PEDIATRICS Vol. 107 No. 4 April 2001, pp. 638-641

Randomized Trial of Nasal Synchronized Intermittent Mandatory Ventilation Compared With Continuous Positive Airway Pressure After Extubation of Very Low Birth Weight Infants

Keith J. Barrington, MBChB, MRCP, FRCP^*, Dale Bull, MD, and Neil N. Finer, MD, FRCP

From the ^* Department of Pediatrics, McGill University, Montreal, Quebec, Canada and  Division of Neonatal/Perinatal Medicine, Department of Pediatrics, University of California-San Diego, San Diego, California.

	ABSTRACT

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Objective.  To determine whether noninvasive, nasal synchronized intermittent mandatory ventilation (nSIMV) improves the likelihood that very low birth weight infants will be successfully extubated.

Methods.  Infants of <1251-g birth weight who were due to be extubated before 6 weeks of age were eligible once they were receiving <35% oxygen and were on a ventilator rate of <18 breaths per minute (bpm). Extubation was performed following intravenous loading with aminophylline, after a successful trial of 12 hours of endotracheal synchronized intermittent mandatory ventilation at a rate of 8. Infants were randomized to either nasal continuous positive airway pressure (nCPAP) at 6 cm H₂O or nSIMV after extubation. nSIMV was commenced at a rate of 12 bpm with pressure on the ventilator set to achieve a delivered pressure of at least 12 cm H₂O and a peak end expiratory pressure of 6 cm H₂O. Continuous recording for diagnosis of apnea was performed for 72 hours after extubation. Objective criteria for failure of extubation were as follows: a PaCO₂ >70; FIO₂ >0.7; or severe recurrent apnea (>2 apneas requiring intermittent positive-pressure ventilation in 24 hours or >6 apneas >20 seconds per day). The study ended after 72 hours postextubation or when infants satisfied failure criteria. A sample size of 54 was determined by power analysis.

Results.  Mean birth weight (831 standard deviation [SD]: 193 g) and gestation (26.3 SD: 1.8 weeks) did not differ between groups. Mean age at extubation was 7.6 (SD: 9.7) days, range 1 to 40 days. The nSIMV group had a lower incidence of failed extubation 4/27 compared with the continuous positive airway pressure group, 12/27. This was attributable to both a decreased incidence of apnea and a decreased incidence of hypercarbia. There was no increase in the incidence of abdominal distension or feeding intolerance.

Discussion.  nSIMV is effective in preventing extubation failure in very low birth weight infants in the first 72 hours after extubation. Noninvasive ventilation may have other roles in the care of the very low birth weight infant.  Key words:  extubation, premature infant, randomized trial, continuous positive airways pressure, noninvasive ventilation.

Early extubation of the very low birth weight (VLBW) infant holds the potential for a number of benefits for the infant, including a decrease in calorie consumption,¹ decreased tracheal and laryngeal injury, decreased nosocomial pneumonia² and sepsis,³ and a decreased incidence and severity of bronchopulmonary dysplasia. VLBW infants, however, frequently fail attempts at extubation because of severe apnea, hypoventilation, atelectasis, or other intercurrent illnesses. It has recently been demonstrated by our group that noninvasive ventilation via nasal prongs can provide respiratory support in the VLBW infant.⁴ This mode of ventilation holds the promise of providing significant respiratory support without endotracheal intubation and its accompanying complications. We wanted to determine if this means of support would improve the likelihood of infants being successfully extubated.

Systematic reviews of the previous randomized controlled trials have demonstrated the efficacy of pre-extubation aminophylline loading, at least in infants <1 kg,⁵ and postextubation continuous positive airway pressure (CPAP)⁶ in improving the chances of successful extubation. A single study of routine pre-extubation doxapram loading proved ineffective, however.⁷ We hypothesized that there would be a significant reduction in the incidence of failed extubation in aminophylline treated infants of <1251 g birth weight, before 42 days of age, with nasal synchronized intermittent mandatory ventilation (nSIMV) compared with nasal CPAP.

	METHODS

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Infants of <1251 g birth weight, in the neonatal intensive care unit of the University of California, San Diego medical center, who were due to be extubated before 6 weeks of age were eligible for the study once they were receiving <35% oxygen and were on a ventilator rate of <18 breaths per minute. Infants with lethal anomalies were excluded. The study took place between March 1996 and January 1999. Parental consent was obtained before randomization. The randomization codes were generated from a table of random numbers and placed in sequentially numbered opaque sealed envelopes. Masked randomization was to either nasal continuous positive airway pressure (nCPAP) or nSIMV after extubation. Infants were loaded with intravenous aminophylline in a dose of 6 mg/kg before extubation, followed by a maintenance dose of 2 mg/kg every 8 hours. If >24 hours elapsed between aminophylline loading and extubation, the serum concentration was checked. The ventilator rate was weaned every 3 hours as long as the arterial or capillary blood PCO₂ was <65 mm Hg. Transcutaneous PCO₂ was measured routinely and blood gas analysis was performed at least every 6 hours as well as to confirm significant elevations in the transcutaneous PCO₂. Extubation was performed, after a successful trial of 12 hours of endotracheal synchronized intermittent mandatory ventilation (SIMV) at a rate of 8, without elevation in the PCO₂ to above 65 mm Hg or increase in the FIO₂ to >35%. nSIMV was commenced at a rate of 12 with ventilator pressures set at a peak of 16 cmH₂O and a peak end expiratory pressure of 6 cmH₂O. The Infantstar ventilator with the pneumatic Starsync capsule applied to the infant's abdomen was used (Mallinckrodt, St Louis, MO) with the Hudson nasal prong system (Hudson Co, Temecula, CA). Set ventilator pressures were increased to achieve a measured pressure of at least 12 cmH₂O; nCPAP was administered with the same prong system at a pressure of 6 cmH₂O.

Continuous recording for diagnosis of apnea was performed for 72 hours after extubation. Recordings of transthoracic impedance, heart rate, pulse oximeter saturation, and nasal air flow by thermistor were performed, although the thermistor signal was often difficult or impossible to interpret because of the gas flow from the CPAP system. Failure of extubation was diagnosed when any 1 of the following was present: a PaCO₂ >70, an FIO₂ >0.7 to maintain pulse oximeter saturation above 92%, or severe recurrent apnea (>2 apneas requiring IPPV in 24 hours or >6 apneas >20 seconds per day). Apnea was diagnosed from the recordings when bradycardia to <100 beats per minute or acute desaturation to <80% was seen, without obvious respiratory airflow on the recording. The system used for nSIMV will deliver a breath every 5 seconds at a regular rate when the infant is apneic; these breaths were often visible on the recordings during spontaneous apnea, and may be differentiated from spontaneous breaths by their precisely regular appearance. However, we recognize that there is potential for error in the interpretation of these recordings. The majority of the apneas were diagnosed from the occurrence of acute bradycardia, and with the frequent failure to obtain nasal airflow tracings, obstructive apneas without bradycardia will have been missed. The study ended at 72 hours after extubation or when infants satisfied failure criteria.

During nCPAP or nSIMV, the infants continued to be fed either by bolus feedings every 3 hours or by continuous nasogastric infusion. Gastric aspirates were measured every 3 hours and if the volume was >20% of the previous feed or the past 3 hours feeding volume, then the next feed was usually withheld or the continuous feeds were stopped, particularly if accompanied by abdominal distension. After an additional 3 hours, if there was no longer a residual and the clinical examination of the abdomen was acceptable, then feeds were restarted at a lower volume.

The study was approved by the institutional review board of University of California San Diego medical center.

We hypothesized that a reduction in extubation failure as defined above from 30% to 10% would be clinically useful. Using a  of 0.8 and  of 0.05 and a 2-tailed test, a sample size of 54 was determined.

Statistical comparison of the outcomes of the 2 groups was by Fisher's exact test for proportions and by the 2-tailed unpaired t test for continuous variables.

	RESULTS

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Fifty-four infants were enrolled in the study; 27 per group. Mean birth weight (831 standard deviation [SD]:193 g) and gestation (26.3 SD: 1.8 weeks) did not differ between groups. Mean age at extubation was 7.6 (SD: 9.7) days, range 1 to 40 days; there was no significant difference between groups (Table 1). The age of extubation had a very skewed distribution with a preponderance of infants extubated in the first 3 days. Median age of extubation was 3 days in each group, with ranges from 12 hours to 29 days in the nSIMV group and 12 hours to 40 days in the nCPAP group. The nSIMV group had a lower incidence of failed extubation (4/27) compared with the nCPAP group, (12/27), Fisher's exact test P < .05. This was attributable to both a decreased incidence of apnea and a decreased incidence of hypercarbia (Table 2). There was no increase in the incidence of abdominal distension or feeding intolerance. There were no cases of GI perforation, and no infants developed necrotizing enterocolitis after randomization.

	DISCUSSION

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We have demonstrated an improvement in the success rate of extubation of VLBW infants by the application of nSIMV in comparison to nasal CPAP. This is a relatively new approach to respiratory assistance in the newborn and holds the potential for reducing the iatrogenic complications of neonatal intensive care. Previous work from this center showed that the application of nSIMV was associated with a reduction in thoraco-abdominal asynchrony.⁴ This suggested that the chest wall was effectively stabilized during nSIMV, and that overall lung mechanics were thereby improved.

Failure of extubation is a common problem in very premature infants, and methods for preventing such failure have been the subject of a number of studies.^5-7 We combined the 2 techniques previously demonstrated effective, nasal CPAP and aminophylline, to compare with the application of the new technique.

Noninvasive ventilation by nasal mask or prongs has been long practiced in adults⁸ and older children⁹ with many reports of efficacy and reduced complications² compared with endotracheal intubation. However, there are no previous controlled studies of nSIMV in the newborn infant. Older uncontrolled studies of unsynchronized nasal ventilation suggested that occasional gastrointestinal perforation could occur,¹⁰ and a controlled study of unsynchronized nasal intermittent mandatory ventilation, which we performed, showed no advantages in the treatment of apnea of prematurity.¹¹ A more recent small trial of unsynchronized intermittent mandatory ventilation¹² suggested, in contrast, that there may be an effect in the therapy of apnea of prematurity, but apnea diagnosis in that trial was largely from nursing observations, which are notoriously unreliable for that purpose.¹³ The development of synchronized ventilators for the newborn infant presents a number of potential advantages for nasal ventilation. Thus, positive pressure ventilator breaths will be delivered only after initiation of a respiratory effort by the infant, when the glottis is likely to be open, or after an apneic interval, the duration of which would depend on ventilator settings. There are 2 additional studies using nSIMV that we are aware of, both of which are published as abstracts. Visveshwara et al ¹⁴ presented preliminary information on the use of nSIMV in a group of infants recovering from respiratory distress syndrome and showed that those infants with a low expiratory resistance may be successfully managed with this approach. Friedlich et al ¹⁵ have provided results of a prospective trial of 41 VLBW infants who were randomized at extubation to either nSIMV or nasal CPAP. They reported a significantly lower incidence of extubation failure in the nSIMV group (5% vs 37%, P = .016). Friedlich's study (n = 41) used a different methodology, using a single, long nasopharyngeal prong, but the similar direction of the results supports the suggestion that noninvasive ventilation may have a role to play in the extubation of the VLBW infant.

The current study has confirmed that nSIMV has a therapeutic effect in decreasing apnea and decreasing the incidence of elevated PaCO₂. As a result, nSIMV is effective in preventing extubation failure, as we defined it, in VLBW infants in the first 72 hours after extubation when extubated during the first 42 days of life. We chose to only study infants during this period as we believed that extubation failure in infants with established fibrotic lung disease, ie, after 6 weeks of age, would be less likely to be affected by nSIMV, although we do not have any data to support that contention. We did not demonstrate an increase in complications, but the power of the study to detect an increase in rare complications was low.

We also recognize the difficulties in diagnosing apnea while receiving nasal ventilation; although frequently the apneas were obvious, the large airflows made recordings from the thermistor frequently difficult or impossible to interpret.

Noninvasive ventilation may have other roles in the care of the VLBW infant; whether this method could be used for initial respiratory support in preference to endotracheal intubation deserves investigation. Use of nSIMV for primary or back-up therapy of apnea should also be studied. Larger prospective studies would be required to determine the potential incidence of rare complications such as gastrointestinal perforation, and the effects of longer term nSIMV.

Our study was not designed to evaluate long-term outcomes, which would require a much larger study. We suggest that a trial of noninvasive ventilation used as both an alternative to initial intubation and an aid to even earlier successful extubation should be considered. The primary outcome for such a study should be the development of bronchopulmonary dysplasia, as this disorder has substantial health implications. Secondary outcomes, such as length of hospital stay and cost of treatment, should also be considered. Although our average age of extubation was between 6 to 8 days, the median age was 3 days, and we currently believe that an even shorter period of intubation is possible using noninvasive ventilatory support. We believe that the use of noninvasive ventilatory techniques will significantly reduce neonatal morbidity, and hope that our observations will stimulate additional prospective evaluations of these approaches.

	FOOTNOTES

Received for publication Jan 20, 2000; accepted Aug 3, 2000.

Reprint requests to (K.J.B.) Royal Victoria Hospital, 687 Pine Ave W, Room C7.68, Montreal, Quebec, H3A 1A1 Canada. E-mail: kbarri{at}po-box.mcgill.ca

	ABBREVIATIONS

VLBW, very low birth weight; CPAP, continuous positive airway pressure; nSIMV, nasal synchronized intermittent mandatory ventilation; nCPAP, nasal continuous positive airway pressure; SIMV, synchronized intermittent mandatory ventilation; SD, standard deviation.

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