Permissive hypercapnia and permissive hypoxemia in neonates

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1 ORIGINAL ARTICLE Permissive hypercapnia and permissive hypoxemia in neonates (2007) 27, S64 S70 r 2007 Nature Publishing Group All rights reserved /07 $30 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA There are physiological rationale and experimental data that suggest permissive hypercapnia and/or permissive hypoxemia may be well tolerated and result in reduced lung injury. Controlled studies in neonates report potential benefits of both permissive hypercapnia and permissive hypoxemia. The limited randomized controlled trials assessing early short-term postnatal use of permissive hypercapnia demonstrate positive or neutral results. The trials of permissive hypoxemia enrolled infants after the first week of life and also reported positive or neutral results. There is a need for further research testing whether these strategies improve pulmonary outcomes without an increased risk of impaired neurodevelopmental or other adverse effects. (2007) 27, S64 S70. doi: /sj.jp Keywords: ventilator; ventilator weaning; infant; hypercapnia hypoxemia; preterm Introduction Advances in perinatal care such as surfactant, antenatal steroids, and improved ventilatory support have markedly reduced mortality rates of extremely low birth weight infants, allowing the survival of many critically ill infants previously thought to be non-viable. The improved survival of these vulnerable newborns has increased the number of infants at risk for various forms of respiratory morbidities including bronchopulmonary dysplasia (BPD) and air leaks. There are limited data on the precise pathophysiology leading to these pulmonary complications or the specific therapies that can prevent them. It is possible that optimal ventilatory strategies can reduce the incidence of BPD and air leaks as lung injury may be partially dependent on the ventilatory approach. There is an emerging consensus that mechanical ventilation leads to lung injury 1,2 and that clinicians should use more gentle ventilatory strategies in which gas trapping and alveolar overdistention are minimized, whereas blood gas targets are modified to accept higher than normal alveolar partial pressure of carbon dioxide (PaCO 2 ) values and lower than normal PaO 2 =arterial oxygen saturation (SaO 2 )values. 1 This approach to respiratory support targeting higher alveolar partial pressure of carbon dioxide PaCO 2 and lower PaO 2 /SaO 2 values may be called Correspondence: Professor, Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham, 525 New Hillman Building, 619 South 19th Street, Birmingham, AL , USA. wcarlo@peds.uab.edu permissive hypercapnia and permissive hypoxemia, respectively. The clinical studies and randomized trials that have evaluated this approach will be reviewed. The ongoing and future trials will determine if permissive hypercapnia and permissive hypoxemia are safe and effective in neonates with respiratory failure. There is consensus that mechanical ventilation can cause lung injury, 1 3 but there is still controversy about the specific mechanisms involved in the injury. Ventilator-associated lung injury or ventilator-induced lung injury has been thought to be because of the use of high pressures, thus, the term barotrauma. However, experimental and clinical studies have raised questions about this purported mechanism. Investigators used combinations of high and low volumes and pressures in an attempt to determine if volume or pressure is the major culprit responsible for lung injury in immature animals. Using negative pressure ventilation and chest strapping, various investigators have dissociated the effects of volumes and pressures. These studies consistently demonstrate that markers of lung injury (pulmonary edema, epithelial injury, hyaline membranes, and others) are present with the use of high tidal volume and high pressure as well as high volume and low pressure but not with the use of low tidal volume and high pressure. 4,5 Filtration coefficient and lymphatic flow, two other measures of lung injury, are normal with the use of small tidal volumes despite high pressures. 6 Experimental data suggest end inspiratory volume rather than tidal volume or functional residual capacity may be the most critical determinant of lung injury. 7 Thus, it appears that use of high maximal lung volume and transalveolar pressure may be more important in the etiology of lung injury than high airway pressure. Hence, many investigators and clinicians prefer the term volutrauma to the more classical barotrauma term. In addition, repeated collapse and reopening of the alveoli during the breath cycle also results in lung injury, 8 that can be reduced with high positive-end expiratory pressure. 9 This further limits the tidal volume that can be used safely (Figure 1). Thus, reduction of volutrauma would require the use of lower tidal values. This would result in decreased carbondioxide (CO 2 ) elimination, which can be in part managed with higher ventilatory rates, but expiratory time may become insufficient. However, maintenance of an equilibrium of CO 2 elimination with a higher PaCO 2 may be an alternative compromise to reduce volutrauma. Furthermore, accurate measurements of tidal volume and functional residual capacity are

2 Hypercapnia and Hypoxemia S65 WHICH VOLUMES CAUSE LUNG INJURY? EFFECT of PaCO 2 on CO 2 ELIMINATION Volutrauma Zone Overdistention Normocapnia Volutrauma Zone Time A B A High V T low PEEP W. Carlo 2003 B Normal V T, high PEEP C Atelectasis not very accurate so clinicians historically have focused on blood gas management. Preterm infants may be at higher risk for volutrauma. Ventilation of immature animals with large tidal volumes immediately after birth leads to a marked decrease in lung compliance. Within 4 hours after birth, high tidal volumes reduce lung compliance as much as 50% or more. 10 As few as six lung inflations with tidal volumes of 35 to 40 cm 3 /kg (volumes that approximate inspiratory capacity of normal lungs) reduce lung compliance in surfactant-deficient lungs. Surfactant replacement before the large inflation prevents some of the volume injury that manifests as decreases in compliance. 11 Oxidant injury may be another important cause of the ventilator-associated lung injury, but there are limited data on the subject. 12 Preterm rabbits have low levels of antioxidant enzymes that improve with maturation. 13 Free radical-mediated oxidation of protein may impair protein function and cause cellular damage. 14 Physiologic rationale for permissive hypercapnia and permissive hypoxemia Permissive hypercapnia or controlled mechanical hypoventilation are strategies for the management of patients requiring mechanical ventilation in which priority is given to the prevention or limitation of overventilation rather than maintenance of normal blood gases and alveolar ventilation. Mild to moderate alveolar hypoventilation and respiratory acidosis may be well tolerated and may lead to prevention of pulmonary volutrauma. Hypercapnia has physiological effects on gas exchange that when taken together should provide important benefits. The increase in alveolar CO 2 that occurs during permissive hypercapnia increases CO 2 elimination for the same minute ventilation D C Normal V T low PEEP D Optimal ventilation Figure 1 Volutrauma may be caused by a large tidal volume (V T ) with (A) or without low positive end expiratory pressure (PEEP). A normal tidal volume with high PEEP (B) may also cause lung over distention and volutrauma. A low PEEP (A and C) may cause repeated collapse and re-opening of the alveoli, which also causes lung injury. Hypercapnia Hypercapnia 0 and decreased tidal volume 80 Inspired Alveoli tidal volume Expired tidal volume (Figure 2). With constant CO 2 production, the level of arterial (and thus alveolar) CO 2 determines the need for alveolar ventilation as shown by the following equation: KV CO 2 ¼ PaCO 2 Va In this equation K is a constant, V CO 2 is CO 2 elimination, PaCO 2 is alveolar CO 2, and V a is alveolar ventilation. For example, in a critically ill neonate receiving alveolar ventilation of 300 cc/kg/min to maintain a PaCO 2 of 40 mm Hg, the equation for CO 2 elimination can be calculated as follows: KV CO 2 ¼ð40 mm HgÞð300 cc=kg=minþ: Allowing PaCO 2 to increase to 50 mm Hg would maintain comparable CO 2 elimination at an alveolar ventilation of 240 cm 3 / kg/min. Thus, as CO 2 equilibrates at a higher level, alveolar ventilation requirements decrease because CO 2 elimination becomes more effective. This decrease is higher than expected as the relationship between PaCO 2 and minute ventilation is hyperbolic. 15 Furthermore, for a given PaCO 2, the shift to the right of the oxygen dissociation curve permits more unloading of oxygen to the tissues during hypercapnia (Bohr effect). Respiratory drive may be stabilized, resulting in less apnea. 16 Cardiac output may improve as a result of the decrease in mean airway pressures 17 and as tidal volumes and peak inspiratory pressures used during permissive hypercapnia are lowered. Possible negative effects of hypercapnia on gas exchange include a small reduction in PaCO 2 (caused by the increased alveolar CO 2, which can be overcome by a slight increase in fraction of inspired oxygen (FiO 2 )), a reduction in the transported oxygen in the arterial blood (owing to the right shift of the O 2 dissociation curve), an increase in pulmonary vascular resistance, a risk of a right-to-left shunt, and an increase Alveoli Figure 2 Effect of increases in alveolar CO 2 on CO 2 elimination. The fluids in the beakers represent volumes and concentration of gases in these compartments. With permissive hypercapnia an increase in alveolar CO 2 (as a consequence of increased arterial CO 2 ) results in improved CO 2 elimination, whereas adequate CO 2 elimination is maintained. Thus, permissive hypercapnia can result in effective CO 2 elimination at lower tidal volumes.

3 S66 Hypercapnia and Hypoxemia in the work of breathing. Hypercapnia has been associated with an increased risk of impairment of cerebral blood flow autoregulation 18 and intracranial hemorrhage in neonates, 19 but the only study that analyzed high and low partial pressure of carbon dioxide (PCO 2 ) ranges reported that both hypocapnia and hypercapnia as well as wide fluctuations in PaCO 2 were associated with the increased risk of hemorrhage. 20 The randomized controlled trials of permissive hypercapnia in neonates have not reported increased intracranial hemorrhage (see later). It may be that acute increases or decreases in PaCO 2 can lead to intracranial hemorrhage but gradual small elevations in PaCO 2 are relatively safe as long as the ph stops above 7.20 (see later). Because hypocapnia can result in cerebral palsy, 21 a potential advantage of mild to moderate permissive hypercapnia is the prevention of hypocapnia. Other possible beneficial or adverse effects should be of lesser consequences. 22 The lower limit of oxygen saturation and PaCO 2 that provide adequate oxygen for metabolic activities of the various organs in the neonate has not been determined. Fetal hemoglobin has a greater affinity for oxygen than adult hemoglobin A. Thus, the neonate has a higher oxygen saturation at each PaCO 2. Neonates also have a higher hemoglobin concentration at birth that increases the oxygen content of the blood at a given saturation. Thus, neonates may maintain normal aerobic metabolism at relatively low oxygen saturations and PaCO 2. Experimental research on permissive hypercapnia and permissive hypoxemia Experimental research on hypercapnia has been conducted in animals and humans. Hypercapnia resulted in decreased lung injury including interstitial edema, alveolar edema, polymorphonuclear infiltrate, and pulmonary hemorrhage. 23 Hypercapnia also resulted in decreased markers of pulmonary and systemic injury in normal 24 and endotoxin-induced lung injury in animals. 25 In perinatal rats, hypocapnia attenuated hypoxic brain injury 26 and lung injury. 27 In contrast, buffering of the hypercapnia attenuated its protection. 28 Even though, in human adults a crossover study showed that permissive hypercapnia resulted in increased pulmonary shunt, 29 data from animals with therapeutic hypercapnia show that this effect is caused by low tidal volume ventilation and not hypercapnia. 30 In very low birth weight infants, permissive hypercapnia reduced autoregulation of cerebral blood flow, 18 but randomized clinical trials have not shown an increase in intracranial hemorrhage (see later). Thus, although most experimental data suggest that permissive hypercapnia is beneficial, caution should be exercised to prevent potential adverse effects. The potential effects of oxidant stress in newborns have been reviewed and there is now concern to what extent this oxidant injury is part of the pathophysiology of BPD and other neonatal diseases. 31 Infants who developed BPD had high protein carbonylation during the first week after birth. 14 However, trials on antioxidant therapy have failed to prevent BPD. Clinical Data on Permissive Hypercapnia In a meta-analysis of trials of adults with acute respiratory distress syndrome, a lung protective strategy with lower versus traditional tidal volumes (and hypercapnia) was reported to result in significant reductions in mortality by 28 days [(relative risk (RR) 0.74 and 95% confidence interval (CI) 0.61, 0.88) and hospital mortality (P ¼ 0.009)]. 32 Two retrospective studies in neonates designed to determine risk factors for lung injury concurred on the importance of ventilatory strategies as higher PaCO 2 values were associated with less lung injury. 33,34 Using multiple logistic regression analysis, these two studies independently concluded that ventilatory strategies leading to hypocapnia during the early neonatal course resulted in an increased risk of BPD (odds ratio (OR) 1.45 and 95% CI 1.04, 2.01; and OR 4.3 and 95% CI 1.5, 12.0, respectively). Kraybill et al. performed a multicenter analysis on 235 infants with birth weights between 751 and 1000 g admitted to ten neonatal intensive care units before the introduction of surfactant administration. With a similar design, Garland et al. analyzed data on 188 infants less than 1700 g who received surfactant. Both of these studies reported that low PaCO 2 levels were associated with BPD even when several measures of respiratory illness severity were forced into the model. Peak levels of PaCO 2 greater than 50 mm Hg in the first 4 days of life and greater than 40 mm Hg before the administration of surfactant, respectively, were found to be associated with a lower incidence of BPD in these two studies. A population-based study of 407 infants, less than 28 weeks and/or less than 1000 g using historic controls suggested that permissive hypercapnia resulted in a decreased rate of BPD. Other studies have found that low PaCO 2 values are not associated with BPD, but that would not be as expected as these infants may not have or have minimal lung disease and may have received excellent ventilatory support. The observations that low PaCO 2 values during the first days after birth are associated with increased risk of lung injury or that high PaCO 2 values reduce the risk of lung injury are counterintuitive at first glance. It is generally thought that infants with lower PaCO 2 values have less severe pulmonary disease and are at lower risk of lung injury. However, the low PaCO 2 values in these infants may be the result of overventilation with large tidal volumes because of relatively good lung compliance. These large tidal volumes can result in lung injury. This mechanism could be an important cause of lung injury particularly in the less ill neonates. Thus, it is possible that ventilatory strategies that target mild hypercapnia and/or prevent hypocapnia, particularly during the first days of life, result in reduced incidence and/or severity of lung injury.

4 Hypercapnia and Hypoxemia S67 Retrospective studies in neonates with congenital diaphragmatic hernia, including the data on 1210 neonates from 53 centers from the Congenital Diaphragmatic Study Group 35 reported that permissive hypercapnia resulted in an increase in survival 35,36 and a decreased need for extra corporeal membrane oxygenation. 35 It should be noted that some of these studies, including the Congenital Diaphragmatic Study Group, reported the use of permissive hypercapnia in combination with permissive hypoxemia. Randomized clinical trials of permissive hypercapnia or permissive hypoxemia in infants. Three randomized controlled trials of permissive hypercapnia have been performed in neonates. The first pilot trial randomized 49 preterm infants with respiratory distress syndrome to a target PaCO 2 of mm Hg or mm Hg for 96 h. 37 The need for assisted ventilation was decreased (P<0.005, log rank test) in the permissive hypercapnia group during the intervention period. The total number of days on assisted ventilation was 2.5 ( ) in the permissive hypercapnia group and 9.5 ( ) in the normocapnia group (P ¼ 0.17). The National Institutes of Health (NIH) multicenter trial randomized infants of g birth weight to a PaCO 2 target below 48 mm Hg or above 52 mm Hg during the first 10 postnatal days. 38 There was a trend towards a lower incidence of BPD or death in the group randomized to minimal ventilation (63 versus 68%), which was not statistically significant. One percent of the infants in the permissive hypercapnia group compared with 16% of the infants in the routine ventilation group required ventilator support at 36 weeks postmenstrual age (P<0.01). The incidence of severe intraventricular was comparable between the groups. Survival without neurodevelopmental impairment at months corrected age occurred in 36% of infants randomized to permissive hypercapnia and 32% of those randomized to the control group with 11 versus 20% having cerebral palsy and 51 versus 55% neurodevelopmental impairment in the hypercapnia and control groups, respectively. A third small trial (n ¼ 65) of higher PaCO 2 targets (55 65 mm Hg) in more immature infants did not reveal benefits of permissive hypercapnia. 39 Hypercapnia results in an increased respiratory drive, which may help in weaning infants from the ventilator. 37,40 On the other hand, increased work of breathing as well as increased oxygen and energy consumption may increase metabolic demands. However, randomized clinical studies did not demonstrate an adverse effect of permissive hypercapnia on weight gain. 37,38 Indeed, one study even reported a higher weight (1792±318 versus 1733±372 g, P<0.05) and a larger head circumference (30.8±2.6 versus 30.3±2.0 cm, P<0.01) at 36 weeks postmenstrual age in infants randomized to permissive hypercapnia. 38 Increased respiratory efforts can also cause fluctuations in cerebral blood flow, another possible risk factor for intraventricular hemorrhage, but an increased risk was not reported in the randomized clinical trials using permissive hypercapnia. A summary of the evidence on the effect of permissive hypercapnia on lung injury in the developing lung is included in Table 1. Data on permissive hypoxemia in neonates are limited. The evidence for the level of oxygenation that should be used in neonates comes from surveys, controlled studies, and randomized controlled trials. A survey in the 1990s revealed that usual targets for oxygen saturations were in the mid to high 90 s. 41 For example, high oxygen saturation alarms were set above 95% O 2 in 54 of 74 neonatal intensive care units in the United States and the maximum accepted oxygen saturation was 95% or above in 80 of 100 U. The minimum acceptable saturations were below 88% in only 17 of 100 U. A more recent survey of the Vermont Oxford Network center and neonatal-perinatal training program directors indicated that the majority of the centers aimed for oxygen saturations above 88%, usually above 90%, but targets above 95% were less frequently used. 42 A retrospective review using a population-based sample reported neonatal intensive care and follow-up outcomes in infants treated in units that used different oxygen saturation targets. 43 Infants cared for in units with the lowest saturation targets (70 90%) had a significantly lower risk for BPD (18 versus 46%, Table 1 Data of permissive hypercapnia on lung injury in the developing lung by level of evidence Level of evidence Meta-analysis RCT Controlled study Experimental research Physiologic rationale Expert opinion For (protective) Mariani et al. (1999) Kraybill et al. (1989) Garland et al. (1995) Bagolan et al. (2004) Kamper et al. (2004) 51 Neutral Against (injurious) Woodgate and Davis (2001) Carlo et al. (2002) Thome et al. (2006) Vannucci et al. (1995) Kantores et al. (2005) Carlo (2000) 49 Thome and Carlo (2002) Carlo (2004) Carlo (2000) 49 Thome and Carlo (2002) Miller and Carlo (2007) 50 Abbreviations: RCT, randomized controlled trial.

5 S68 Hypercapnia and Hypoxemia Table 2 Evidence for effects of permissive hypoxemia on lung injury in the developing lung by level of evidence Level of evidence Meta-analysis RCT Controlled study Experimental research Physiologic rationale Expert opinion For (protective) STOP-ROP (2000) Tin et al. (2001) Varsila et al. (1995) Tin (2004) 52 Cole (2003) Askie et al. (2003) Sun (2002) Saugstad (2005) Neutral Ellsbury et al. (2002) Vijayakumar et al. (1997) Against (injurious) Abbreviations: RCT, randomized controlled trial. P<0.001) and retinopathy (6 versus 28%, P<0.01) without increased risk for cerebral palsy or mortality. Another retrospective study conducted in seven neonatal intensive care units, which included infants g reported that infants in units that did not accept SaO 2 targets over 95% had a lower incidence of BPD (27 versus 53%, P<0.001) and retinopathy (10 versus 29%, P<0.001). 44 Two randomized controlled trials tested the effect of different levels of saturations in preterm infants beyond the first weeks of life. The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) trial included 649 infants with a diagnosis of prethreshold retinopathy of prematurity. 45 The enrolled infants had a mean gestational age of 25.4 weeks and had a mean birth weight of 726 g. Infants were randomized at a mean age of 35.6 weeks post-menstrual age to oxygen saturations of 96 99% or 89 94%. Those randomized to the higher saturations required significantly more oxygen supplementation (46.8 versus 37.0%, P ¼ 0.02), diuretics (35.8 versus 24.4%, P ¼ 0.002), and hospitalizations (12.7 versus 6.8%, P ¼ 0.01) at the 50 weeks postmenstrual age follow-up evaluation than the infants randomized to lower saturations. Similarly, the BOOST trial randomized 358 babies <30 weeks at an average of 6 weeks postnatal age to saturations of 95 98% versus 91 99% using masked, altered pulse oximeters. 46 There was more oxygen dependence at 36 weeks (64 versus 46%, P<0.001) and longer duration of oxygen supplementation (40 versus 17 days, P<0.01) in the high oxygen saturation group without neurodevelopmental or growth benefits. Thus, current data suggest that targeting oxygen saturation in the low 90s following the first few weeks after birth in very preterm infants may result in less pulmonary morbidity than targeting oxygen saturations in the high 90s. Further trials of targeting saturation values particularly around 90% are needed. 47 Because morbidities are likely to evolve early after birth, these studies should include infants enrolled soon after birth. Until data from further studies are available, clinicians should use judgment in avoiding hyperoxia. Not all babies who are receiving oxygen continuously may need it. A test to determine and standardize oxygen need at 36 weeks has been developed. 48 Walsh and collaborators tested 227 former very low birth weight infants at 36 weeks postmenstrual age who were receiving less than or equal to 30% FiO 2 (hood or cannula equivalent) in a multicenter study. Forty-four percent of these infants maintained saturations above 90% following a rapid wean to room air. As saturations just above 90% have been found to be acceptable in long term studies, this suggests that many infants on oxygen at 36 weeks could be weaned off oxygen supplementation safely. A summary of the evidence on the effect of permissive hypoxemia on lung injury in the developing lung is included in Table 2. Summary Permissive hypercapnia and permissive hypoxemia offer the potential to reduce ventilator-induced lung injury and improve pulmonary outcome. Permissive hypercapnia may also protect against hypocapnia-induced brain hypoperfusion injury. On the other hand, severe hypercapnia or hypoxia may have adverse neurological effects. Recent randomized clinical studies demonstrate the safety of mild permissive hypercapnia or permissive hypoxemia but found only small clinical benefits. The optimal PaCO 2 and PaO 2 /SaO 2 targets for infants at various gestational ages and postnatal ages remain to be elucidated. Further research is necessary to test whether permissive hypercapnia and/or permissive hypoxemia are effective strategies to improve pulmonary outcomes without an increased risk of impaired neurodevelopment or other adverse effects. This research needs to address the specific PCO 2 and ph target levels, the duration of the intervention, and the long-term effects. References 1 Slutsky AS. ACCP Consensus Conference. Mechanical Ventilation. Chest 1993; 104: Artigas A, Bernard GR, Carlet J, Dreyfuss D, Gattinoni L, Hudson L et al. and the Consensus Committee Conference Report. The American-European Consensus Conference on ARDS, Part 2. Ventilatory, pharmacologic,

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