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September 2007: VOLUME 5, NUMBER 1 Advances and Options in Neonatal Mechanical Ventilation In this Issue... The majority of infants that require ventilation are premature infants born with surfactant deficient lungs that lead to the development of Respiratory Distress Syndrome (RDS). Historically, these neonates have been ventilated with continuous flow, time cycled, pressure-limited ventilators. Early efforts at volume-cycled ventilation with first-generation ventilators in the 1980s did not meet with consistent success for many practical and technical issues. However, the advent of microprocessor-controlled devices in the early 1990s created a new generation of volume ventilators that allow for much improved monitoring, sensitivity, and feedback mechanisms that can respond to changes in milliseconds. These technical advances allow for more consistent tidal volume delivery and the ability to compensate for endotracheal tube leaks. In this issue, we review current research on volume ventilation in the neonatal population. THIS ISSUE IN THIS ISSUE COMMENTARY from our Guest Author VOLUME GUARANTEE AND CARBON DIOXIDE LEVELS IN NEONATES THE ABILITY OF VOLUME-CONTROLLED VENTILATION TO REDUCE HYPOXEMIC EPISODES IN NEONATES IS VOLUME OR PRESSURE A BETTER TARGETED VARIABLE IN LOW-BIRTH WEIGHT NEONATES? VOLUME CONTROL VENTILATION VERSUS HFOV ON LUNG INFLAMMATION IN PRETERM INFANTS PRESSURE-REGULATED VOLUME CONTROL VENTILATION VERSUS SIMV DIFFERENCES AND ACCURACY OF VOLUME-TARGETED VENTILATORS Course Directors Edward E. Lawson, MD Professor Department of Pediatrics Division of Neonatology The Johns Hopkins University School of Medicine Christoph U. Lehmann, MD Assistant Professor Department of Pediatrics Division of Neonatology The Johns Hopkins University School of Medicine Lawrence M. Nogee, MD Associate Professor Department of Pediatrics Division of Neonatology The Johns Hopkins University School of Medicine Mary Terhaar, DNSc, RN Assistant Professor Undergraduate Instruction The Johns Hopkins University School of Nursing Robert J. Kopotic, MSN, RRT, FAARC Director of Clinical Programs ConMed Corporation GUEST AUTHOR OF THE MONTH   Commentary & Reviews: Timothy R. Myers, BS, RRT-NPS Director, Asthma & Diagnostic Centers & Pediatric Respiratory Care Adjunct Assistant Professor of Pediatrics University Hospital’s Rainbow Babies & Children's Hospital Case Western Reserve University School of Medicine Guest Faculty Disclosure Timothy R. Myers, BS, RRT-NPS has indicated that he has not received financial support for consultation, research or evaluation and does not have a financial interest relevant to this literature review. Unlabeled/Unapproved Uses The author has indicated that there will be no reference to unlabeled / unapproved uses of drugs or products in this presentation. Program Directors' Disclosures LEARNING OBJECTIVES At the conclusion of this activity, participants should be able to: Discuss the current research in volume-targeted ventilation in RDS Explain the potential advantages of volume-targeted ventilation on managing oxygenation and ventilation parameters Describe the differences in accuracy of different manufacturers’ volume-targeted ventilators		Program Information CE Info Accreditation Credit Designations Target Audience Learning Objectives Internet CME/CNE Policy Faculty Disclosure Disclaimer Statement Length of Activity 1.0 hours Physicians 1 contact hour Nurses Expiration Date September 11, 2009 Next Issue October 11, 2007 COMPLETE THE POST-TEST Step 1. Click on the appropriate link below. This will take you to the post-test. Step 2. If you have participated in a Johns Hopkins on-line course, login. Otherwise, please register. Step 3. Complete the post-test and course evaluation. Step 4. Print out your certificate. Respiratory Therapists Visit this page to confirm that your state will accept the CE Credits gained through this program or click on the link below to go directly to the post-test.

SEPTEMBER PODCAST eNeonatal Review is proud to continue our accredited PODCASTS for 2007. Listen here. This audio interview with Timothy Myers, BS, RRT-NPS of University Hospital’s Rainbow Babies & Children's Hospital and the Case Western Reserve University School of Medicine discusses additional topics related to volume ventilation in the neonatal population. Participants can now receive 0.5 credits per podcast after completing an online post-test. In addition to our monthly newsletters, there will be 6 podcasts throughout the year. To learn more about podcasting and how to access this exciting new feature of eNeonatal Review, please visit this page.

COMMENTARY For nearly 3 decades, mechanical ventilation of neonates has relied on some form of pressure-controlled ventilation, where the ventilator delivers a variable volume with a constant pressure throughout the entire inspiratory cycle. The tidal volume (Vt) delivered, while dependent on many of the ventilator’s set parameters, is also dependent on the infant’s lung compliance and airway resistance. In contrast, in volume-targeted ventilation (VTV), the clinician sets a tidal volume, which generates a variable inspiratory pressure that is dependent primarily on the patient’s lung compliance and airway resistance. The complexity in ventilating infants with lung diseases like RDS in pressure control modes is that surfactant-deficient lungs frequently develop rapid changes in compliance and resistance, resulting in altered tidal volumes and minute ventilation. These alterations can potentially result in excess tidal volumes (ie, volutrauma or stretch injury) or decreases in tidal volume (atelectrauma or collapse injury) or, at the very least, unacceptable fluctuations in carbon dioxide. A review of the growing literature over the last decade has consistently demonstrated that these rapid changes in compliance and resistance can result in excessive tidal volumes that cause either ventilator-induced lung injury and inflammation,1,2 or excessive hypocarbia that can result in cystic periventricular leukomalacia (PVL) injury of the neonatal brian.3,4 In part due to these types of iatrogenic complications, clinicians have developed a renewed interest in controlling or targeting specific tidal volumes. Fourth generation microprocessor-controlled ventilators have hypothetically addressed many of the original concerns that arose from the initial attempts of VC ventilation in the early 1980s5 and provide a number of different methods of VTV. For example, today’s VTV allows for the computer microprocessor to modify inspiratory pressures and/or times to achieve the target volume on either a breath-by-breath basis or within a breath. A recent Cochrane Review meta-analysis6 concluded that VTV was associated with significant reductions in pneumothoraces and ventilator lengths of stay, but was not associated with an improvement in mortality or bronchopulmonary dysplasia (BPD) rates. The difficulty with this meta-analysis is that it involved only 4 clinical trials of slightly less than 200 patients, and utilized multiple nuances of VTV. While each of the modes of VTV has its advantages and disadvantages, and the results obtained are often times contradictory, the potential advantages offered from pulmonary, cardiovascular, and cerebral standpoints are without a doubt important and worth pursuing. Volume-control ventilation is a vast departure from the historical methodologies of time-cycle, pressure limited ventilation, and while the literature is still somewhat sparse, this intervention potentially offers some unique advantages in stability and consistency of tidal volumes, especially in highly ventilated populations like RDS. However, the variations in VTV with different manufacturers’ ventilators, and the parameters that they produce, demand a sense of caution until more definitive, larger randomized clinical trials are conducted. References 1. Dreyfuss D, Saumon G. Role of tidal volume, FRC, and end-inspiratory volume in the development of pulmonary edema following mechanical ventilation. Am Rev Respir Dis. 1993;148:1194-1203. 2. Attar MA, Donn SM. Mechanisms of ventilator-induced lung injury in premature infants. Semin Neonatol. 2002 Oct;7(5):353-60. Review. 3. Wiswell TE, Graziani LJ, Kornhauser MS et al. Effects of hypocarbia on the development of cystic periventricular leukomalacia in premature infants treated with high frequency jet ventilation. Pediatrics. 1996;98:918-24. 4. Okumura A, Hayakawa F, Kato T et al. Hypocarbia in preterm infants with periventricular leukomalacia: the relation between hypocarbia and mechanical ventilation. Pediatrics. 2001 Mar;107(3):469-75. 5. Keszler M. Volume-targeted Ventilation. eNeoReviews. 2006;7(5):e250-e258. 6. McCallion N, Davis PG, Morley CJ. Volume targeted versus pressure limited ventilation in the neonate. Cochrane Database Syst Rev (2005 CD003666 pub 2).

VOLUME GUARANTEE AND CARBON DIOXIDE LEVELS IN NEONATES Cheema IU, Sinha AK, Kempley ST, Ahluwalia JS. Impact of volume guarantee ventilation on arterial carbon dioxide tension in newborn infants: A randomised controlled trial. Early Hum Dev. 2007;83:183-189. (For non-journal subscribers, an additional fee may apply for full text articles.) View journal abstract View full article Investigating the use of Volume Guarantee (VG) ventilation to improve the frequency of normal carbon dioxide tension in the first arterial blood gas after admission to the neonatal unit, Cheema et al prospectively randomized 40 infants from 2 participating centers to receive VG ventilation at 4 ml/kg or Synchronized Intermittent Positive Pressure Ventilation (SIPPV). The ventilator settings from the SIPPV remained unchanged from those selected by the clinical team at the time of intubation. The investigators targeted a PaCO2 range of 37-52 mm Hg for their normal range. The study was completed upon analysis of the first arterial blood gas. The authors report that the mean PaCO2 value (36.8 mm Hg) for the SIPPV group was below the target range, while the mean PaCO2 (42.8 mm Hg) of the VG group was well within the targeted range (p= 0.02). Further, while not statistically significant, VG demonstrated a trend for fewer out-of-range PaCO2 levels and less incidence of hypocarbia. In addition, above 25 weeks gestation, the VG group had a significantly lower incidence of out-of-range PaCO2 than the SIPPV group – a finding entirely related to reduced incidence of hypocarbia (p< 0.05). The authors appropriately conclude that VG was of potential benefit in reducing hypocarbia upon initial stabilization in infants >25 weeks gestation. It is interesting to note, however, that there were only 7 patients (18%) total <25 weeks gestation entered into the study – which would leave this group underpowered.

THE ABILITY OF VOLUME-CONTROLLED VENTILATION TO REDUCE HYPOXEMIC EPISODES IN NEONATES Hummler HD, Engelmann A, Pohlandt F, Franz AR. Volume-controlled intermittent mandatory ventilation in preterm infants with hypoxemic episodes. Intens Care Med. 2006;32:577-584. (For non-journal subscribers, an additional fee may apply for full text articles.) View journal abstract View full article This 2006 randomized, crossover design study by Hummler et al compared the use of volume-controlled (VC) ventilation versus pressure-controlled (PC) ventilation to decrease the frequency of hypoxemic desaturations in preterm infants. Fifteen preterm infants with a predefined history of frequent desaturations were ventilated in 4 hour blocks of VC or PC synchronized intermittent ventilation (SIMV). Standardized criteria and timed interventions were applied during both ventilatory conditions to adjust FiO2 in relation to the SpO2, as measured by pulse oximetry. No significant differences between ventilation modes were found for time with hypoxemia. However, compared to the PC-SIMV group, infants ventilated with VC-SIMV spent significantly less time (p=0.04) experiencing hyperoxia (SpO2 >92%), significantly less bradycardias with desaturation (p=0.03), and showed a trend (p= 0.09) towards more time within the targeted SpO2 range. While the average FiO2 used during the study did not differ, the authors report a trend toward higher FiO2 (0.7–1.0), and more standardized FiO2 adjustments necessary to maintain SpO2, within the target range than with PC-SIMV. VC-SIMV also displayed a trend for less SpO2 troughs during episodes of desaturation. In assessing pulmonary mechanics, VC-SIMV maintained more consistent tidal volumes during episodes of desaturation (p < 0.01) than PC-SIMV. When assessing lung compliance, PC-SIMV demonstrated (p < 0.05) a significantly larger decline in lung compliance than VC-SIMV, as well as a trend (p= 0.07) toward an overall lower lung compliance with desaturations. The authors concluded that although VC-SIMV did not decrease hypoxemic episodes, tidal volume was better maintained with less frequent bradycardias during these episodes. However, several limitations – the number of participants, age at enrollment, range for acceptable SpO2, and focus on premature infants with frequent hypoxemic episodes – restrict the ability to generalize these results.

IS VOLUME OR PRESSURE A BETTER TARGETED VARIABLE IN LOW-BIRTH WEIGHT NEONATES? Singh J, Sinha S, Clarke P, et al. Mechanical ventilation of very low birth weight infants: Is volume or pressure a better target variable? J Pediatr. 2006;149(3):308-13. (For non-journal subscribers, an additional fee may apply for full text articles.) View journal abstract View full article Comparing the use of volume-controlled ventilation to time-cycled, pressure-limited ventilation for efficacy and safety in low-birth-weight premature infants, Singh et al performed a prospective, randomized trial of 109 low-birth-weight (600-1500 grams) infants managed according to a strict protocol. Infants received a targeted tidal volume of 4-6 ml/kg, either with volume-controlled ventilation (VC), or by hourly clinician adjustments in time-cycled, pressure-limited ventilation (TCPL). Standard parameters were utilized for ventilator manipulations in both groups. The investigators found no significant differences in the time to reach a predetermined extubation criterion (mean Paw or AaDO2), duration of oxygen therapy, mortality, or complication for either group. However, a trend toward faster weaning to extubation in VC infants was achieved versus TCPL (p = 0.15) — primarily due to faster obtainment of AaDO2 <100 mm Hg (p = 0.08) compared to a mean Paw airway pressure <8 torr for 12 consecutive hours (p = 0.79). In infants weighing <1000 gm (n = 59), a significant reduction in the time to achieve extubation criterion was realized in the VC infants compared to the TCPL arm (p = 0.03). A post-study analysis of infants (n=41) with moderate to severe respiratory failure (AaDO2 >100 mm Hg) on study entry demonstrated a significantly shorter time to extubation criteria for the VC group as well (p = 0.03). The authors suggest that VC ventilation is safe and efficacious in very low birth weight infants and may have advantages when compared with TCPL, especially in smaller infants. The strategy to allow hourly clinician manipulations of the TCPL groups’ peak inspiratory pressure (PIP) to achieve a targeted tidal volume may have made these 2 study groups more the same than different. It should be noted that real-life clinical trials are frequently difficult to conduct, and a high rate of protocol violations at one of the centers may have further biased the results in this intent-to-treat trial.

VOLUME CONTROL VENTILATION VERSUS HFOV ON LUNG INFLAMMATION IN PRETERM INFANTS Dani C, Bertini G, Pezzati M, et al. Effects of pressure support ventilation plus volume guarantee vs. high-frequency oscillatory ventilation on lung inflammation in preterm infants. Pediatr Pulmonol. 2006; 41: 242-249. (For non-journal subscribers, an additional fee may apply for full text articles.) View journal abstract View full article Lista G, Castoldi F, Bianchi S, et al. Volume guarantee versus high frequency ventilation: lung inflammation in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2007; published on-line 3 Apr 2007. (For non-journal subscribers, an additional fee may apply for full text articles.) View journal abstract Full article not available online To evaluate the abilities of High Frequency Oscillatory Ventilation (HFOV) and VG to reduce lung inflammation, Dani et al performed a prospective randomized study of 25 infants, <30 weeks gestation, ventilated with HFOV or Pressure Support with Volume Guarantee Ventilation (PSV-VG). The PSV-VG initial targeted tidal volume was 5 ml/kg. Ventilator settings manipulation in each group was based on specific blood gas criteria. Infants were extubated within 2 hours of achieving standardized criteria, with post-extubation support at the physician’s discretion. Cytokine assays were measured at 4 specific intervals for inflammation evaluation. The study found no differences in secondary outcomes for mechanical ventilation duration, need for oxygen therapy, nasal continuous positive airway pressure (NCPAP) or second dose of surfactant, length of ICU or hospital stay, or the development of patent ductus arteriosus (PDA), pneumothorax, BPD, intra-ventricular hemorrhage (IVH), PVL, retinopathy of prematurity (ROP), and necrotizing enterocolitis (NEC). The mean values of IL-1b (p= 0.042), IL-8 (p= 0.021), and IL-10 (p< 0.0001) at extubation were significantly lower in HFOV infants. While IL-1b was significantly less with HFOV, there was no change in PSV-VG levels across the study duration. Interleukin (IL)-8 significantly increased (p= 0.026) prior to extubation in pressure sensitive ventilation (PSV)-VG ventilated infants, while remaining unchanged in HFOV infants. IL-10 levels significantly increased in the PSV-VG group at both 1 to 2 days of ventilation (p=0.028) and prior to extubation (p=0.021), while significantly decreasing in the HFOV group prior to extubation (p=0.026). Lista’s group conducted a prospective, randomized study of 45 premature infants (gestation 25-32 weeks) to evaluate lung inflammation between Assist/Control Volume Guarantee (AC-VG) ventilation and HFOV during the acute phase of RDS. The AC-VG initial targeted tidal volume was 5 ml/kg. Surfactant was initially administered to all infants and re-dosed based on standard criteria. Ventilator manipulations were based on arterial blood gas values, and infants were extubated within 2-3 hours of achieving standardized criteria. Cytokine assays were obtained prior to randomization and again at 3 days and 7 days post randomization. Ventilation randomization was maintained until the 96th hour, when HFOV neonates met unit criteria for switching to AC ventilation. By day 7, no infants randomized to HFOV were still receiving HFOV. Approximately two thirds of each group were receiving AC-VG at the final aspirate sample, while one third of each group were extubated and spontaneously breathing. The authors report no differences in mechanical ventilation duration, need for second dose of surfactant or postnatal steroids, mortality, development of pulmonary hemorrhage, pneumothorax, BPD, IVH, PVL, ROP, and NEC. HFOV infants had significantly longer oxygen dependency (p<0.05). Cytokines levels in AC-VG group were stable during the study. IL-6 levels were significantly higher on day 3 (p<0.05) and day 7 (p=0.03) in HFOV infants. HFOV also demonstrated a trend for higher levels of IL-6, IL-8 and TNF-αlevels on day 7 (p=0.09). Infants that developed BPD had high IL-8 (>20ng/ml) and TNF-α (>0.35ng/ml) levels on day 7. Dani et al concluded that early HFOV treatment is associated with reduced lung inflammation compared with PSV-VG in preterm infants with RDS, while Lista et al concluded VG ventilation is an effective lung-protective strategy to be used in acute RDS, inducing a lower expression of early inflammation markers when compared to HFOV. Each study had some limitations that may explain the differences in conclusion (and highlight the need for additional studies). Dani’s group used a spontaneous breathing mode pressure-sensitive ventilation (PSV) as a comparator to HFOV, a low positive and expiratory pressure (PEEP) (3-4 cm H20) strategy, and possibly introduced study bias by allowing physicians to change tidal volumes in (PSV)+VG. Limitations to Lista et al include a relatively small number of patients, use of a different high-frequency ventilator (Dräger Babylog versus SensorMedics 3100), and the allowance of HFOV crossover to AC+VG ventilation prior to study conclusion.

PRESSURE-REGULATED VOLUME CONTROL VENTILATION VERSUS SIMV D’Angio CT, Chess PR, Kovacs SJ, et al. Pressure-regulated volume control ventilation vs synchronized intermittent mandatory ventilation for very low-birth-weight infants. Arch Pediatr Adolesc Med. 2005;159:868-875. (For non-journal subscribers, an additional fee may apply for full text articles.) View journal abstract View full article D’Angio and colleagues conducted a prospective, randomized study of 213 premature infants (< 32 weeks gestation) evaluating 14-day morbidity and mortality rates between pressure-regulated volume control (PRVC) and pressure-controlled, synchronized intermittent mandatory ventilation (PC-SIMV). Patients were randomized after 6 hours of ventilation. Targeted arterial blood gas values provided a standard management protocol. If the infant met any of the failure criteria, the mode of ventilation could be changed. Extubation parameters were standardized for all patients. Upon randomization and at 6 hours post-randomization, PC-SIMV patients had a significantly lower respiratory rate, while PRVC patients had significantly lower peak pressures and tidal volumes. These significant differences continued at Days 1, 2 and 3. The investigators report a lack of adherence to PaCO2 to the target range (maintained lower) at 6 hours post-randomization. Approximately a third of the patients in each group were extubated by 72 hours, with a significant difference for extubation at 14 days for PC-SIMV. The number of infants alive and extubated at 14 days, 28 days, or 36 weeks post-menstrual age (PMA)