hypoxemia was persistent, peak
inspiratory pressure was increased. If
FIO2 was <0.40, increases in oxygen
concentration were performed for hypoxemia. When the
FIO2 was between 0.40 and 0.70, the
parameter modified was decided based on the level of mean airway
pressure and chest excursion. Although the algorithm was based on
arterial blood gas measurements, clinical assessment, including, but
not limited to, chest wall movements, breath sounds, and cardiovascular function, was performed simultaneously. The algorithm suggested the
type of ventilator setting change but not its magnitude, which was
decided on clinical grounds.
Objective criteria were used for extubation to minimize bias. Infants
were extubated from assisted ventilation if all the following criteria
were met: peak inspiratory pressure General Care
At least one dose of surfactant (Survanta, Ross Laboratories,
Columbus, OH) was administered before randomization. Repeated doses
were given if the FIO2 was >0.3
and/or if the mean airway pressure was >7 cm
H2O. Dexamethasone was considered for infants who
were ventilator-dependent at 10 days of age, if they had radiologic findings consistent with developing chronic lung injury in the absence
of confounding circumstances, such as patent ductus arteriosus, pneumonia, or sepsis. A 7-day course of dexamethasone at 0.6 mg/kg per
day was used. A second, tapering 9-day course (0.6, 0.4, and 0.2 mg/kg
per day for 3 days each) was given as clinically indicated.
Intravenous fluids were started at 130 to 200 mL/kg per day in infants
Data Collection and Definitions
Maternal demographics and obstetric history of pregnancy, labor,
and delivery were obtained from the mother's medical record. Gestational age was assessed by the best obstetrical estimate and the
Ballard examination of the neonate. Infants whose birth weight was
below two standard deviations were considered small for gestational
age.14 An initial cranial ultrasound was performed before
study entry. Subsequent studies were performed routinely on days 5 through 7 and 28 ± 7 or when clinically indicated. The arterial
blood gas values were recorded before randomization and closest to 6, 12, 24, 36, 48, 60, 72, 84, and 96 hours postrandomization while the
infant received assisted ventilation. The corresponding ventilator
settings at these times were recorded. Data were collected at
prospectively scheduled times and recorded on standardized forms.
The total duration of assisted ventilation was calculated from the sum
of all periods of assisted ventilation until final extubation. Time on
continuous positive airway pressure was not counted as assisted
ventilation. The total duration of oxygen supplementation was
calculated from the sum of all periods of any technique of oxygen
supplementation, including after transfer or discharge. BPD was defined
as oxygen requirement and abnormal chest radiograph on day 28 of
postnatal age, with oxygen requirement for at least 21 of the first 28 days.15 Air leaks included pneumothorax and/or pulmonary
interstitial emphysema. The severity of intraventricular hemorrhage was
graded according to the criteria of Papile et al.16 A
hemorrhage was considered to have progressed if: 1) a new
intraventricular hemorrhage developed from an initial negative head
ultrasound; 2) there was a progression in any grade of intraventricular
hemorrhage; or 3) a second intraventricular hemorrhage was noted in the
hemisphere opposite from the existing hemorrhage. A diagnosis of
periventricular leukomalacia was made if the cranial ultrasound showed
postnatal development of multiple cystic echolucencies in the cerebral
white matter. Proven sepsis was defined as a positive blood culture
result for bacteria or fungus treated by the clinicians at any time
during hospitalization. The presence of patent ductus arteriosus was
confirmed by echocardiography. Modified Bell's criteria were used for
necrotizing enterocolitis staging.
Sample Size Determination and Statistical Methods
At the time when the study was designed, the mean number of days
on assisted ventilation for infants weighing 601 to 1250 g in our
unit was 14 days. Using an estimated standard deviation of 6 days, a
sample size of 24 infants per group would be required to detect a 5-day
difference (a reduction of 35%) in days on assisted ventilation
between the groups with a power of 0.80 and a type I error of 0.05 (two-tailed). The analysis was performed according to intention to
treat, and crossover was not allowed. Results were analyzed by the
Student's t test, During the enrollment period, a total of 171 preterm infants
weighing 601 to 1250 g at birth were born at the University of Alabama at Birmingham (Fig 1). Of these
infants, 57 did not receive assisted ventilation in the first 24 hours
after birth; thus, 114 infants were potentially eligible. A total of 65 neonates were excluded for the following reasons: Apgar score <3 at 5 minutes (n = 7); small for gestational age
(n = 5); congenital anomalies/infection (n = 11); triplet (n = 1); not expected
to need prolonged mechanical ventilation (n = 24);
consent denied (n = 12); or the attending physician's
decision not to randomize based on evidence of pulmonary hypertension
or early pulmonary interstitial emphysema (n = 5). Of
the infants, 49 were randomly assigned, 24 to the PHC group and 25 to
the NC group. All patients had radiographs consistent with RDS. Birth
weight, gestational age, gender, race, prenatal steroid administration,
maternal chorioamnionitis, percentage of cesarean section, postnatal
age at study entry, Apgar scores, and prerandomization arterial blood
gases and oxygenation indexes did not differ significantly between the
two groups (Table 1). In addition, the
degree and need for resuscitation, the overall delivery room
management, and time to intubation did not differ between the groups.
TABLE 1
METHODS
Top
Abstract
Methods
Results
Discussion
References
stage II-A), and length of hospitalization.
7.25. In the PHC group, ventilatory management was directed to
maintain PaCO2 between 45 and 55 mm
Hg and pH 7.20. These goals were used for the first 96 hours after
randomization. After that time, the changes in the ventilator settings
were directed at the pH criteria, allowing high levels of
PaCO2 also in the NC group. The goal
for PaO2 level was between 50 and 80 mm Hg in both groups.
19 cm H2O,
ventilator rate 10 per minute, FIO2
0.4, and arterial pH 7.25. An aminophylline loading dose was given
before extubation. Continuous positive airway pressure was used as
clinically indicated. Reintubation was performed for a pH <7.20,
respiratory failure, or severe apneic episodes needing assisted
ventilation according to the attending physician. The defined
extubation criteria were followed for every period on assisted
ventilation, except when patients required more than one reintubation
for apnea. In these patients, a new extubation was attempted 5 to 7 days after the previous failure. Patients were weaned from oxygen
supplementation when they were able to maintain oxygen saturation
90% while breathing air.
750 g, and at 100 to 150 mL/kg per day in infants between 751 and
1250 g. The total fluid intake was adjusted as needed, based on
urinary output, weight change, and serum sodium values. All patients
received indomethacin for intraventricular hemorrhage prophylaxis (a
daily dose of 0.1 mg/kg for 3 days). Sodium bicarbonate was given for
serum bicarbonate 16 mEq/L.
2, or Fisher's
exact test, as appropriate for parametric data and by Mann-Whitney
U rank sum test for nonparametric data. A Kaplan-Meier analysis was performed, comparing the time on assisted ventilation during the first 96 hours after randomization and throughout the hospital stay in the two groups. A P value <0.05 was
considered to be statistically significant.
RESULTS
Top
Abstract
Methods
Results
Discussion
References
View larger version (19K):
[in a new window]
Fig. 1.
Trial profile summarizing participant screening and randomization. The
primary reason for exclusion was no need for assisted ventilation or
not expected to need prolonged ventilation.
Demographic Data and Prerandomization Ventilator Settings and Blood Gas
Values
Respiratory Outcomes
The duration of assisted ventilation was not reduced significantly in the PHC group (Table 2). Because the results were not distributed normally, the median and the 25th-75th percentiles are used to express these values. The total number of days on assisted ventilation was 2.5 (1.5-11.5) in the PHC group and 9.5 (2.0-22.5) in the NC group (P = .17; Mann-Whitney U test). However, the number of patients on assisted ventilation during the 96 hours after randomization was lower (P < .005; 1og rank test) in the PHC group (Fig 2).
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During the first 96 hours after randomization, the ventilated patients in the PHC group had higher (P < .05) PaCO2 values (Fig 3) and lower peak inspiratory pressures, mean airway pressures, and ventilator rates than did those in the NC group at most 12 hour intervals after randomization (Fig 4); impairment of oxygenation, reflected by arterial to alveolar oxygen ratio and FIO2, was comparable in the two groups (Fig 5).
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The total duration of oxygen supplementation, the incidence of BPD, oxygen requirement at 36 weeks, air leaks, reintubations, and the use of postnatal steroids and postextubation continuous positive airway pressure did not differ significantly between the two groups (Table 2). The rate of reintubation within 24 hours postextubation was 17% in the PHC group and 28% in the NC group (not significant). The mean peak inspiratory pressure before extubation was 15 cm H2O in the PHC group and 16 cm H2O in the NC group (not significant). Of the survivors in the PHC group, 67% (14/21) required at least one reintubation at some point during their hospitalization (7 for respiratory failure, 5 for apnea, 1 for necrotizing enterocolitis, and 1 for ventriculo-peritoneal shunt placement). Of the survivors in the NC group, 55% (12/22) were reintubated (8 for respiratory failure, 3 for apnea, and 1 for necrotizing enterocolitis). Only 2 infants (both randomized to the NC group) received high-frequency ventilation at any time during the hospitalization.
Nonrespiratory Outcomes
Three patients in each group died. The causes of death in the PHC group were grade 4 intraventricular hemorrhage in 2 patients and necrotizing enterocolitis/sepsis in 1 patient. In the NC group, 2 patients died from grade 4 intraventricular hemorrhage and 1 died because of respiratory failure. There were no significant differences in any of the nonrespiratory outcome measures between the two groups (Table 3). Three patients (all in the PHC group) did not have a head ultrasound performed before randomization.
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DISCUSSION |
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Top
Abstract
Methods
Results
Discussion
References
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Assisted ventilation in infants with RDS has resulted in improved neonatal survival.17 However, its excessive or prolonged use has been associated with an increased incidence of BPD/CLD.18-20 In this pilot study, we found that a ventilatory strategy of PHC for the management of preterm infants on assisted ventilation is feasible and not associated with an increased rate of complications, compared with a traditional normocapnic approach. The duration of assisted ventilation was decreased in the first 96 hours after randomization in the PHC group, but the total duration of assisted ventilation in the PHC group did not decrease significantly.
Our study has some limitations that preclude firm conclusions. The failure to attain a level of statistical significance in the total duration of assisted ventilation may be primarily attributable to the marked variability in duration of ventilation and a small sample size, with the possibility of a type II error, because the power of the test was below the desired power of 0.80. The variability in the duration of ventilation was in part because a ventilatory strategy of PHC may not necessarily decrease the need for assisted ventilation in infants with apnea or other nonrespiratory causes. A choice of ranges of PaCO2 that separated the groups more may have led to larger differences in the duration of ventilation. Because this study could not have been masked, to decrease the influence of any potential bias on duration of assisted ventilation, we defined and followed strict extubation and reintubation criteria and used precise indications for those therapies that have been reported to influence extubation success, such as aminophylline17 and dexamethasone.21
PHC was compared with NC during the first 96 hours based on two
reasons. First, the available evidence relates BPD/CLD to aggressive
ventilation in the early (<96 hours) course of respiratory disease.4,5 Second, after the first few days of treatment,
it is common practice in our unit to allow
PaCO2 levels to rise, so a consensus
was reached among the neonatologists to allow
PaCO2 increases in the NC group also
after the first 96 hours. The range of safe levels of
PaCO2 in neonates is unknown. The
benefits of PHC may be counterbalanced by the potential adverse consequences of mild hypercapnic acidosis. Severe hypercapnic acidosis
increases cerebral blood flow, which may lead to cerebral edema,
increased intracranial pressure, and intraventricular
hemorrhage.22,23 However, data collected retrospectively
show an association between intraventricular hemorrhage and severe
(PaCO2: 60 mm Hg) but not mild
hypercapnia.24,25 PaCO2
levels >60 mm Hg also have been associated with the development of
retinopathy of prematurity in a mouse model.26 On the
other hand, recent clinical studies suggest that hypocapnia increases
the risk for periventricular leukomalacia and cerebral
palsy.27-29 Indeed, it is possible that mild hypercapnia
may be protective to the immature brain.30 Based on this
information and on the traditional thought that normal
PaCO2 levels in ventilated infants
are ~40 mm Hg, the target PaCO2
ranges selected for this pilot trial were considered safe for both
groups. However, tolerance of even higher
PaCO2 values and/or lower pH values
in the PHC group may be acceptable and may have resulted in a larger
effect size. Even when the treating physicians followed the protocol, the magnitude of the ventilator changes were sometimes insufficient and
may have accounted for the lower than expected levels of
PaCO2 in the PHC group. Increased
spontaneous minute ventilation also may have limited the development of
hypercapnia.
The lack of tidal volume measurements in this study may be criticized, because it has been recommended that PHC should be achieved with a reduction in tidal volume. Because tidal volume was not measured in all patients, we cannot relate our results to the tidal volumes used. Experimental and clinical data indicate that ventilator-induced lung injury contributes markedly to lung damage in immature lungs and that the deleterious effect of assisted ventilation is more related to the volumes than to the pressures administered.31 Thus, the term volutrauma is preferred by some over the commonly used term barotrauma.32 Tidal volume may be a sensitive indicator of the relative risk of ventilator-induced lung injury. However, tidal volumes may vary markedly during pressure-limited ventilation. Furthermore, the uniform practice of PaCO2 analysis and the infrequent routine use of tidal volume measurements in neonates make our approach more generalizable.
PHC has not been evaluated previously in a controlled study in
neonates. A low mortality rate with the use of PHC has been reported in
children33 and adults8-11 with acute
respiratory distress syndrome and in neonates with persistent pulmonary
hypertension.34 A report of 151 patients weighing 1500
g, managed with a protocol emphasizing minimization of ventilatory
support, suggested that the use of low ventilator settings may reduce
the incidence of pneumothorax and lung injury in neonates who receive
assisted ventilation.35 Two large retrospective studies,
designed to determine risk factors for BPD/CLD, concur on the
importance of ventilatory strategies.4,5 Using multiple
logistic regression analysis, these two studies independently concluded
that ventilatory strategies that lead to hypocapnia during the early
neonatal course result in an increased risk of BPD/CLD (relative risk:
1.45; 95% confidence interval: 1.04-2.01; odds ratio: 3.3; 95%
confidence interval: 1.3-8.3). Kraybill et al4 performed
a multicenter analysis in 235 infants with birth weights between 751 and 1000 g admitted to 10 neonatal units. In this study, only low
levels of PaCO2 on days 2 and 4 of
life and male gender were independent predictors of BPD (defined as
receiving oxygen at 30 days of life). With a similar design, Garland et
al5 analyzed data on 188 patients weighing <1700 g at
birth. They observed that low levels of
PaCO2 on the first day of life
remained associated with CLD (defined as receiving oxygen at 36 weeks'
gestational age) even when several typical measures of respiratory
illness severity were put into the model. Peak levels of
PaCO2 >50 mm Hg in the first 4 days
of life and PaCO2 41 mm Hg before
the administration of surfactant were reported to be associated with a
lower incidence of BPD/CLD in these two studies, respectively. The lack
of a statistically significant reduction in the incidence of BPD in the
current pilot study may be attributable to a type II error caused by
the relatively small sample size.
Hypercapnia has physiologic effects on gas exchange that should provide important benefits. The ventilatory requirements in patients with respiratory failure are determined by the targeted PaCO2.36,37 If PaCO2 is permitted to increase, alveolar CO2 will increase. The increase in alveolar CO2 that occurs during PHC increases CO2 elimination for the same minute ventilation. Thus, as CO2 equilibrates at a higher level in the body, alveolar ventilation requirements decrease because the higher alveolar CO2 makes elimination more effective. Furthermore, for a given PaO2 the shift to the right of the oxygen dissociation curve during hypercapnia (Bohr effect) permits more unloading of oxygen to the tissues. Cardiac output may improve as a result of the decreased mean airway pressure that can be used during PHC. The possible negative effects of PHC, thought to be of less clinical importance, include, among others, a small reduction in PaO2 as a result of the increased alveolar CO2, a reduction in the transported oxygen in the arterial blood as a result of the right shift of the O2 dissociation curve, and the potential increases in work of breathing, pulmonary vascular resistance, and cerebral blood flow.6,7,9,10,36,37
PHC has been recommended as the preferred ventilatory strategy for the management of acute respiratory distress syndrome,37 although the data to support its use are limited. The data on potential benefits of PHC in neonates come from retrospective studies. Despite the extraordinarily common use of assisted ventilation in neonates, few prospective, randomized trials have been conducted to determine strategies that limit the severity or prevent the development of BPD/CLD in neonates requiring assisted ventilation. The results of this pilot study provide additional evidence that PHC is likely to be a safe alternative to the traditional normocapnic approach and may reduce lung injury and the duration of assisted ventilation. Moreover, PHC may be combined with other promising techniques such as high frequency ventilation17 and tracheal gas insufflation.38 However, caution must be exercised before widespread use of PHC as a mode of assisted ventilation in preterm infants. The small sample size, the relatively low incidence of some of the outcome measures and adverse events, and the wide confidence intervals of the treatment effects preclude firm conclusions about potential benefits or adverse effects of PHC. Additional clinical trials to evaluate the effect of PHC in neonates are warranted.
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ACKNOWLEDGMENTS |
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This work was supported in part by Grant M01-RR00032 from the National Institutes of Health.
We thank the respiratory therapists, nurses, residents, fellows, and attending physicians whose collaboration made this trial possible. We also thank Cassandra Hudson and Maria G. Peroni, who helped us in the preparation of the manuscript.
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FOOTNOTES |
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Received for publication Jun 30, 1998; accepted Mar 2, 1999.
This work was presented at the Annual Meeting of the Society of Pediatric Research, Pediatric Academic Society; May 2-6, 1997; Washington, DC.
Reprint requests to (W.A.C.) University of Alabama at Birmingham, 525 New Hillman Building, 619 S 19th St, Birmingham, AL 35233-7335. E-mail: wcarlo{at}peds.uab.edu
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ABBREVIATIONS |
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BPD, bronchopulmonary dysplasia; CLD, chronic lung disease; PHC, permissive hypercapnia; RDS, respiratory distress syndrome; NC, normocapnia.
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REFERENCES |
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Results
Discussion
References
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J. G. LAFFEY, M. TANAKA, D. ENGELBERTS, X. LUO, S. YUAN, A. KEITH TANSWELL, M. POST, T. LINDSAY, and B. P. KAVANAGH Therapeutic Hypercapnia Reduces Pulmonary and Systemic Injury following In Vivo Lung Reperfusion Am. J. Respir. Crit. Care Med., December 1, 2000; 162(6): 2287 - 2294. [Abstract] [Full Text]
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G. DASSIEU, L. BROCHARD, M. BENANI, S. AVENEL, and C. DANAN Continuous Tracheal Gas Insufflation in Preterm Infants with Hyaline Membrane Disease . A Prospective Randomized Trial Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): 826 - 831. [Abstract] [Full Text]
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