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 hypercapnia and permissive hypoxemia in neonates WA Carlo Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA permissive hypercapnia 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 lung 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 respiratory failure. The limited randomized controlled trials assessing early short-term postnatal There is consensus that mechanical ventilation 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. Ventilator-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 pressures, thus, the term barotrauma. 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 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 Introduction demonstrate that markers of lung injury (pulmonary edema, Advances in perinatal care such as surfactant, 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 tidal volume and high pressure as well as high extremely low birth weight 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 therapies 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 gas reopening of the alveoli during the breath cycle also results in lung 8 trapping and alveolar overdistention are minimized, whereas blood injury, that can be reduced with high positive-end expiratory 9 gas targets are modified to accept higher than ‘‘normal’’ alveolar partial pressure. This further limits the tidal volume that can be used safely (Figure 1). Thus, reduction of volutrauma would require the pressure of carbon dioxide (PaCO2 ) values and lower than ‘‘normal’’ 1 use of lower tidal values. This would result in decreased PaO2 =arterial oxygen 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 Neonatology, 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 concentration of gases 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 lungs) 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 hypoventilation to the tissues during hypercapnia (Bohr effect). Respiratory drive are strategies for the management of patients requiring mechanical may be stabilized, resulting in less apnea.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 acidosis may be well tolerated and may lead to hypercapnia on gas exchange include a small reduction in PaCO2 prevention of pulmonary volutrauma. (caused by the increased alveolar CO2, which