Original Article. Effects of Pressure Support during an Acute Reduction of Synchronized Intermittent Mandatory Ventilation in Preterm Infants

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1 Original Article Effects of Pressure Support during an Acute Reduction of Synchronized Intermittent Mandatory Ventilation in Preterm Infants Waldo Osorio, MD Nelson Claure, PhD Carmen D Ugard, RRT Kamlesh Athavale, MD Eduardo Bancalari, MD BACKGROUND: During weaning of synchronized intermittent mandatory rate in preterm infants, the spontaneous breaths must overcome the resistance of the endotracheal tube and the disease-induced respiratory loads. Pressure Support (PS) can be used as an adjunct to synchronized intermittent mandatory ventilation (SIMV) to partially unload the spontaneous breaths. OBJECTIVE: To evaluate the effects of two levels of PS as an adjunct to SIMV on gas exchange and breathing effort during an acute reduction in SIMV rate in preterm infants. METHODS: In all, 15 infants (birth weight 793±217 g, gestational age 26.4±1.5 weeks, postnatal age 15±16 days). Ventilatory support consisted of SIMV with peak inspiratory pressure (PTP) 16.3±1.3 cmh 2 O, positive endexpiratory pressure (PEEP) 4.3±0.6 cmh 2 O, and fraction of inspired oxygen (FiO 2 ) 0.26±0.06. Infants were studied during four 30-minute periods: Two baseline SIMV periods and two periods of SIMV plus PS, in random order. During SIMV þ PS, SIMV rate was lowered by 10 breaths per minute (b/minute) and PS was set at 3 and 6 cmh 2 O (SIMV þ PS3 and SIMV þ PS6, respectively). Division of Neonatology, Department of Pediatrics, University of Miami School of Medicine, Miami, FL, USA. This work was supported by University of Miami Project NewBorn and The National Institutes of Health, Fogarty Grant # 1 D43 TW Equipment grant provided by Viasys Healthcare. This work was presented in part at the 2002 meeting of the Society for Pediatric Research. Address correspondence and reprint requests to Nelson Claure, Division of Neonatology, Department of Pediatrics, University of Miami School of Medicine, P.O. Box R-131, Miami, USA. 412 RESULTS: SIMV rate was reduced during SIMV þ PS from 21.4±6.6 to 11.4±6.6 b/ minute. Arterial oxygen saturation, transcutaneous carbon dioxide tension and FiO 2 remained unchanged. Minute ventilation, total respiratory rate and mean airway pressure were higher during SIMV þ PS. Per-breath inspiratory effort was lower during SIMV þ PS and this was more striking during SIMV þ PS6. Spontaneous inspiratory effort per minute increased during SIMV þ PS3, but this increase was averted during SIMV þ PS6. CONCLUSION: Assistance of the spontaneous breaths with pressure support maintained gas exchange. PS of 6 cm H 2 O prevented an increase in breathing effort during an acute 50% reduction in SIMV rate. Journal of Perinatology (2005) 25, doi: /sj.jp Published online 21 April 2005 INTRODUCTION Conventional pressure-limited time-cycled intermittent mandatory ventilation (IMV) and synchronized-imv (SIMV) are widely used in neonatal mechanical ventilation. These modalities deliver a fixed number of mechanical breaths every minute at a constant peak inspiratory pressure (PIP) and inspiratory time. As the ventilator rate is weaned, the infant must add an increasing number of spontaneous breaths to maintain minute ventilation (V 0 E) and gas exchange. The preterm infant s spontaneous breathing effort must overcome loads imposed by the resistance of the endotracheal tube 1,2 and disease-elevated lung elastance and airway resistance. 3 5 Spontaneous tidal volume(v T ) may not be sufficiently large and consistent to maintain V 0 E, often requiring ventilator PIP and rate settings high enough to maintain adequate gas exchange at all times. Early weaning of the ventilatory support in preterm infants is aimed at minimizing the risk of lung injury. 6,7 During SIMV weaning, ventilator PIP and rate are gradually reduced with the expectancy of a larger contribution of the spontaneous breathing to V 0 E. However, weaning is often delayed by an inconsistent respiratory drive, 8,9 poor chest wall stability, 10,11 and increased mechanical loads. 3 5 Journal of Perinatology 2005; 25: r 2005 Nature Publishing Group All rights reserved /05 $30

2 Mandatory Ventilation in Preterm Infants Osorio et al. Pressure support (PS) is a patient-triggered mode where the positive pressure breath is initiated by the onset and terminated at the end of spontaneous inspiration. PS can be used to partially reduce resistive and elastic loads on the respiratory pump. 12,13 While PS can provide different levels of assistance, the level required for partial unloading is lower than the PIP of a conventional SIMV breath. Thus, it seems reasonable to provide PS to facilitate spontaneous breathing combined with a low SIMV rate that can maintain a background V 0 E and lung volume. The objective of this study was to evaluate the effects of two levels of PS as an adjunct to SIMV on gas exchange and spontaneous breathing effort during an acute reduction in SIMV rate in a group of preterm infants recovering from respiratory failure. The study hypothesis was that PS would maintain oxygenation, ventilation and prevent an increase in spontaneous respiratory effort during an acute reduction in SIMV rate. MATERIALS AND METHODS Patient Population Clinically stable preterm infants weighing less than 1500 g at birth, ventilated on SIMV at a ventilator rate of 30 breaths per minute (b/ minute) or less, and requiring less than 50% supplemental oxygen were eligible for the study. Infants with symptomatic patent ductus arteriosus, major congenital malformations, hemodynamically unstable, or those receiving sedation or muscle relaxants were excluded from the study. Exclusion criteria also included a significant leak around the endotracheal tube during the mechanical expiratory phase. Infants were included after written parental consent was obtained. The study was approved by the University of Miami Medical Sciences Subcommittee for the Protection of Human Subjects in Research. It was estimated that enrollment of at least 15 infants was needed to detect a 40% decrease in breathing effort with 50% SD, when PS is used to assist spontaneous breaths, at an alpha of 5% and a power of 80%. Study Protocol Infants were studied while in their incubators during four consecutive 30-minute periods. These consisted of two baseline SIMV periods with settings as determined by the clinical team and two periods of SIMV at a rate 10 b/minute lower than the clinical setting plus PS (SIMV þ PS), in random order. PS was set at 3 and 6 cmh 2 O above positive end-expiratory pressure (PEEP) (SIMV þ PS3 and SIMV þ PS6, respectively). Each infant was randomly assigned into one of four possible sequences: Sequence A (SIMV, SIMV þ PS3, SIMV, SIMV þ PS6), sequence B (SIMV þ PS3, SIMV, SIMV þ PS6, SIMV), sequence C (SIMV, SIMV þ PS6, SIMV, SIMV þ PS3), and sequence D (SIMV þ PS6, SIMV, SIMV þ PS6, SIMV). Ventilator settings of PEEP, PIP and inspiratory time (IT) of SIMV breaths remained unchanged. All modes were provided by a neonatal mechanical ventilator (VIP Gold, Viasys Healthcare, CA) set in time-cycled, pressure-limited, flow-triggered mode. Measurements Airflow was measured by the ventilator sensor placed in line between the endotracheal tube and the ventilator circuit. The airflow sensor, a variable orifice pneumotachograph, was connected to a differential pressure transducer (Validyne Engineering, Northridge, CA, USA) powered by a transducer amplifier (Gould Instrument Systems, Valley View, OH, USA). The flow signal was digitally corrected for non-linearity and integrated to obtain V T. Error in exhaled V T was less than 5% at 5 ml measured with a calibration syringe. Airway pressure (P AW ) was measured at the side port of the endotracheal tube adapter and esophageal pressure (P ES ) was measured with a water-filled size 6 French feeding tube placed in the lower esophagus. Both pressure transducers (Sorenson Transpac , Abbot Critical Care Systems) were connected to a transducer coupler (Gould Instrument Systems, OH, USA) and calibrated by water manometry. Patency and validity of P ES was verified by brief end-expiratory airway occlusion at the beginning of each recording period. Arterial oxygen saturation was measured continuously by pulse oximetry (SpO 2 ) (Masimo Radical, Masimo Corp., CA, USA or Oxypleth 520-A. Novametrix Medical Systems Inc., CT, USA). Transcutaneous carbon dioxide tension (TcPCO 2 ) was measured using a Microgas 7560 transcutaneous monitoring system (Viasys Healthcare, CA, USA). The fraction of inspired oxygen (FiO 2 ) was measured by an oxygen analyzer (O2000, Maxtec, UT). All signals were digitized at 100 samples per second and recorded in a personal computer (AT-CODAS, Dataq Instruments, OH). Data Analysis The parameters described below were obtained from the last 15 minutes of every 30-minute recording period and were compared between ventilatory modes: Mean exhaled mechanical V T was obtained from the first five SIMV breaths of every minute (V T SIMV ). Mean exhaled V T from unassisted spontaneous breaths (V T spont ) during both SIMV periods and from PS-assisted spontaneous breaths (V T spont þ ps ) during both SIMV þ PS periods was obtained from the first five breaths of every minute. V 0 E was calculated as the sum of exhaled V T from all SIMV and unassisted spontaneous breaths or from all SIMV and PS-assisted spontaneous breaths during SIMV and SIMV þ PS, respectively. Spontaneous respiratory rate (RR spont ) was calculated from the number of unassisted spontaneous or PS-assisted spontaneous breaths occurring every minute during SIMV and SIMV þ PS, respectively. Total respiratory rate (RR total ) was calculated as the sum of SIMV rate and RR spont. Per-breath spontaneous inspiratory effort was calculated from the area under the P ES -time curve (P ES area per breath ) and the peak Journal of Perinatology 2005; 25:

3 Osorio et al. Mandatory Ventilation in Preterm Infants esophageal pressure (P ES peak ). These were obtained from the first five artifact-free unassisted spontaneous or PS-assisted spontaneous breaths of every minute during SIMV and SIMV þ PS, respectively. Minute spontaneous inspiratory breathing effort (P ES area per minute ) was calculated as the product of RR spont and P ES area per breath. SpO 2, FiO 2 and TcPCO 2 were averaged over the analyzed minutes of every recording period. Within subjects comparisons were carried out using Repeated Measures Analysis of Variance (ANOVA) or ANOVA on Ranks. Results are reported as Mean±SD or Medians and range. A p<0.05 was considered statistically significant. RESULTS In all, 15 mechanically ventilated preterm infants were studied. All infants tolerated well the four study periods and there were no adverse events. This group of infants had a birth weight (mean±sd) of 793±217 g, a mean gestational age of 26.4±1.5 weeks. Their mean age at the time of the study was 15±16 days. They were all ventilated through an uncuffed endotracheal tube of 2.5 mm internal diameter and 10 to 12 cm length. Ventilatory support before the study consisted of PIP 16.3±1.3 cmh 2 O, a PEEP 4.3±0.6 cmh 2 O, a FiO ±0.06, and SIMV rate 21.4±6.6 b/ minute. Three infants were assigned to sequence A (SIMV, SIMV þ PS3, SIMV, SIMV þ PS6), three infants to sequence B (SIMV þ PS3, SIMV, SIMV þ PS6, SIMV), two infants to sequence C (SIMV, SIMV þ PS6, SIMV, SIMV þ PS3) and seven infants to sequence D (SIMV þ PS6, SIMV, SIMV þ PS6, SIMV). The 10 b/minute reduction in SIMV rate during SIMV þ PS resulted in a rate of 11.4±6.6 b/minute. Oxygenation and CO 2 elimination did not differ between the four study periods as described by the average SpO 2, FiO 2 and TcPCO 2 values of each period (Table 1). V 0 E and RR total during both SIMV þ PS periods were higher than during the baseline SIMV periods. V T spont þ ps during both SIMV þ PS periods was larger than V T spont during the baseline SIMV periods. There was a reduction in V T SIMV during SIMV þ PS6 in comparison to the baseline SIMV. There was an increase in V T spont þ ps and V 0 E during SIMV þ PS6 in comparison to SIMV þ PS3. RR total did not differ between both SIMV þ PS periods (Table 1). In this study, PS was used to partially unload the infant s respiratory pump. PS of 6 cmh 2 O was estimated to provide 75% elastic unloading to an infant with an elastance of 2 cmh 2 O/ml/kg and V T of 4 ml/kg. As it turned out, the average elastance of these infants was 1.6 cm H 2 O/ml/kg. Thus, 6 cmh 2 Oof PS provided 93% elastic unloading with the average V T of 4.3 ml/ kg, while 3 cmh 2 O of PS provided 59% elastic unloading with a V T of 3.6 ml/kg. PS assistance of every spontaneous inspiratory effort increased mean airway pressure (P AW mean ) during both SIMV þ PS periods compared to the baseline SIMV. The increase in P AW mean was larger during SIMV þ PS6 compared to SIMV þ PS3 (Table 1). Per-breath inspiratory effort was significantly lower during both SIMV þ PS periods as indicated by a smaller P ES area per breath compared to both SIMV periods (Table 2). Minute inspiratory effort, reported as P ES area per minute, increased significantly during SIMV þ PS3 and there was a slight but not consistent reduction during SIMV þ PS6 in comparison to the SIMV periods. P ES area per minute was significantly lower during SIMV þ PS6 compared to SIMV þ PS3. Peak inspiratory effort during SIMV þ PS6 was significantly lower than baseline SIMV periods and SIMV þ PS3. Table 1 Ventilation and Gas Exchange SIMV (1) SIMV+PS3 cmh 2 O SIMV (2) SIMV+PS6 cmh 2 O SIMV rate (b/minute) 21.4± ± ± ±6.6 V T SIMV (ml/kg) 6.0± ± ± ±1.1 z V T spont or V T spont+ps (ml/kg) 2.7 ( ) 3.5 ( ) y 2.4 ( ) 4.2 ( ) y V 0 E (ml/min/kg) 217±59 251±59* 214±61 275±74* P AW mean ðcmh2 OÞ 6.0± ±1.0* 5.9± ±1.0* RR total (b/minute) 51.5± ±9.0 y 48.5± ±11.1 w SpO 2 (%) 93.3± ± ± ±2.5 TcPCO 2 (mmhg) 56.2± ± ± ±12.4 FiO ± ± ± ±0.06 *p<0.05 vs all others, w p<0.05 vs SIMV (1) and SIMV (2); z p<0.05 vs SIMV (2) by repeated measures ANOVA. y p<0.05 vs all others by ANOVA on ranks. 414 Journal of Perinatology 2005; 25:

4 Mandatory Ventilation in Preterm Infants Osorio et al. Table 2 Spontaneous Respiratory Effort SIMV (1) SIMV+PS 3 cmh 2 O SIMV (2) SIMV+PS 6 cmh 2 O P ES peak ðcmh2 OÞ 4.3± ± ± ±1.0 w P ES area per breath ðcmh2 O secondsþ 1.5± ±0.6* 1.5± ±0.3 w P ES area per minte ðcmh2 O seconds minuteþ (cmh 2 O sec/min) 44.1 ( ) 49.4 ( ) w 44.7 ( ) 34.9 ( ) *p< 0.05 vs SIMV (1) and SIMV (2) by repeated measures ANOVA. w p<0.05 vs all others by ANOVA on ranks. There were no differences between the two baseline SIMV periods as well as between the different infants when grouped by randomization sequence. DISCUSSION Successful weaning of the SIMV rate in preterm infants must be accompanied by an increase in spontaneous inspiratory effort to compensate for the reduction in mechanical support. However, increased mechanical loads and poor spontaneous respiratory effort are common in preterm infants 3 5 and delay the weaning process. This study evaluated the effects of assisting the spontaneous inspiratory effort with two PS levels (3 and 6 cmh 2 O) during an acute reduction in SIMV rate. PS assistance of the spontaneous breathing effort during an average 50% reduction in SIMV rate helped in maintaining oxygenation and CO 2 elimination. Most importantly, this was achieved without a significant rise in breathing effort. Partial mechanical unloading by PS reduced the spontaneous per-breath effort. This may be particularly important in infants with severely impaired lung mechanics or a weak respiratory pump. PS did not only provide elastic unloading, but it also alleviated some of the resistive work. Although not quantified in the present study, the resistive unloading may be even more important in overcoming the resistance of the narrow endotracheal tubes used in very small preterm infants. The reduction in SIMV rate by 10 b/minute during SIMV þ PS does not reflect routine weaning. This was aimed at lowering the mechanical support and acutely challenge the infant s spontaneous breathing in maintaining ventilation and gas exchange. This reduction was proportionally smaller in infants who needed a higher basal SIMV rate. Complete elimination of SIMV may result in hypoventilation during absence of spontaneous breathing. In SIMV þ PS, a low SIMV rate assures a background ventilation level for infants with inconsistent respiratory drive. PS could also be instituted as a stand-alone mode, thus completely eliminating SIMV breaths. However, this may result in hypoventilation during periods of poor respiratory effort and apnea, unless a backup ventilator rate is provided. Further investigation in this area is warranted since such backup ventilation mode is already available in newer neonatal ventilators. The increase in V 0 E during the reduction in SIMV rate, was in part due to a higher RR spont in order to maintain alveolar ventilation. During the reduction in SIMV rate, PS of 3 cmh 2 O was insufficient and minute-effort increased by 12%. In contrast, minute-effort tended to be lower with PS of 6 cmh 2 O. A greater increase in patient effort should be expected during a reduction in SIMV rate without support to the spontaneous breaths. The latter was not tested in this study because such an acute reduction in SIMV rate without PS assistance to the spontaneous breaths could also increase the risk of hypercapnia. As P AW mean becomes less dependent on PIP at low SIMV rates and PS assists every spontaneous inspiration, there was a slight but consistent increase in P AW mean during SIMV þ PS compared to baseline in spite of the lower SIMV rate. An opposite change in P AW mean could occur with a higher baseline SIMV rate. The observed increase in P AW mean during SIMV þ PS is not likely to be of clinical significance. However, an excessive PS may have adverse pulmonary and hemodynamic effects. The level at which the increase in P AW mean due to PS may become detrimental requires further investigation. It is possible that some of the observed decreased negativity in esophageal pressure resulted from transmission of the positive pressure during SIMV þ PS, which is dependent on the compliance of the chest wall and the degree of lung inflation. Gerhardt et al. 10 showed that transmission of positive pressure to the esophagus ranged between 12 17% in a group of infants that were more mature at birth than the infants included in this study (and therefore with a less compliant chest wall) and that transmission increased with gestational age. Thus, transmission of PS is likely to be smaller than the observed differences in P ES. The long-term ability of the infants to compensate for a reduction in ventilatory support is an important issue. This study evaluated the short-term effects of PS as an adjunct to SIMV during an acute reduction in SIMV rate during a relatively short period of time. Therefore, these results cannot be directly extrapolated to situations where the reduction in mechanical support is longer. It is possible that the effect of PS may vary with other factors such as the maturity of the respiratory center or the use of Journal of Perinatology 2005; 25:

5 Osorio et al. Mandatory Ventilation in Preterm Infants respiratory stimulants. Although this data does not lend itself to assess the effect of PS in combination with those factors, their possible role could be important and should be further investigated. The power of some of the comparisons was below 80% and although there were no trends indicating differences that were not significant due to sample size limitations, some caution is recommended in their interpretation. The relatively short duration of the ventilation periods could lead to the existence of carry-over effects. Although statistical comparisons between study sequences did not show differences, carry-over effects cannot be entirely ruled out due to the small number of infants in some of the sequences. In summary, assistance of the spontaneous inspiratory efforts with relative low PS levels maintained gas exchange and prevented a large increase in spontaneous breathing effort during an acute reduction in SIMV rate. Although it remains to be proven, this combined modality may facilitate weaning from mechanical support by enhancing the spontaneous contribution to ventilation and thus prevent associated morbidity. References 1. LeSouef PN, England SJ, Bryan AC. Total resistance of the respiratory system in preterm infants with and without an endotracheal tube. J Pediatr 1984;104: Oca MJ, Becker MA, Dechert RE, Donn S. Relation of neonatal endotracheal tube size and airway resistance. Respir Care 2002;47(9): Graff MA, Novo RP, Diaz M, Smith C, Hiatt IM, Hegyi T. Compliance measurement in respiratory distress syndrome: the prediction of outcome. Pediatr Pulmonol 1986;2(6): Cunningham MD. Intensive care monitoring of pulmonary mechanics for preterm infants undergoing mechanical ventilation. J Perinatol 1989;9(1): Kavvadia V, Greenough A, Itakura Y, Dimitriou G. Neonatal function in very immature infants with and without RDS. J perinat Med 1999;27(5): Clark RH, Gerstmann DR, Jobe AH, Moffitt ST, Slutsky AS, Yoder BA. Lung injury in neonates: causes, strategies for prevention, and long-term consequences. J Pediatr 2001;139: Dreyfuss D, Basset G, Soler P, Saumon G. Intermittent positive-pressure hyperventilation with high inflation pressures produces pulmonary micro vascular injury in rats. Am Rev Respir Dis 1985;132: Gerhardt T, Bancalari E. Apnea of prematurity: II. Respiratory reflexes. Pediatrics 1984;74: Gerhardt T, Bancalari E. Apnea of prematurity: lung function and regulation of breathing. Pediatrics 1984;74: Gerhardt T, Bancalari E. Chest wall compliance in fullterm and premature infants. Acta Paediatr Scand 1994;69: Heldt GP, Mcllroy MB. Distorsion of chest wall and work of diaphragm in preterm infant. J Appl Physiol 1987;62: Tokioka H, Kinjo M, Hirakawa M. The effectiveness of pressure support ventilation for mechanical ventilatory support in children. Anesthesiology 1993;78: Banner MJ, Kirby RR, Gabrielli A, Blanch PB, Layon AJ. Partially and totally unloading respiratory muscles based on real-time measurements of work of breathing. A clinical approach. Chest 1994;106(6): Shelledy DC, Rau JL, Thomas-Goodfellow L. A comparison of the effects of assist-control, SIMV, and SIMV with pressure support on ventilation, oxygen consumption, and ventilatory equivalent. Heart Lung 1995;24: Brochard L, Harf A, Lorino H, Lemaire F. Inspiratory pressure support prevents diaphragmatic fatigue during weaning from mechanical ventilation. Am Rev Respir Dis 1989;139: Sinha SK, Donn SM, Gavey J, McCarty M. Randomised trial of volume controlled versus time cycled, pressure limited ventilation in preterm infants with respiratory distress syndrome. Arch Dis Child 1997;777:F Journal of Perinatology 2005; 25: