Early Human Development 85 (2009) S53S56

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Early Human Development

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev

INSURE, Infant Flow, Positive Pressure and Volume Guarantee Tell us what is best: Selection of respiratory support modalities in the NICU
Martin Keszler
Georgetown University, Washington, DC, United States

a r t i c l e

i n f o

a b s t r a c t
Selecting the optimal mode of respiratory support remains a daily challenge for the practicing neonatologist. We are faced with a bewildering array of modalities and a paucity of denitive studies to guide our decisions. In this context the choice of therapies must be guided by evidence-based guidelines, supplemented by a solid understanding of the pathophysiology of lung injury, an appreciation of the individual patient's specic disease process/physiologic derangement. The sequential application of the least invasive treatment to achieve the relevant therapeutic goal with frequent re-evaluation of the patient's need and possible escalation of support as needed, coupled with the application of lung-protective strategies of respiratory support appears to offer the best chance of minimizing adverse pulmonary and neurodevelopmental outcomes. 2009 Published by Elsevier Ireland Ltd.

1. Introduction Respiratory support practice in newborn intensive care continues to evolve rapidly. A host of new modalities and techniques have become available for the infant with respiratory insufciency over the past decade. Our understanding of how to optimally use these techniques continues to improve, but lags behind the pace of technological innovation [1]. Additionally, improvements in outcomes such as bronchopulmonary dysplasia (BPD) are increasingly difcult to demonstrate, as each incremental improvement moves us closer to the irreducible minimum. Despite a plethora of publications, there is a surprising paucity of clear Level 1 evidence to guide our selection of therapies. In part, this is a reection of the difculties involved in designing good randomized trials, but also is due to the fact that individual patients may respond differently to various modalities based on their unique physiology, severity of illness, and variable susceptibility to ventilatorinduced lung injury (VILI).

2. Non-invasive respiratory support Avoidance of mechanical ventilation by means of early application of continuous positive airway pressure (CPAP) may be the most effective way to reduce the risk of chronic lung disease [2,3]. In the rst decade of the 21st century, utilization of non-invasive respiratory support has become widely accepted as the most effective means of reducing the risk of VILI. The concept is very attractive and supported
Georgetown University Hospital, 3800 Reservoir Rd. N.W., Washington DC, 20007, United States. E-mail address: keszlerm@gunet.georgetown.edu. 0378-3782/$ see front matter 2009 Published by Elsevier Ireland Ltd. doi:10.1016/j.earlhumdev.2009.08.016

by a number of uncontrolled and cohort studies [48]. However, we currently lack the denitive randomized clinical trial data to validate the presumed benets of nasal CPAP as the primary mode of respiratory support. The only published large randomized trial of nCPAP compared to conventional management, the COIN trial, failed to demonstrate superiority of nCPAP, as utilized in the study over traditional intubation and mechanical ventilation [9]. The rate of BPD, dened as need for oxygen at 36 weeks corrected gestational age was similar for the two groups with signicantly less surfactant use, but greater incidence of pneumothorax in the CPAP group. Another large trial has been completed (the NICHD SUPPORT Trial), but the results have not been reported. The European REVE trial has been presented in abstract form only at this time with insufcient detail available for meaningful conclusions. This situation leaves us with a signicant degree of uncertainty at present. It is not clear why CPAP did not appear to perform as well as anticipated in the COIN trial. The possibilities include (but are not limited to): 1. the trial was not well designed; 2. CPAP was not done well in the trial; 3. the wrong end-points were chosen; 4. the wrong kind of CPAP was used (e.g. not bubble CPAP, not Infant Flow); 5. CPAP is not as good as we thought; 6. mechanical ventilation is not as bad as we thought; 7. the problem was related to lack of surfactant. Let us consider these possibilities. The study was designed and carried out by a group of experienced investigators with considerable expertise in both mechanical ventilation and CPAP. All the appropriate statistical considerations were taken into account, there was good training and oversight of participating centers; therefore study design and execution do not appear to be at fault. The only study design issue that may have handicapped the CPAP group was the relatively high threshold for failure of CPAP at FiO2 of 0.60 or greater. This may have contributed to the higher incidence of pneumothorax in the CPAP group [10,11].

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However, it is important to note that higher risk of airleak with CPAP is not a new nding [12]. BPD at 36 weeks corrected gestational age is the most widely accepted primary end-point for studies of respiratory support, but it is of interest that the secondary end-point of BPD at 28 days, did reach statistically signicant difference favoring CPAP [9]. Whether or not the type of CPAP used makes a difference remains a contentious subject. There are strong proponents of variable ow CPAP, which has been shown to result in more stable level of CPAP and lower work of breathing, compared to ventilator-generated CPAP [13,14]. However, while this offers a theoretical advantage, the only large randomized trial comparing variable ow to constant ow CPAP with the primary end-point of failure of extubation, did not support any advantage of the variable ow CPAP device [15]. As a practical matter, it is more convenient to use ventilator-generated CPAP, because it does not require going back and forth between devices when utilizing mechanical ventilation and CPAP, sometimes for short periods. With mounting evidence that nasal IMV may be superior to CPAP alone, there is additional rationale for using ventilator-generated CPAP [1618]. Nasal IMV may be able to augment an extremely low birth weight (ELBW) infant's inadequate respiratory effort without the complications associated with endotracheal intubation. This approach may reduce the need for intubation for inadequate/inconsistent respiratory effort and reduce the incidence of ventilator associated pneumonia and thus avoid the contribution of postnatal inammatory response to the development of BPD. Some may argue that the problem in the COIN trial, as well as all the other large trials currently underway or just completed, is failure to use bubble CPAP. Whether bubble CPAP has advantages over standard CPAP that go beyond the near-religious fervor with which its adherents embrace the concept remains to be determined. Though earlier studies failed to support the notion that the bubbling generates oscillations of sufcient magnitude to aid in CO2 removal [19], there are several more recent studies that suggest that, at least under some circumstances, bubble CPAP may indeed augment CO2 removal [20,21]. There are no large randomized trials comparing bubble CPAP to either variable ow or constant ow CPAP as a primary treatment for RDS, so any advantage of bubble CPAP remains speculative. A recent comparison of the variable ow CPAP to bubble CPAP after extubation did not show signicant differences for the primary outcome of successful extubation at 3 or 7 days, although secondary analyses suggested some advantage of bubble CPAP [22]. Many cohort studies and historical control reports suggest that bubble CPAP may reduce the incidence of BPD when compared to traditional mechanical ventilation [58], but there are no large randomized trials of bubble CPAP vs conventional management with mechanical ventilation, a fact that reects the common dilemma in clinical research. Conducting a large trial too early risks failure due to inadequate knowledge of optimal treatment strategy to design the trial correctly and lack of expertise in the use of the new technique/device, such as seemed to be the case with the HI-FI trial [23]. Waiting until such expertise has evolved risks not being able to do the study at all due to a lack of equipoise. Such appears to be the case with bubble CPAP; those who do it well no longer have the equipoise to conduct a randomized trial [24]. What is clear, however, is that in resource-limited settings bubble CPAP is an effective and inexpensive way to provide respiratory support that appears to be at least as good as that generated by far more expensive equipment. 3. Interaction of surfactant and CPAP: is INSURE the answer? Currently available options in the management of preterm infants with RDS include: 1. avoidance of intubation by early initiation of nCPAP with intubation and surfactant administration only if CPAP fails, 2. brief intubation and surfactant administration in the delivery suite in infants deemed to be at very high risk of surfactant deciency, followed by extubation to CPAP or 3. intubation, surfactant administration and continued mechanical ventilation, which has been considered the conventional management (Fig. 1).

Fig. 1. Respiratory support options for extremely low birth weight infants in the CPAP Era. Infants with inadequate respiratory effort typically require intubation, receive early surfactant and continue on mechanical ventilation. Infants with good respiratory effort who are at high risk of RDS may be intubated and given prophylactic surfactant in the delivery room, then either extubated to CPAP (INSURE) or continued on mechanical ventilation. Alternately, such infants may be placed on nasal CPAP and receive rescue surfactant only when they reach failure criteria. Uncertainty exists regarding appropritae denition of these failure criteria. After rescue surfactant, once more the options are extubation to CPAP (delayed INSURE) or continued ventilation. Delivery of surfactant via nebulization during CPAP is a theoretically attractive option.

The traditional use of CPAP and the one tested in the COIN and SUPPORT trials involves a choice between CPAP as a primary form of support compared to the conventional therapy that includes intubation, early surfactant administration and continued mechanical ventilation. In the CPAP group of the COIN trial, surfactant was given only after failure criteria were met; this resulted in surfactant being administered in late rescue mode, which has been shown not to be as effective as prophylactic surfactant [25]. The higher incidence of pneumothorax in the group that received less surfactant is not surprising in view of the documented reduction in airleak associated with the use of surfactant in a large number of clinical trials [26]. As a potential alternative, the INSURE (INtubate, SURfactant, Extubate) approach is very attractive in principle, because it potentially preserves the well-documented benets of surfactant replacement therapy, while avoiding the known dangers of prolonged mechanical ventilation [27]. However, it must be recognized that important potential hazards are associated with intubation in fragile preterm infants (Table 1). Recent studies have documented the challenges involved in endotracheal intubation and the degradation in technical skills of pediatric residents that suggests that those added risks may add to these concerns [28,29]. Additionally, drugs used for analgesia/sedation for the procedure may affect the infant's respiratory drive. Therefore, despite its attractiveness, INSURE cannot be assumed to be the optimal treatment approach without sufcient experimental evidence. Earlier studies suggested overall benet [3032], but new data from the recently completed CURPAP study (available in abstract form only) failed to substantiate these presumed benets [33]. In that study, the administration of analgesics in the prophylactic group may have contributed to this failure. On the other hand a recent trial conducted in a developing country, albeit in substantially larger infants (mean GA 29 weeks, mean BW 1300 g) demonstrated a signicant reduction in subsequent need for mechanical ventilation and a lower incidence of pneumothorax [34]. Thus, once more we are left without
Table 1 Risks associated with endotracheal intubation. Interferes with normal cardio-pulmonary transition PPV may lead to excessive VT, PPV often used without PEEP = VILI Exposes infant to risk of hyperoxia Exposes infant to risk of hyperventilation Invasive, painful, stressful, may lead to bradycardia = alterations in cerebral blood ow Potential for soft tissue trauma Need for narcotic analgesia (?) = respiratory depression PPV = positive pressure ventilation; PEEP = positive end-expiratory pressure; VILI = ventilator-induced lung injury.

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denitive evidence on which to base our practice, though in experienced hands, this physiologically sound approach remains an attractive option. Administration of nebulized surfactant during nCPAP is a potentially attractive alternative that is currently under investigation. The ability to effectively administer surfactant without the need to invade the airway is clearly desirable. Early attempts at surfactant replacement therapy involved nebulization, but the results were disappointing [35,36]. The problem appeared to be lack of a device capable of delivering adequate amount of aerosolized drug and the fact that biophysical properties of the surfactant may be altered by the process of aerosolization. Recent preliminary studies suggest that this approach is feasible with more modern aerosol technology and the use of surfactant protein B analogue containing synthetic surfactants [37]. 4. Modern mechanical ventilation The possibility that advances in mechanical ventilation have rendered ventilation less harmful must be considered as a possible explanation. Although the evidence remains, at best circumstantial, a similar explanation has been advanced to explain the progressively less convincing evidence for superiority of high-frequency ventilation over conventional mechanical ventilation [38]. The way we ventilate small preterm infants has changed considerably over the past few years. Greater use of antenatal steroids has changed the severity of lung disease we treat today, compared to 1015 years ago. Neonatologist no longer believe that they should target normal blood gases, rather we strive to use the lowest possible settings to achieve acceptable blood gas values; permissive hypercapnia is now extensively practiced and lower oxygen saturation targets have been adopted widely. More aggressive weaning and extubation policies have reduced the typical duration of mechanical ventilation and the formerly widespread practice of keeping ELBW infants on mechanical ventilation for weeks, ostensibly to promote weight gain, has been abandoned. We have adopted the use of more rapid ventilator rates and smaller tidal volumes as neonatologists are increasingly recognizing the critical role of excessive tidal volume as a cause of VILI as well as brain injury. Finally, the formerly widespread PEEP-o-phobia (the irrational fear of using adequate end-expiratory pressure) is slowly giving way to an understanding of the importance of adopting an open lung strategy as an important element in lung-protective strategies [39,40]. 5. Volume-targeted ventilation Over the past decade, ventilators have become more sophisticated and, for the rst time, these microprocessor controlled devices offer the ability to control the delivered tidal volume even in small infants with uncuffed endotracheal tubes. These infants cannot be ventilated effectively with traditional volume-controlled ventilation because of loss of tidal volume to compression of gas in the circuit and humidier, stretching of the circuit and leakage around the uncuffed ET tube. However, avoiding excessive tidal volume is very important in limiting lung injury as well as reducing the well-documented dangers of hypocapnia [41,42]. Devices differ in the way they measure and control tidal volume delivery using pressure-limited ventilation (Table 2). Tidal volume measurement is a key element in how well the control of tidal volume is accomplished. Measuring tidal volume with a ow sensor placed at the airway opening has been shown to be the most accurate way [43,44]. The dead space of the ow sensor is not as large a problem as previously believed, probably because fresh gas penetrates though the dead space gas, rather than pushing it back into the lungs [45]. Volume Guarantee (VG) is a specic volume-targeted mode available on the Draeger Babylog 8000+ ventilator that has been studied more extensively than any of the other volume-targeted modes. VG may be combined with any of the available basic modes of ventilation, but has been shown to be more effective when combined with assist control than with SIMV [46]. Its advantages include the use exhaled tidal volume of

Table 2 Modalities of volume-targeted ventilation. Mode Servo (PRVC) VIP bird (VAPS) Bear, SLE (volume limit) Avea (VAPS + VL) P. Bennett 840 (volume vent) Draeger (VG, Neoow) Controls VT to circuit Minimum VT to patient VT to patient Min/Max VT to circuit/pt VT to circuit VT to patient Adjusts PIP Inspiratory time () Inspiratory time () Inspiratory time () Inspiratory time/ow PIP Based on Inspiratory VT of last breath Inspiratory VT Inspiratory VT Inspiratory VT Inspiratory VT Exhaled VT of last breath

Devices that use a ow sensor at the ventilator end of the circuit control tidal volume delivered to the ventilator circuit; devices that regulate tidal volume based on measurement at the airway opening regulate tidal volume delivered to the patient.

the previous breath (to minimize impact of ETT leak), use of a low resistance, low dead space hot wire anemometer at the airway opening to accurately sense ow, trigger and terminate breaths and a separate control algorithm for assisted and controlled (un-triggered) breaths. VG has been demonstrated to reduce variability of tidal volume delivery, decrease by 40% the proportion of excessively large tidal volumes and reduce by 50% the proportion of low PCO2 values [47]. Lista et al. showed that pro-inammatory cytokine levels were reduced and duration of mechanical ventilation was reduced using VG with an appropriate tidal volume target [48]. Cochrane meta-analysis concluded that volumetargeted ventilation reduced duration of mechanical ventilation and incidence of pneumothorax [49]. More detailed discussion of VG can be found in a recent review [50]. 6. Conclusion Notwithstanding the lack of unequivocal data, substantial shifts in clinical practice in favor of non-invasive respiratory support have become evident, resulting in fewer infants receiving mechanical ventilation. Most of the infants who now receive mechanical ventilation are much smaller and more immature than those ventilated only 10 years ago. They often require ventilation for extended periods for reasons not directly related to lung disease and are much more vulnerable to VILI. For this reason, greater attention has been focused on more gentle modes of ventilatory support for those infants who still require invasive respiratory support. Although we do not have evidence from large randomized trials that VG will reduce the risk of BPD, available evidence suggests that, when combined with other lung-protective strategies aimed at optimizing lung volume and ensuring even distribution of the delivered tidal volume, volume-targeted ventilation appears to offer the best hope of making a signicant impact on ventilator-induced lung injury. Given the paucity of unequivocal evidence on which to base denitive recommendations, our choice of modalities of support needs to be guided by a combination of evidence-based guidelines, thorough understanding of the factors involved in VILI and the principles of lung-protective ventilator strategies. Equally important is careful observation of an individual patient's response to treatment. Beginning with the least invasive approach and escalating therapy as needed without being unduly committed to any one modality appears to be the most appropriate approach to optimizing respiratory and neurodevelopmental outcomes. Conict of interest Dr. Keszler is a consultant to Draeger Medical and to Discovery Laboratories. He does not have any equity or other ownership interest in either company. The commercial entities have not provided any materials for the lecture or paper and had no inuence on the content of the paper.

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