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Journal of Perinatology (2007) 27, S64–S70 r 2007 Nature Publishing Group All rights reserved. 0743-8346/07 $30 www.nature.com/jp ORIGINAL ARTICLE Permissive and permissive in neonates

WA Carlo Department of , University of Alabama at Birmingham, Birmingham, AL, USA

and permissive hypoxemia, respectively. There are physiological rationale and experimental data that suggest The clinical studies and randomized trials that have evaluated this permissive hypercapnia and/or permissive hypoxemia may be well tolerated approach will be reviewed. The ongoing and future trials will and result in reduced injury. Controlled studies in neonates report determine if permissive hypercapnia and permissive hypoxemia are potential benefits of both permissive hypercapnia and permissive hypoxemia. safe and effective in neonates with . The limited randomized controlled trials assessing early short-term postnatal There is consensus that can cause lung use of permissive hypercapnia demonstrate positive or neutral results. The trials injury,1–3 but there is still controversy about the specific of permissive hypoxemia enrolled infants after the first week of life and also mechanisms involved in the injury. -associated lung reported positive or neutral results. There is a need for further research testing injury or ventilator-induced lung injury has been thought to be whether these strategies improve pulmonary outcomes without an increased because of the use of high , thus, the term . risk of impaired neurodevelopmental or other adverse effects. However, experimental and clinical studies have raised questions Journal of Perinatology (2007) 27, S64–S70. doi:10.1038/sj.jp.7211715 about this purported mechanism. Investigators used combinations Keywords: ventilator; ventilator weaning; infant; hypercapnia of high and low volumes and pressures in an attempt to determine hypoxemia; preterm if volume or 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 Introduction demonstrate that markers of lung injury (, Advances in perinatal care such as , antenatal steroids, and epithelial injury, hyaline membranes, and others) are present with improved ventilatory support have markedly reduced mortality rates of the use of high and high pressure as well as high extremely low birth infants, allowing the survival of many volume and low pressure but not with the use of low tidal volume 4,5 critically ill infants previously thought to be non-viable. The improved and high pressure. Filtration coefficient and lymphatic flow, two survival of these vulnerable newborns has increased the number of other measures of lung injury, are normal with the use of small 6 infants at risk for various forms of respiratory morbidities including tidal volumes despite high pressures. Experimental data suggest bronchopulmonary dysplasia (BPD) and air leaks. There are limited end inspiratory volume rather than tidal volume or functional data on the precise pathophysiology leading to these pulmonary residual capacity may be the most critical determinant of lung 7 complications or the specific that can prevent them. injury. Thus, it appears that use of high maximal lung volume It is possible that optimal ventilatory strategies can reduce the and transalveolar pressure may be more important in the etiology incidence of BPD and air leaks as lung injury may be partially of lung injury than high airway pressure. Hence, many dependent on the ventilatory approach. There is an emerging investigators and clinicians prefer the term volutrauma to the more consensus that mechanical ventilation leads to lung injury1,2 and that classical barotrauma term. In addition, repeated collapse and clinicians should use more gentle ventilatory strategies in which reopening of the alveoli during the breath cycle also results in lung 8 trapping and alveolar overdistention are minimized, whereas injury, that can be reduced with high positive-end expiratory 9 gas targets are modified to accept higher than ‘‘normal’’ alveolar . This further limits the tidal volume that can be used safely (Figure 1). Thus, reduction of volutrauma would require the pressure of (PaCO2 ) values and lower than ‘‘normal’’ 1 use of lower tidal values. This would result in decreased PaO2 =arterial saturation (SaO2 )values. This approach to respiratory support targeting higher alveolar partial pressure of carbondioxide (CO2) elimination, which can be in part managed with higher ventilatory rates, but expiratory time may become carbon dioxide PaCO2 and lower PaO2 /SaO2 values may be called insufficient. However, maintenance of an equilibrium of CO2 Correspondence: Professor WA Carlo, Division of , Department of Pediatrics, elimination with a higher PaCO may be an alternative University of Alabama at Birmingham, 525 New Hillman Building, 619 South 19th Street, 2 Birmingham, AL 35233-7335, USA. compromise to reduce volutrauma. Furthermore, accurate E-mail: [email protected] measurements of tidal volume and functional residual capacity are Hypercapnia and Hypoxemia WA Carlo S65

WHICH VOLUMES CAUSE EFFECT of PaCO2 on CO2 ELIMINATION LUNG INJURY? Volutrauma Zone Overdistention 0 Normocapnia 40 20 20

0 Volutrauma Zone Atelectasis Hypercapnia Time 80 40 40 ABC D Hypercapnia 0 A High VT B Normal VT, C Normal VT D Optimal and decreased low PEEP high PEEP low PEEP ventilation tidal volume 80 50 50 © W. Carlo 2003 Inspired Alveoli Expired Alveoli Figure 1 Volutrauma may be caused by a large tidal volume (VT) with tidal volume tidal volume (A) or without low positive end expiratory pressure (PEEP). A Figure 2 Effect of increases in alveolar CO2 on CO2 elimination. The normal tidal volume with high PEEP (B) may also cause lung over ’’fluids’’ in the beakers represent volumes and of in distention and volutrauma. A low PEEP (A and C) may cause these compartments. With permissive hypercapnia an increase in repeated collapse and re-opening of the alveoli, which also causes alveolar CO2 (as a consequence of increased arterial CO2) results in lung injury. improved CO2 elimination, whereas adequate CO2 elimination is maintained. Thus, permissive hypercapnia can result in effective CO2 not very accurate so clinicians historically have focused on blood elimination at lower tidal volumes. gas management. Preterm infants may be at higher risk for volutrauma. (Figure 2). With constant CO2 production, the level of arterial (and Ventilation of immature animals with large tidal volumes thus alveolar) CO2 determines the need for alveolar ventilation as immediately after birth leads to a marked decrease in lung shown by the following equation: compliance. Within 4 hours after birth, high tidal volumes reduce 10 KV CO2 ¼ PaCO2 Va lung compliance as much as 50% or more. As few as six lung In this equation K is a constant, V CO is CO elimination, PaCO is inflations with tidal volumes of 35 to 40 cm3/kg (volumes that 2 2 2 alveolar CO2, and Va is alveolar ventilation. For example, in a approximate inspiratory capacity of normal ) reduce lung critically ill neonate receiving alveolar ventilation of 300 cc/kg/min compliance in surfactant-deficient lungs. Surfactant replacement to maintain a PaCO2 of 40 mm Hg, the equation for CO2 before the large inflation prevents some of the volume injury that elimination can be calculated as follows: manifests as decreases in compliance.11 Oxidant injury may be another important cause of the KV CO2 ¼ð40 mm HgÞð300 cc=kg=minÞ: ventilator-associated lung injury, but there are limited data on the 12 subject. Preterm rabbits have low levels of antioxidant Allowing PaCO2 to increase to 50 mm Hg would maintain 13 3 enzymes that improve with maturation. Free radical-mediated comparable CO2 elimination at an alveolar ventilation of 240 cm / oxidation of protein may impair protein function and cause kg/min. Thus, as CO2 equilibrates at a higher level, alveolar 14 cellular damage. ventilation requirements decrease because CO2 elimination becomes more effective. This decrease is higher than expected as

the relationship between PaCO2 and minute ventilation is Physiologic rationale for permissive hypercapnia and 15 hyperbolic. Furthermore, for a given PaCO2 , the shift to the right permissive hypoxemia of the oxygen dissociation curve permits more unloading of oxygen Permissive hypercapnia or controlled mechanical to the tissues during hypercapnia (). Respiratory drive are strategies for the management of patients requiring mechanical may be stabilized, resulting in less .16 Cardiac output may ventilation in which priority is given to the prevention or limitation improve as a result of the decrease in mean airway pressures17 and of overventilation rather than maintenance of normal blood gases as tidal volumes and peak inspiratory pressures used during and alveolar ventilation. Mild to moderate alveolar hypoventilation permissive hypercapnia are lowered. Possible negative effects of and respiratory may be well tolerated and may lead to hypercapnia on include a small reduction in PaCO2 prevention of pulmonary volutrauma. (caused by the increased alveolar CO2, which can be overcome by a Hypercapnia has physiological effects on gas exchange that slight increase in fraction of inspired oxygen (FiO2)), a reduction when taken together should provide important benefits. The in the transported oxygen in the arterial blood (owing to the right increase in alveolar CO2 that occurs during permissive hypercapnia shift of the O2 dissociation curve), an increase in pulmonary increases CO2 elimination for the same minute ventilation vascular resistance, a risk of a right-to-left shunt, and an increase

Journal of Perinatology Hypercapnia and Hypoxemia WA Carlo S66 in the work of . Hypercapnia has been associated with an protein carbonylation during the first week after birth.14 However, increased risk of impairment of cerebral blood flow trials on antioxidant have failed to prevent BPD. autoregulation18 and intracranial hemorrhage in neonates,19 but the only study that analyzed high and low partial pressure of carbon dioxide (PCO2 ) ranges reported that both and hypercapnia as well as wide fluctuations in PaCO2 were associated Clinical Data on Permissive Hypercapnia with the increased risk of hemorrhage.20 The randomized In a meta-analysis of trials of adults with acute respiratory distress controlled trials of permissive hypercapnia in neonates have not syndrome, a lung protective strategy with lower versus traditional reported increased intracranial hemorrhage (see later). tidal volumes (and hypercapnia) was reported to result in

It may be that acute increases or decreases in PaCO2 can lead significant reductions in mortality by 28 days [(relative risk (RR) to intracranial hemorrhage but gradual small elevations in PaCO2 0.74 and 95% confidence interval (CI) 0.61, 0.88) and hospital are relatively safe as long as the pH stops above 7.20 (see later). mortality (P ¼ 0.009)].32 Because hypocapnia can result in cerebral palsy,21 a potential Two retrospective studies in neonates designed to determine risk advantage of mild to moderate permissive hypercapnia is the factors for lung injury concurred on the importance of ventilatory prevention of hypocapnia. Other possible beneficial or adverse strategies as higher PaCO2 values were associated with less lung effects should be of lesser consequences.22 injury.33,34 Using multiple logistic regression analysis, these two

The lower limit of oxygen saturation and PaCO2 that provide studies independently concluded that ventilatory strategies leading adequate oxygen for metabolic activities of the various organs in to hypocapnia during the early neonatal course resulted in an the neonate has not been determined. Fetal hemoglobin has a increased risk of BPD (odds ratio (OR) 1.45 and 95% CI 1.04, 2.01; greater affinity for oxygen than adult hemoglobin A. Thus, the and OR 4.3 and 95% CI 1.5, 12.0, respectively). Kraybill et al. neonate has a higher oxygen saturation at each PaCO2 . Neonates performed a multicenter analysis on 235 infants with birth also have a higher hemoglobin concentration at birth that between 751 and 1000 g admitted to ten neonatal intensive care increases the oxygen content of the blood at a given saturation. units before the introduction of surfactant administration. With a Thus, neonates may maintain normal aerobic at similar design, Garland et al. analyzed data on 188 infants less relatively low oxygen saturations and PaCO2 . than 1700 g who received surfactant. Both of these studies reported

that low PaCO2 levels were associated with BPD even when several measures of respiratory illness severity were forced into the model.

Peak levels of PaCO2 greater than 50 mm Hg in the first 4 days of Experimental research on permissive hypercapnia and life and greater than 40 mm Hg before the administration of permissive hypoxemia surfactant, respectively, were found to be associated with a lower Experimental research on hypercapnia has been conducted in incidence of BPD in these two studies. A population-based study of animals and humans. Hypercapnia resulted in decreased lung injury 407 infants, less than 28 weeks and/or less than 1000 g using including interstitial edema, alveolar edema, polymorphonuclear historic controls suggested that permissive hypercapnia resulted in 23 infiltrate, and pulmonary hemorrhage. Hypercapnia also resulted a decreased rate of BPD. Other studies have found that low PaCO2 in decreased markers of pulmonary and systemic injury in normal24 values are not associated with BPD, but that would not be as and endotoxin-induced lung injury in animals.25 In perinatal rats, expected as these infants may not have or have minimal lung hypocapnia attenuated hypoxic injury26 and lung injury.27 In disease and may have received excellent ventilatory support. 28 contrast, buffering of the hypercapnia attenuated its protection. The observations that low PaCO2 values during the first Even though, in human adults a crossover study showed that days after birth are associated with increased risk of lung injury 29 permissive hypercapnia resulted in increased pulmonary shunt, or that high PaCO2 values reduce the risk of lung injury are data from animals with therapeutic hypercapnia show that this effect counterintuitive at first glance. It is generally thought that infants 30 is caused by low tidal volume ventilation and not hypercapnia. In with lower PaCO2 values have less severe pulmonary disease and very low birth weight infants, permissive hypercapnia reduced are at lower risk of lung injury. However, the low PaCO2 values in autoregulation of cerebral blood flow,18 but randomized clinical these infants may be the result of overventilation with large tidal trials have not shown an increase in intracranial hemorrhage (see volumes because of relatively good lung compliance. These large later). Thus, although most experimental data suggest that tidal volumes can result in lung injury. This mechanism could be permissive hypercapnia is beneficial, caution should be exercised to an important cause of lung injury particularly in the less ill prevent potential adverse effects. The potential effects of oxidant stress neonates. Thus, it is possible that ventilatory strategies that target in newborns have been reviewed and there is now concern to what mild hypercapnia and/or prevent hypocapnia, particularly during extent this oxidant injury is part of the pathophysiology of BPD and the first days of life, result in reduced incidence and/or severity of other neonatal diseases.31 Infants who developed BPD had high lung injury.

Journal of Perinatology Hypercapnia and Hypoxemia WA Carlo S67

Retrospective studies in neonates with congenital diaphragmatic higher PaCO2 targets (55–65 mm Hg) in more immature infants hernia, including the data on 1210 neonates from 53 centers did not reveal benefits of permissive hypercapnia.39 from the Congenital Diaphragmatic Study Group35 reported that Hypercapnia results in an increased respiratory drive, which permissive hypercapnia resulted in an increase in survival35,36 and may help in weaning infants from the ventilator.37,40 On the other a decreased need for extra corporeal membrane oxygenation.35 hand, increased as well as increased oxygen and It should be noted that some of these studies, including the energy consumption may increase metabolic demands. However, Congenital Diaphragmatic Study Group, reported the use of randomized clinical studies did not demonstrate an permissive hypercapnia in combination with permissive of permissive hypercapnia on weight gain.37,38 Indeed, one study hypoxemia. even reported a higher weight (1792±318 versus 1733±372 g, P<0.05) and a larger head circumference (30.8±2.6 versus Randomized clinical trials of permissive hypercapnia or 30.3±2.0 cm, P<0.01) at 36 weeks postmenstrual age in infants permissive hypoxemia in infants. randomized to permissive hypercapnia.38 Increased respiratory Three randomized controlled trials of permissive hypercapnia have efforts can also cause fluctuations in cerebral blood flow, another been performed in neonates. The first pilot trial randomized 49 possible risk factor for intraventricular hemorrhage, but an preterm infants with respiratory distress syndrome to a target increased risk was not reported in the randomized clinical trials 37 using permissive hypercapnia. A summary of the evidence on the PaCO2 of 35–45 mm Hg or 45–55 mm Hg for 96 h. The need for assisted ventilation was decreased (P<0.005, log rank test) in the effect of permissive hypercapnia on lung injury in the developing permissive hypercapnia group during the intervention period. The lung is included in Table 1. total number of days on assisted ventilation was 2.5 (1.5–11.5) in Data on permissive hypoxemia in neonates are limited. The the permissive hypercapnia group and 9.5 (2.0–22.5) in the evidence for the level of oxygenation that should be used in normocapnia group (P ¼ 0.17). neonates comes from surveys, controlled studies, and randomized The National Institutes of Health (NIH) multicenter trial 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, randomized infants of 501–1000 g birth weight to a PaCO2 target below 48 mm Hg or above 52 mm Hg during the first 10 postnatal high oxygen saturation alarms were set above 95% O2 in 54 of 74 days.38 There was a trend towards a lower incidence of BPD or neonatal intensive care units in the United States and the in the group randomized to minimal ventilation (63 versus maximum accepted oxygen saturation was 95% or above in 80 of 68%), which was not statistically significant. One percent of the 100 U. The minimum acceptable saturations were below 88% in infants in the permissive hypercapnia group compared with 16% of only 17 of 100 U. A more recent survey of the Vermont Oxford the infants in the routine ventilation group required ventilator Network center and neonatal-perinatal training program directors support at 36 weeks postmenstrual age (P<0.01). The incidence of indicated that the majority of the centers aimed for oxygen severe intraventricular was comparable between the groups. saturations above 88%, usually above 90%, but targets above 95% Survival without neurodevelopmental impairment at 18–22 were less frequently used.42 months corrected age occurred in 36% of infants randomized to A retrospective review using a population-based sample permissive hypercapnia and 32% of those randomized to the reported neonatal intensive care and follow-up outcomes in infants control group with 11 versus 20% having cerebral palsy and 51 treated in units that used different oxygen saturation targets.43 versus 55% neurodevelopmental impairment in the hypercapnia Infants cared for in units with the lowest saturation targets and control groups, respectively. A third small trial (n ¼ 65) of (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) Vannucci et al. (1995) Carlo (2000)49 Carlo (2000)49 Garland et al. (1995) Kantores et al. (2005) Thome and Carlo (2002) Thome and Carlo (2002) Bagolan et al. (2004) Carlo (2004) Miller and Carlo (2007)50 Kamper et al. (2004)51 Neutral Woodgate and Carlo et al. (2002) Davis (2001) Thome et al. (2006) Against (injurious)

Abbreviations: RCT, randomized controlled trial.

Journal of Perinatology Hypercapnia and Hypoxemia WA Carlo S68

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 36 weeks has been developed.48 Walsh and collaborators tested increased risk for cerebral palsy or mortality. Another retrospective 227 former very low birth weight infants at 36 weeks postmenstrual study conducted in seven neonatal intensive care units, which age who were receiving less than or equal to 30% FiO2 (hood or included infants 500–1000 g reported that infants in units that cannula equivalent) in a multicenter study. Forty-four percent of did not accept SaO2 targets over 95% had a lower incidence of these infants maintained saturations above 90% following a rapid BPD (27 versus 53%, P<0.001) and retinopathy (10 versus 29%, wean to room air. As saturations just above 90% have been found P<0.001).44 to be acceptable in long term studies, this suggests that many Two randomized controlled trials tested the effect of different infants on oxygen levels of saturations in preterm infants beyond the first weeks at 36 weeks could be weaned off oxygen supplementation safely. of life. The Supplemental Therapeutic Oxygen for Prethreshold A summary of the evidence on the effect of permissive hypoxemia Retinopathy of Prematurity (STOP-ROP) trial included 649 infants on lung injury in the developing lung is included in Table 2. 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 Summary a mean age of 35.6 weeks post-menstrual age to oxygen saturations Permissive hypercapnia and permissive hypoxemia offer the of 96–99% or 89–94%. Those randomized to the higher potential to reduce ventilator-induced lung injury and improve saturations required significantly more oxygen supplementation pulmonary outcome. Permissive hypercapnia may also protect (46.8 versus 37.0%, P ¼ 0.02), diuretics (35.8 versus 24.4%, against hypocapnia-induced brain hypoperfusion injury. On the P ¼ 0.002), and hospitalizations (12.7 versus 6.8%, P ¼ 0.01) at other hand, severe hypercapnia or may have adverse the 50 weeks postmenstrual age follow-up evaluation than the neurological effects. Recent randomized clinical studies infants randomized to lower saturations. Similarly, the BOOST trial demonstrate the safety of mild permissive hypercapnia or randomized 358 babies <30 weeks at an average of 6 weeks permissive hypoxemia but found only small clinical benefits. postnatal age to saturations of 95–98% versus 91–99% using The optimal PaCO2 and PaO2 /SaO2 targets for infants at various masked, altered oximeters.46 There was more oxygen gestational ages and postnatal ages remain to be elucidated. dependence at 36 weeks (64 versus 46%, P<0.001) and longer Further research is necessary to test whether permissive duration of oxygen supplementation (40 versus 17 days, P<0.01) hypercapnia and/or permissive hypoxemia are effective strategies in the high oxygen saturation group without neurodevelopmental to improve pulmonary outcomes without an increased risk of or growth benefits. Thus, data suggest that targeting impaired neurodevelopment or other adverse effects. This research oxygen saturation in the low 90s following the first few weeks after needs to address the specific PCO2 and pH target levels, the birth in very preterm infants may result in less pulmonary duration of the intervention, and the long-term effects. 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 References after birth, these studies should include infants enrolled soon after 1 Slutsky AS. ACCP Consensus Conference. Mechanical Ventilation. Chest 1993; birth. Until data from further studies are available, clinicians 104: 1833–1859. should use judgment in avoiding . 2 Artigas A, Bernard GR, Carlet J, Dreyfuss D, Gattinoni L, Hudson L et al. and Not all babies who are receiving oxygen continuously may the Consensus Committee Conference Report. The American-European need it. A test to determine and standardize oxygen need at Consensus Conference on ARDS, Part 2. Ventilatory, pharmacologic,

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supportive therapy, study design strategies, and issues related to recovery and 20 Fabres J, Carlo W, Phillips V et al. Both extremes of PaCO2 and the remodeling. Am J Respir Crit Care Med 1998; 157: 1332–1347. magnitude of fluctuations are associated with severe intraventricular 3 Dreyfus D, Saumon G. Role of tidal volume, FRC and end-inspiratory hemorrhage in preterm infants. Pediatrics 2007; 119: 299–305. volume in the development of pulmonary edema following mechanical 21 Collins MP, Lorenz JM, Jetton JR, Paneth N. Hypocapnia and other ventilation. Am Rev Respir Dis 1993; 48: 1194–1203. ventilation-related risk factors for cerebral palsy in low birth weight infants. 4 Peevy KJ, Hernandez LA, Moise AA, Parker JC. Barotrauma and Pediatr Res 2001; 50: 712–719. microvascular injury in lungs of nonadult rabbits: effect of ventilation 22 Thome UH, Carlo WA. Permissive hypercapnia. Semin Neonatol 2002; 7: pattern. Crit Care Med 1990; 18: 634. 409–419. 5 Parker JC, Hernandez LA, Peevy KJ. 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