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PEDIATRICS Vol. 105 No. 6 June 2000, pp. 1202-1208
, and
From * Pediatric and Neonatal Intensive Care Unit, and
Department of Radiology, Hôpital des Enfants, University
Hospital of Geneva, Geneva, Switzerland.
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ABSTRACT |
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Abstract
Methods
Results
Discussion
References
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Objectives. The lack of decline in chronic lung disease of prematurity despite the generalized use of surfactant and alternative modes of ventilation such as high-frequency oscillation (HFO) has been attributed to some misunderstanding of how HFO has to be used. We used a new ventilatory strategy in very low birth weight (VLBW) infants, by initiating HFO immediately after intubation and attempting early lung volume optimization before surfactant was administered.
Study Design. The outcome of 32 VLBW infants, managed with first intention HFO over a period of 24 months (September 1, 1996 and August 31, 1998) was compared by chart review with 39 historical controls, consecutively managed with conventional mechanical ventilation (CMV) over a period of 24 months (January 1, 1994 and December 31, 1995).
Setting. An 11-bed tertiary care pediatric and neonatal intensive care unit of a university teaching hospital.
Results. The 2 groups of patients were similar in demographic distribution of birth weight, gestational age, race, and gender. Patients on first intention HFO were ventilator-dependent (median [95% confidence interval]: 5 [3-6] vs 14 [6-23] days) and oxygen-dependent (12 [4-17] vs 51 [20-60] days) for a shorter time than patients on CMV. The incidence of chronic lung disease at 36 weeks of gestational age was significantly lower in the HFO group compared with the CMV group (0% vs 34%).
Conclusions. First intention HFO with early lung volume optimization shortened the need for respiratory support and improved pulmonary outcome of VLBW infants with respiratory distress syndrome significantly. Key words: respiratory failure, high-frequency oscillatory ventilation, conventional mechanical ventilation, preterm newborn infant, bronchopulmonary dysplasia, chronic lung disease, patient outcome assessment.
Initial clinical experiences using high-frequency
oscillation (HFO) in premature infants presenting with hyaline membrane disease (HMD) failed to demonstrate any benefit over conventional mechanical ventilation (CMV) regarding the development of chronic lung
disease (CLD) of prematurity.1 These disappointing results
have been attributed to the absence of a clear strategy regarding the
lung volume at which HFO had to be operated.2 Studies in
different animal models of surfactant deficiency have demonstrated that
a high volume strategy was a prerequisite to prevent lung
injury,3-5 and that by combining HFO (at high lung
volumes) with exogenous surfactant a further reduction in lung injury
could be achieved.5,6 Indeed by combining higher
distending pressures and administration of surfactant, some more recent
studies could show a benefit on pulmonary outcome.7,8
Animal studies had further shown, that: 1) HFO at high lung volumes was
more effective in the atelectatic lung (ie, surfactant-depleted lung)
than in the lung presenting already with secondary injury (ie, with
hyaline membrane formation),9 and 2) HFO begun at birth
could limit the development of alveolar proteinaceous edema in
premature primates at risk for HMD.10,11 Although these latter observations might have suggested that the very early use of HFO
could prevent secondary lung injury, it is not yet commonly used as a
first intention therapy in premature infants at high risk to develop
CLD.
Based on these observations and the promising results from the later
clinical studies,7,8 we started to use HFO with a high
volume strategy as the first and exclusive mode of mechanical
ventilation in premature infants at high risk to develop CLD. We report
our experience with this new strategy.
Definitions
In absence of a standard clinical definition of CLD of
prematurity,12 the following indicators were used: 1) use of supplemental oxygen at 28 days of life13; 2) use of
supplemental oxygen at 30 days of life in association with a
persistently abnormal chest radiograph7,14,15; and 3) use
of supplemental oxygen at 36 weeks of postconceptional age.16
Patients
Over 24 months, we used a new ventilatory strategy (initiation
of HFO as primary mode of mechanical ventilation and aggressive lung
volume optimization) to treat all infants at high risk to develop CLD
(<1500 g and <32 weeks of gestation, and presenting with respiratory
distress syndrome [RDS]). The outcome of this group on first
intention HFO was compared with the outcome of a historical cohort on
patient-triggered CMV.
For both groups, the charts of consecutively treated eligible patients
were reviewed. CMV was used as standard practice until the end of 1995, and HFO was only used occasionally. We started to use HFO more
regularly from the beginning of 1996, and it became standard practice
during the same year. Neonates were eligible if their gestational age
was <32 weeks, their birth weight was <1500 g, and they were
diagnosed to have RDS of prematurity on usual epidemiologic and
radiologic criteria, requiring mechanical ventilation and supplemental
oxygen. Neonates with hydrops fetalis, congenital lung malformations,
or congenital diaphragmatic hernia, and those who were later proven to
have congenital pneumonia were excluded from analysis.
Treatment Strategies
HFO
HFO was provided by a piston-driven oscillator (Sensor Medics
3100A, Sensor Medics Inc, Anaheim, CA). Initial settings were as
follows: frequency, 12 to 15 Hz; Ti, 33%,
continuous distending pressure (CDP), 12 to 16 cm
H2O; pressure amplitude that produced visible
chest wall vibrations, and inspired oxygen fraction
(FIO2) to achieve a transcutaneous
oxygen saturation of 88% to 92%. Normoventilation (partial pressure
of carbon dioxide: 4.7-6.0 kPa [35-45 mm Hg]) was achieved by
adjusting, in order of priority, the pressure amplitude or frequency.
Lung volume optimization was attempted immediately after initiation of
HFO according to the following strategy. If the required
FIO2 was >.4, CDP was increased
repeatedly, in steps of 1 to 2 cm H2O every 1 to
2 minutes (up to a maximum of 25 cm H2O), until
the FIO2 could be lowered to or below
.4. Pressures were then lowered rapidly again to levels of 12 to 16 cm
H2O. Gas exchange was judged to be acceptable
once the partial pressure of arterial oxygen
(PaO2) was CMV
CMV was delivered by a time-cycled, continuous-flow,
pressure-controlled neonatal ventilator (Babylog 8000, Draeger Co,
Lübeck, Germany). Initial ventilator settings were usually the
following: patient-triggered intermittent positive pressure ventilation
(IPPV), peak inspiratory pressure of 18 to 24 cm
H2O, end-expiratory pressure of 3 to 5 cm
H2O, inspiratory time of .3 to .4 seconds,
frequency of 40 to 60 per minute, and
FIO2 of .4 to 1.0 to achieve a
transcutaneous oxygen saturation of 88% to 92%. Lung inflation was
controlled regularly with a chest radiograph and, if necessary,
ventilator pressures were adjusted (positive end-expiratory pressure
[PEEP] range: 3-6 cm H2O; maximal positive
inspiratory pressure: 30 cm H2O) if lung
inflation was at less than the seventh or at more than the ninth
posterior rib.
METHODS
Top
Abstract
Methods
Results
Discussion
References
8.0 kPa (60 mm Hg)
and/or oxygen saturation was at least 88%. If at this pressure
settings a drop in saturation requiring higher
FIO2 concentrations to maintain adequate oxygenation could be observed, CDP was increased again to
allow a reduction in FIO2 to .4. When
this oxygenation goal could not be met, higher airway pressures (16-22
cm H2O) and
FIO2 concentrations were maintained.
Heart rate and blood pressure were continuously monitored and lung
inflation was evaluated after this attempt of lung recruitment with a
chest radiograph. If signs of lung overinflation were present
(flattened diaphragms <9 posterior ribs) CDP was decreased by 2 cm
H2O. After disconnection of the endotracheal tube
for tracheal suctioning with occurring desaturation, CDP was increased
in repeated steps of 2 cm H2O (usually an
additional 4-6 cm H2O were required) until a
stabilization of oxygenation could be observed. At this point, CDP was
lowered again to the preaspiration level.
.4), and once the
infant was in stable hemodynamic condition. Surfactant was administered
at a dose of 5 mL/kg of body weight (dipalmitoyl-phosphatidylcholin: 67.5 mg/kg) divided in 4 aliquots with the patient repositioned between
aliquots: during CMV after disconnection from the ventilator on handbag
ventilation through the sideport of the endotracheal tube adapter, and
during HFO through the sideport of the endotracheal tube adapter
without any disconnection from the ventilator. All patients received a
second dose of surfactant, which was administered the same way as
described, 12 hours later.
Data Collection
Data on demographic, ventilator parameters, gas exchange, and outcome variables were collected for each patient by chart review. Uniformity between groups was evaluated based on gestational age, birth weight, the use of antenatal steroids, Apgar scores at 1 and 5 minutes, and the severity of RDS (radiologic grading on first chest radiograph and aA-ratio).
Ventilator settings with the corresponding gas exchange data were recorded using the first blood gas analysis on ventilation at 2, 6, 12, and 24 hours after intubation, and every 24 hours for the following 15 days, if patients were still ventilated and blood gas samples were available.
Chest radiographs from day 1, day 30 (± 5), and at 36 weeks of postconceptional age (if available) were reviewed by a single pediatric radiologist (S.H.) who was not informed which patient belonged to which group. Severity scoring of initial lung disease was performed using the first available radiograph according to the following system: grade 1, normal lung inflation with diffuse, bilateral, granular opacities (ground-glass appearance) with no or only rare air bronchograms; grade 2, ground-glass appearance or reticulogranular opacities with frequent air bronchograms; grade 3, decreased lung inflation with dense reticulogranular opacities, diminished but still visible cardiac border, and prominent air bronchograms; and grade 4, poor lung inflation with generalized or complete radiopacifiation and loss of the cardiac border.
The following primary endpoints were evaluated for differences in morbidity and outcome between the 2 groups: 1) length of ventilatory support (days), 2) length of supplemental oxygen requirements (days), 3) oxygen dependency at 28 days of life, 4) oxygen dependency at 30 days of life with radiologic evidence of CLD, 5) oxygen dependency beyond 36 weeks of gestational age, and 6) mortality. Secondary endpoints for assessment of possible adverse effects were 1) intraventricular hemorrhage and 2) air leak syndrome (pneumothorax, pulmonary interstitial emphysema).
Statistical Analysis
An unpaired t test was used for parametric data.
Mann-Whitney U-statistics were used for evaluation of
nonparametric data but also for parametric data when standard
deviations (SDs) were not equal between the 2 groups.
Categorical data were analyzed by means of a Fisher's exact test or
2 analysis as appropriate.17 Repeated
measures were analyzed using 1-way analysis of covariance for repeated
measures followed by a posthoc Bonferroni multiple comparison
test.18 Survival curves were calculated according to the
product limit (Kaplan-Meier) method, and compared with the Mantel-Cox
log-rank test. Median survival time is given with its 95% confidence
interval according to Brookmeyer and Crowley.19 Although
limited by the relatively small patient number, multiple logistic
regression analysis was used to rule out bias from a potential
covariate on primary outcome. For all testing, a P value
<.05 was accepted as significant.
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RESULTS |
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Results
Discussion
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The charts of 71 very low birth weight infants (birth weight <1500 g and gestational age <32 weeks), presenting with RDS as a primary diagnosis, consecutively admitted between September 1, 1996 and August 31, 1998 (HFO: n = 32) and between January 1, 1994 and December 31, 1995 (CMV: n = 39) were reviewed.
No differences were noted in demographic data between the 2 groups in regard to gestational age, birth weight, gender, incidence of prenatal steroid treatment, low Apgar score at 1 and 5 minutes, and severity of RDS of prematurity (radiologic grading on first chest radiograph and aA-ratio; Table 1). There was no difference in the time delay of intubation after delivery between the 2 groups (1.0 [.1-20] h in the HFO group vs .5 [.1-14] h in the CMV group; median [range]; P = .22, Mann-Whitney U test). Both groups were identical in terms of surfactant treatment (2 doses/12-hour interval) with 25 of 32 patients treated in the HFO group and 27 of 39 treated in the CMV group, respectively (P = .28, Fisher's exact test). The delay between time of intubation and surfactant application was greater in the HFO group compared with the CMV group (2.7 ± 1.0 hours vs 2.0 ± .7 hours; mean ± SD; P = .004, t test), as would be expected by the difference of the strategies applied.
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Within the first week of life, 5 infants died in the HFO group and 4 in the CMV group. In all 9 of these infants, care was withdrawn because of the presence of a severe intraventricular hemorrhage (grade 3 or 4). Care was discontinued only after obtaining parental consent. For further analysis, therefore, data from 27 patients in the HFO group and 35 patients in the CMV group, respectively, were available.
Patients on first intention HFO were ventilator-dependent (Table 2, Fig 1) over a significantly shorter time than patients on CMV. N-CPAP was used in both groups after extubation, with no detectable difference between the 2 groups in terms of days on N-CPAP. When combining days of ventilation and N-CPAP (ie, duration of pressure support), the difference between the 2 groups, in favor for the HFO group, remained significant (Table 2, Fig 2). Patients on HFO were oxygen-dependent (Table 2, Fig 3) over a significantly shorter time than patients on CMV, with less patients in the HFO group requiring supplemental oxygen at 28 days (Table 2), and a significantly lower incidence of CLD of prematurity, defined by the need of supplemental oxygen at 36 weeks' postconceptional age in the HFO group. To determine whether the finding of a highly significant reduction in CLD among survivors was confounded by gestational age, we used a logistic regression model that controlled for the effect of gestational age. The ventilator effect remained significant (P = .012). Detailed pulmonary outcome data are given in Table 2.
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Analysis of short-term effects showed that the PaO2/FIO2 ratio improved more rapidly over the first 24 hours in the HFO group compared with the CMV group (P = .0011, 1-way analysis of covariance for repeated measures; Fig 4). Posthoc testing showed that this difference was also significant for each time interval (2, 6, 12, and 24 hours; P < .05).
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There were no differences between the groups in the incidence of mild or severe intraventricular hemorrhage or pulmonary air leaks (Table 3).
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DISCUSSION |
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Results
Discussion
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The results of this retrospective analysis support the hypothesis that the early and exclusive use of HFO, combined with an initial aggressive lung volume recruitment, may decrease the incidence of ventilator-induced CLD in premature infants with established RDS. Using first intention HFO as the standard ventilation approach was associated with an impressive improvement in short- and long-term pulmonary outcome data. Not only did gas exchange improve more rapidly in the HFO group, but also the length of ventilator support and time of oxygen dependency were significantly shortened.
With the absence of CLD at 36 weeks of postconceptional age (95% confidence interval: 0%-11%) in the HFO group, the maximal possible frequency of CLD is below the one recently documented in the literature.1220-24 Our results are in close agreement with the findings of 2 randomized, controlled trials,7,8 which could demonstrate that the use of HFO as the predominant mode of mechanical ventilation decreased the incidence of CLD in term or preterm neonates, respectively. Indeed, pulmonary outcome in our patients was even better considering the absence of CLD at 36 weeks of gestational age in a patient group that was of younger gestational age and, therefore, at higher risk to develop CLD. We believe that these results are explained by 2 new clinical constructs. First, in the 2 positive trials previously reported,7,8 HFO was used as an early rescue therapy. In both studies, patients were switched to HFO from conventional ventilation after randomization at a mean age of 9 hours in 1 study,7 or after at least a 2-hour stabilization period on conventional ventilation (mean age: 2.9 hours) in the other study.8 In our patients, HFO was initiated as first mechanical ventilatory support after intubation and a short period (ie, 10-15 minutes) of handbag ventilation during patient transfer from the delivery room to the neonatal intensive care unit. The advantage of this approach in preventing ventilator-induced lung injury is strongly supported by animal data3,4,10,1125-27 and goes along with the observation that ventilator-induced lung injury may occur only within a relatively short period of CMV in the surfactant-deficient lung.328-30
Second, while using a less aggressive recruitment strategy, by accepting oxygen requirements of .6 FIO2 during the first 96 hours, and while giving priority to decreasing mean airway pressure as soon as a level of .6 FIO2 was reached, Clark et al7 observed no benefit on short-term outcome (ie, more rapid improvement in gas exchange) in the HFO group. In contrast, our strategy of working from the beginning at high distending pressures, in an attempt to increase (recruit) maximally the gas-exchanging surface, resulted in a rapid improvement in oxygenation (Fig 4). Very early in the course of RDS of prematurity, alveolar collapse with reduced functional residual capacity is the predominant feature, and surfactant deficiency is the predominant pathophysiology of disease. At this stage, the lung is easily recruitable, whereas once additional lung injury, characterized by neutrophil infiltration,31,32 epithelial injury,29 and the presence of proteinaceous edema, occurs, lung volume recruitment may become more difficult.3,9 The importance of combining HFO with aggressive lung volume recruitment for improving short- and long-term outcome is further illustrated by 2 negative HFO studies.33,34 In both, HFO was initiated early but operated at relatively low mean airway pressures. Although these studies could show that HFO, as a primary ventilation mode in premature infants with RDS, is as safe and efficacious as CMV, they failed, like the earlier HIFI trial,1 to show a benefit of HFO compared with CMV.
Experimental studies in surfactant-depleted animals showed that an increase in mean airway pressure, like CDP during HFO, induces more homogenous alveolar recruitment while reducing the risk of bronchopulmonary injury, compared with the situation during CMV.4,10,35 However, according to the inflation characteristics of the pressure-volume (PV) curve, a modest increase in CDP during HFO will only induce a relatively modest increase in lung volume.9,36 In contrast, if the lung is first inflated to high pressures to allow maximal alveolar recruitment, pressures can be rapidly reduced without loosing much volume, because lung volume will follow now the deflation limb of the overall PV curve.9,37 In the presence of PV hysteresis, the lung will contain more volume at any given pressure, if preceded by a volume recruitment history. Our strategy was not to apply sustained inflation up to a fixed airway pressure of 25 or even 30 cm H2O over 10 to 30 seconds as would be suggested by the animal data9,37; airway pressure was slowly increased over 10 to 20 minutes. The latter may induce less abrupt changes in intrathoracic pressures and, therefore, minimize the risk of hemodynamic side effects. In the few patients who required distending airway pressures up to 25 cm H2O over a short period to improve oxygenation and allow FIO2 below .4, no hemodynamic changes were observed. This is an agreement with the observations made by Kinsella et al38 and Gerstmann et al8 (Provo trial). In contrast to the Provo trial,8 routine suctioning was not discouraged and performed every 4 hours; as a result, there was no difference in the frequency of suctioning between both groups.
The retrospective character of our study may hamper the impressive results. However, by using a historical cohort as a control group, we could demonstrate how changes in ventilatory care have drastically changed outcome data in our unit. Whether this can be attributed primarily to the exclusive use of HFO, the use of an open lung strategy early in the course of lung disease, or the combination of both is difficult to know and is open to discussion.
In the historical cohort, CMV was used with a relatively low PEEP approach. This approach is commonly used in the treatment of RDS in newborns despite clear experimental evidence that ventilating collapsed lung units can induce acute lung injury.39 Recent studies in adult RDS patients indicate that the use of an open lung approach during conventional ventilation combined with small tidal volume ventilation can improve pulmonary morbidity and patient survival.40,41 Therefore, based on our observations, we cannot conclude that identical results could not have been achieved while using a similar open lung, small tidal volume approach during CMV. Another recently published negative study by Thome et al,24 comparing high-frequency ventilation (HFV) at high lung volumes with IPPV at high rate and low peak inspiratory pressures in preterm infants did not show any difference in terms of prevention of lung injury between the 2 treatment groups. Although this study might support the hypothesis that both ventilatory modes are equally protective, such a conclusion would be premature for the following reasons. Treatment failure criteria were met in ~50% of all children in both treatment arms, allowing free choice of ventilatory management to the attending physician. The incidence of CLD (ie, ventilator or oxygen dependency at 36 days of postconceptional age) was ~25% in both groups and air leaks (ie, pulmonary interstitial emphysema and gross air leaks) occurred in up to 42% of the HFV group and 31% of the IPPV group. Theses numbers are high compared with our outcome data in the HFO group. Possible reasons for these differences might be the fact that a certain number of patients were not ventilated exclusively with 1 or the other ventilatory mode, the time delay before HFV was instituted (attributable to the randomization procedure) as already discussed above, the use of a less aggressive volume recruitment strategy in the HFV group, the use of a different device for HFV (flow interrupter combined with a Ventury system to generate negative pressure swings), and the use of a different oscillatory rate (10 Hz vs 15 Hz in our trial). These different questions certainly have to be addressed in future trials. In contrast, using high rates and, therefore, small tidal volumes during IPPV resulted in a lower incidence of CLD in the IPPV group compared with our results in the CMV group. The concept of peak airway pressure limitation combined with an open lung approach might, in analogy to the results from the adult RDS studies,40,41 be promising for further improving outcome in conventionally ventilated infants.
While not using a fast acting natural surfactant in our unit, exogenous surfactant (Exosurf) was given in the HFO group once it was thought that atelectatic lung units had been adequately opened, as demonstrated by the rapid improvement in oxygenation. In this sense, we used exogenous surfactant more to stabilize patent airways than to open them. With this in mind, the indication for surfactant treatment in the HFO group was based on the severity of lung disease before and not after recruitment, judged by the aA-ratio calculated from the first blood gas analysis. This concept is supported by some experimental data showing a more important reduction in lung injury by combining HFO (at high lung volumes) with exogenous surfactant than by using HFO solely.5,6 If we had used surfactant only in the infants in whom the aA-ratio remained below .22 after lung volume recruitment, surfactant would have been rarely given in the HFO group. Whether our approach proves to be correct warrants further investigations.
We used HFO exclusively to extubation, followed by N-CPAP when clinically indicated. N-CPAP was used after extubation in infants on CMV (historical controls) as well, applying the same clinical indications as were used in the HFO group. Because the duration of N-CPAP after extubation was not different in both groups and additional survival analysis of the duration of pressure support (ie, sum of days on mechanical ventilation and N-CPAP) remained significant between the 2 groups, it is not likely that the use of N-CPAP has influenced primary outcome data in either group.
Ventilator-induced lung injury can occur rapidly and starts in the delivery room. A promising ventilation strategy for prevention of acute and chronic lung injury in premature infants presenting with RDS is one that uses HFO from the beginning and focuses early on optimal lung recruitment. However, although there is overwhelming evidence that an open lung approach is essential to the avoidance of acute and chronic lung injury, the use of HFO may not be the only way to accomplish these goals.
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ACKNOWLEDGMENTS |
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We thank Bernadette Mermillod (Statistician, University Hospital of Geneva) and Thomas E. Bachmann (Economedtrx, Inc) for assistance in the statistical analysis of our data.
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FOOTNOTES |
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Received for publication Sep 10, 1999; accepted Sep 10, 1999.
Reprint requests to (P.C.R.) Pediatric and Neonatal Intensive Care Unit, Hôpital des Enfants, University Hospital of Geneva, 6, Rue Willy-Donzé, CH-1211 Geneva 14, Switzerland. E-mail: peter.rimensberger{at}hcuge.ch
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ABBREVIATIONS |
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HFO, high-frequency oscillation; HMD, hyaline membrane disease; CMV, conventional mechanical ventilation; CLD, chronic lung disease; RDS, respiratory distress syndrome; CDP, continuous distending pressure; FIO2, inspired oxygen fraction; PaO2, partial pressure of arterial oxygen; IPPV, intermittent positive pressure ventilation; PEEP, positive end-expiratory pressure; aA, arterial-alveolar oxygen; N-CPAP, nasal continuous airway pressure; SD, standard deviation; PV, pressure-volume; HFV, high-frequency ventilation; VLBW, very low birth weight.
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REFERENCES |
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Confidence Intervals and Statistical Guidelines. London, UK: British Medical Journal; 1989:71-79This article has been cited by other articles:
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 A. Doctor, E. Al-Khadra, P. Tan, K. F. Watson, D. L. Diesen, L. J. Workman, J. E. Thompson, C. E. Rose, and J. H. Arnold Extended high-frequency partial liquid ventilation in lung injury: gas exchange, injury quantification, and vapor loss J Appl Physiol, September 1, 2003; 95(3): 1248 - 1258. [Abstract] [Full Text] [PDF]
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W. Hofhuis, M. W. A. Huysman, E. C. van der Wiel, W. P. J. Holland, W. C. J. Hop, G. Brinkhorst, J. C. de Jongste, and P. J. F. M. Merkus Worsening of V'maxFRC in Infants with Chronic Lung Disease in the First Year of Life: A More Favorable Outcome after High-Frequency Oscillation Ventilation Am. J. Respir. Crit. Care Med., December 15, 2002; 166(12): 1539 - 1543. [Abstract] [Full Text] [PDF]
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G. Moriette, J. Paris-Llado, H. Walti, B. Escande, J.-F. Magny, G. Cambonie, G. Thiriez, S. Cantagrel, T. Lacaze-Masmonteil, L. Storme, et al. Prospective Randomized Multicenter Comparison of High-Frequency Oscillatory Ventilation and Conventional Ventilation in Preterm Infants of Less Than 30 Weeks With Respiratory Distress Syndrome Pediatrics, February 1, 2001; 107(2): 363 - 372. [Abstract] [Full Text]
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