Permissive hypercapnia in protective lung ventilatory strategies

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Permissive hypercapnia in protective lung ventilatory strategies

Keywords hypercapnia; acidosis; mechanical ventilation; acute lung injury; acute respiratory distress syndrome; congenital heart disease; congenital diaphragmatic hernia; asthma; neonatal respiratory distress syndrome; pulmonary hypertension; intracranial pressure; buffering

Introduction

Brendan D Higgins

Traditional approaches to the management of CO2 in neonates and children with acute respiratory failure have focused on the potential deleterious effects of hypercapnia and therefore on targeted normocapnia or even hypocapnia. Support for this strategy is derived from the link between hypercapnia and adverse outcome in diverse clinical contexts, including cardiac arrest1 sepsis2 and neonatal asphyxia.3 However, it has been increasingly questioned. Accumulating evidence from experimental and clinical studies supports the contention that mechanical ventilation may directly injure the lungs, a phenomenon termed ‘ventilator-induced lung injury’. Permissive hypercapnia (PHC) is a ventilatory strategy in which relatively high PaCO2 is tolerated in an effort to avoid high tidal volumes and pulmonary over-distension, thereby potentially reducing lung injury and increasing survival.4,5 PHC has been progressively accepted in the critical care of patients requiring mechanical ventilation. Conventionally, the protective effect of ventilatory strategies incorporating PHC is considered to be solely due to reductions in lung stretch, with hypercapnia permitted to achieve this goal. However, protective ventilatory strategies involving hypoventilation result in both limitation of lung stretch and elevation of systemic PCO2. Lung stretch is distinct from elevated PCO2, and by manipulation of respiratory parameters (frequency, tidal volume, dead-space, inspired CO2) can, at least to some extent, be separately controlled. Thus, it is important to determine whether hypercapnia might exert direct effects in critically ill children. If hypercapnia were proved to have independent benefits, deliberately elevating PaCO2 (therapeutic hypercapnia) could provide an additional advantage over low tidal volume strategies alone. Conversely, in patients managed with conventional PHC, adverse effects of elevated PaCO2 might be concealed by the benefits of lower lung stretch. Because ICU outcome might be related to the development of multi-organ failure (as opposed to simply lung injury) it is also necessary to determine the effects of hypercapnia on systemic organs. This review assesses the role of ventilatory strategies involving PHC in the management of neonates and children with acute respiratory failure. The physiological effects of hypercapnia in the lung and systemic organs are discussed, and evidence from laboratory models of lung and systemic organ injury is considered, demonstrating the potential for hypercapnia to modulate the injury process. The role of PHC in various clinical settings relevant to neonatal and paediatric practice, and the risks and benefits of PHC are also considered in specific clinical situations.

Joseph F Costello Martina Ni Chonghaile John G Laffey

Abstract Hypercapnia has traditionally been avoided in paediatric critical illness; indeed, traditional approaches advocated hypocapnia in a number of disease states. However, recent advances in understanding of the role of excessive tidal stretch has prompted clinicians to avoid high tidal volumes or plateau pressures, and to tolerate the resulting ‘permissive’ hypercapnia. Advances in understanding of the biology of hypercapnia have led to consideration of an active role for hypercapnia in the pathogenesis of inflammation and tissue injury. Newer data suggest that elevated CO2 may be protective, but in some experimental situations can cause harm. This review assesses the role of ventilatory strategies involving permissive hypercapnia in the management of neonates and children with acute severe respiratory failure. The physiological effects of hypercapnia on the lung and systemic organs are discussed, and evidence from laboratory models of lung and systemic organ injury is considered, demonstrating the potential for hypercapnia to modulate the injury process. The role of permissive hypercapnia in various clinical settings relevant to neonatal and paediatric practice, and the risks and benefits of hypercapnia in specific clinical situations are also considered.

Brendan D Higgins BSc PhD is Postdoctoral Fellow at the Department of Anaesthesia Clinical Sciences Institute and National Centre for Biomedical Engineering Sciences, National University of Ireland, Galway, Ireland. Joseph F Costello MB FCARCSI is Research Fellow at the Department of Anaesthesia, Clinical Sciences Institute and National Centre for Biomedical Engineering Sciences, National University of Ireland, Galway, Ireland. Martina Ni Chonghaile MB FCARCSI is Research Fellow at the Department of Anaesthesia, Clinical Sciences Institute and National Centre for Biomedical Engineering Sciences, National University of Ireland, Galway, Ireland. John G Laffey MD MA BSc FCARCSI MB FCARCSI is Professor at the Department of Anaesthesia, Clinical Sciences Institute and National Centre for Biomedical Engineering Sciences, National University of Ireland, Galway, Ireland.

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Physiological effects of hypercapnia If PHC is to be used rationally and safely in critically ill neonates and children, its physiological effects must be considered. These

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effects are diverse and incompletely understood, however, and direct effects are often counterbalanced by indirect effects. In addition, the net effect of hypercapnia may occur as a function of acidosis or of CO2 per se. Pulmonary system In the normal lung, CO2 may either regulate regional ventilation in response to primary changes in perfusion, or alter regional perfusion to match primary changes in ventilation. An example is the phenomenon of hypocapnic bronchoconstriction that occurs following acute regional pulmonary artery occlusion.6 It is of concern that hypercapnia can increase pulmonary vascular resistance. This might aggravate primary pulmonary hypertension in newborns managed with a strategy of PHC. Reassuringly, however, data from an animal model of chronic hypoxia-induced pulmonary hypertension suggests that the effect of hypercapnia on pulmonary vascular resistance does not appear to be exacerbated in the setting of pre-existing pulmonary hypertension.7 Administration of CO2 improves matching of ventilation and perfusion and increases arterial oxygenation by this mechanism in both health8,9 and disease.10 A dose–response relationship exists whereby increased FiCO2 results in progressive (Figure 1). In acute respiratory distress augmentation of PaO9,11 2 syndrome (ARDS), the potential for PHC to increase shunt is due to reduced tidal volume and airway closure rather than hypercapnia per se.12 Hypercapnia has been variably reported to either increase13 or decrease14 airway resistance. These effects may be explained by the direct dilatation of small airways and indirect (vagally mediated) large airway constriction.6 These opposing balanced airway actions of CO2 may result in little net alteration in airway resistance. Parenchymal lung compliance increases in response to hypercapnic acidosis. This may be due to increased surfactant secretion or more effective surface tension-lowering properties under acidic conditions.15

Figure 1 Brain tissue oxygen tension, in addition to cerebral perfusion, is progressively increased with increases in inspired CO2 concentration. (Reproduced with permission, Hare GM, et al. Can J Anaesth 2003; 50: 1061–8.)

Central nervous system Hypercapnic acidosis increases cerebral tissue oxygen tension through both augmentation of PaO2 and increased cerebral blood flow9 (Figure 1). Hypercapnia is a potent ventilatory stimulant.16 A modest increase in ventilatory chemosensitivity has been shown in response to acute hypoxia, but no change occurred with acute elevations in CO2.

and oxygen consumption, which may further benefit a supply/ demand imbalance.19

Insights from laboratory studies It is not currently feasible to examine the direct effects of hypercapnic acidosis in humans independent of alterations in ventilatory strategies. An alternative approach, which has been the focus of much recent attention, is to determine the effects of hypercapnic acidosis in various animal models of experimental acute lung and systemic organ injury.

Cardiovascular system Hypercapnic acidosis directly reduces the contractility of cardiac17 and vascular smooth muscle.6 This is counterbalanced by the hypercapnia-mediated sympathoadrenal effects of increased preload and heart rate, increased myocardial contractility and decreased afterload, leading to a net increase in cardiac output.6 Hypercapnia results in a complex interaction of altered cardiac output, hypoxic pulmonary vasoconstriction, and intrapulmonary shunt to produce a net increase in PaO2. Because hypercapnia generally elevates cardiac output, global oxygen delivery is increased. Regional (including mesenteric) blood flow is also increased,18 thereby increasing organ oxygen delivery. Hypercapnia and acidosis shifts the hemoglobin–oxygen dissociation curve to the right, reducing the oxygen affinity of haemoglobin, and may cause an elevation in haematocrit, further increasing tissue oxygen delivery. Acidosis may reduce cellular respiration

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Pulmonary Hypercapnic acidosis attenuates the increased lung permeability seen following free radical-mediated20 and ischaemia–reperfusion-induced reperfusion-induced lung injury.20,21 Hypercapnic acidosis preserved lung mechanics, attenuated protein leakage, reduced pulmonary oedema and improved oxygenation compared with control conditions following in vivo pulmonary ischaemia–reperfusion22 as well as in secondary reperfusioninduced lung injury.11 Such protective effects of hypercapnic acidosis are not mediated via a decrease in pulmonary artery resistance; indeed, protection occurred despite elevated pulmonary artery pressures.11

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Prolonged hypercapnia may impair diaphragmatic function in rats by interfering with neuromuscular transmission and histological structure.34 Alterations in diaphragmatic function could lead to delayed weaning from ventilatory support. However, clinical trials of PHC in infants and children to date do not support this concern.

Hypercapnic acidosis appears to attenuate the development of pulmonary hypertension and vascular remodelling induced by chronic hypoxia in newborn rats.23 Newborn rats were maintained under atmospheric CO2 of less than 0.5% (normocapnia), 5.5% or 10% during exposure from birth for 14 days to normoxia or moderate hypoxia (13%). Inspired CO2 attenuated the increase in pulmonary arterial resistance, right ventricular hypertrophy and dysfunction, medial thickening of pulmonary resistance arteries and distal arterial muscularisation that occurred in rats exposed to hypoxia. A dose–response was seen; 10% CO2 significantly attenuated pulmonary vascular remodelling and alterations in pulmonary arterial resistance, and both increased concentrations of CO2 normalised right ventricular performance. Exposure to 10% CO2 also reduced lung oxidative injury, and prevented up-regulation of endothelin-1, a critical mediator of pulmonary vascular remodelling.23 The effect of hypercapnia in ventilator-induced lung injury (VILI) is more complex. In two key studies, addition of inspired CO2 reduced VILI in isolated rabbit lung24 and in rabbits in vivo.25 However, not all data are so positive. Supplemental CO2 has more modest protective effects in the context of more clinically relevant tidal stretch. Strand et al. showed that significant hypercapnic acidosis (mean PaCO2 95 mmHg) was well tolerated in preterm lambs, and appeared to reduce lung injury.26 In the context of a clinically relevant high tidal volume strategy (tidal volume 12 mL/kg, positive end-expiratory pressure (PEEP) 0 cmH2O, rate 42/min) in an adult model, hypocapnia was potentially deleterious and hypercapnic acidosis somewhat protective.11 However, inspired CO2 did not significantly attenuate lung injury induced by an atelectasis-prone model of lung injury, which may mimic neonatal respiratory distress syndrome more closely than pure stretch models of injury.27 Hypercapnia produced by hypoventilation rather than by increased inspired CO2 did not protect against stretch-induced injury.28 In a subsequent study, hypercapnia was found to minimise the adverse effects of high-volume ventilation on vascular barrier function, but it impaired the ability of lung cells to repair the stretch-induced injury.29 Taken together, these findings suggest that while hypercapnic acidosis substantially attenuates injury due to excessive stretch, its effects in the context of more clinically relevant lung stretch or extensive atelectasis are modest, and there are concerns regarding the effects of hypercapnia on cellular repair following injury. ARDS commonly develops in the context of severe sepsis in children. Hypercapnia may have deleterious effects by impairing the immune system response to bacterial sepsis.30,31 The mechanisms of lung injury in sepsis-induced ARDS are distinct from those in many experimental models. Lipopolysaccharide (LPS), a key endotoxin of Gram-negative bacteria, initiates lung injury by activating a specific receptor called toll-like receptor-4. Hypercapnia appears to have different effects in lung injury caused by pulmonary vs systemic administration of endotoxin. Hypercapnic acidosis induced by the administration of CO2 has been shown to directly protect against acute lung injury induced by intratracheal instillation of endotoxin.32 Conversely, hypercapnia induced by reduced tidal volume and respiratory rate appears to worsen the lung damage induced by systemic administration of endotoxin.33 These issues underline the need to take into account both the means of achieving hypercapnia and the diversity of experimental models.

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Cardiovascular Hypercapnic acidosis appears to have beneficial effects on the myocardium, and protects the heart from ischaemia–reperfusion injury.35 Both hypercapnic and metabolic acidosis have been shown to reduce infarct size in an in vivo canine model of coronary artery ischemia–reperfusion.36 Possible mechanisms for the protective effects of acidosis include reduction of calcium loading to the myocardium through H+ inhibition of calcium uptake, and, in the case of hypercapnic acidosis, the induction of coronary vasodilatation. Nomura et al. found that the greatest coronary artery blood flow occurred with maximal hypercapnia,35 while acute hypercapnia increased both collateral and global coronary blood flow in a swine model of chronic coronary artery obstruction.37 However, normocapnic acidosis protected the myocardium from coronary artery occlusion-induced ischaemia–reperfusion injury in a canine model.38 In contrast, hypercapnic acidosis was found to reduce the success of resuscitation following ventricular fibrillation arrest in a rodent model.39 Neurological Several studies have demonstrated protective effects of hypercapnia in brain injury. Hypercapnic acidosis protects the newborn porcine brain from hypoxia/reoxygenation-induced injury.40,41 Hypercapnia also attenuates hypoxic–ischaemic brain injury in immature rats, while hypocapnia is deleterious.42,43 Cerebral blood flow was better preserved during hypercapnia, and the greater oxygen delivery promoted cerebral glucose utilisation and oxidative metabolism for optimal maintenance of high-energy phosphate reserves in the tissues.42 However, an important dose–response phenomenon was found; mild-tomoderate hypercapnia (PaCO2 40–55 mmHg) was significantly more neuroprotective than higher PaCO2 (470 mmHg).43 Indeed, extremely high PaCO2, which is not generally seen in the clinical context, appeared to have detrimental effects on the developing brain.44 Potential mechanisms underlying these protective effects include reduced levels of glutamate, an excitatory amino acid neurotransmitter, in the CSF,42 free radical inhibition40,41 and attenuation of neuronal apoptosis.45 Hypercapnia may contribute to the pathogenesis of retinopathy of prematurity, an important concern in the context of neonatal respiratory failure. Hypercapnia causes retinal vasodilatation and increases retinal oxygen delivery in newborn (and adult) rats.46 However, hypercapnia was shown to produce preretinal neovascularisation similar to that seen in oxygeninduced retinopathy in a neonatal rat model.47 Others Acidosis markedly delays the onset of cell death in isolated hepatocytes exposed to anoxia48 or chemical hypoxia.49 Buffering of the pH accelerated cell death. This phenomenon may represent a protective adaptation against hypoxic and ischaemic stress. Isolated renal cortical tubules exposed to anoxia have greater ATP

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products from peroxynitrite in vitro.51 The potential for hypercapnic acidosis to promote nitration of lung tissue in vivo appears to depend on the injury process. Hypercapnic acidosis decreased tissue nitration following pulmonary ischaemia–reperfusion,22 but increased nitration following endotoxin exposure.32,33,51

levels on reoxygenation at acidotic pH compared with tubules incubated at pH 7.548. In contrast, the combination of hypoxia and hypercapnia induced apoptosis in rat renal tubular cell cultures.50

Cellular and molecular effects of hypercapnia

Regulation of gene expression Hypercapnic acidosis appears to regulate the expression of genes central to the inflammatory response in models of cell injury. Nuclear factor kappa B (NF-kB) is a key regulator of the expression of multiple genes involved in the inflammatory response, and its activation is a pivotal early step. Hypercapnic acidosis inhibits endotoxin-induced NF-kB activation and DNA binding in pulmonary endothelial cells by decreasing IkB-a degradation (Figure 2).58 Hypercapnic acidosis also suppressed endothelial production of intercellular adhesion molecule-1 and IL-8, which are critically regulated by the NF-kB pathway.58

A clear understanding of the cellular and biochemical mechanisms underlying the effects of hypercapnia is essential. It is a prerequisite for the successful translation of laboratory findings to the bedside, and allows prediction of potential side effects, enabling identification of those in whom hypercapnia should be avoided. Acidosis vs hypercapnia The protective effects of hypercapnic acidosis in experimental lung and systemic organ injury appear to be primarily a function of the acidosis.21,51 In isolated lung, the protective effect of hypercapnic acidosis in ischemia–reperfusion was greatly attenuated if the pH was buffered towards normal.21 The myocardial protective effects of hypercapnic acidosis are also seen with metabolic acidosis in both ex vivo52 and in vivo36,38 models. Furthermore, as discussed earlier, metabolic acidosis exerts protective effects in other organs, including the liver and the kidney.48,49

Role of PHC in specific clinical settings The use of PHC in neonatal and paediatric respiratory failure has long been recognised. The potential deleterious effects of barotrauma on the developing lung were first noted almost 30 years ago. Neonatal respiratory distress syndrome Acute respiratory failure in the preterm newborn results from parenchymal stiffness due to immaturity and surfactant deficiency, and may be complicated by adverse events such as sepsis and aspiration of meconium. Lung injury remains a leading cause of morbidity in neonates who receive ventilatory support.59 The duration and intensity of mechanical ventilation may be important determinants of the development of bronchopulmonary dysplasia (BPD)/chronic lung disease (CLD). The immature lung may be particularly susceptible to barotrauma. The risk of

Anti-inflammatory effects Several key components of the inflammatory response appear to be attenuated by hypercapnic acidosis. It inhibits the release of tumour necrosis factor-a (TNF-a) and interleukin (IL)-1 from stimulated macrophages in vitro53 and reduces bronchoalveolar lavage levels of TNF-a following in vivo pulmonary ischaemia– reperfusion.22 Both hypercapnia and acidosis impair intracellular pH regulation by neutrophils, potentially overwhelming their capacity (especially when activated54) to regulate cytosolic pH. This failure impairs important neutrophil functions such as chemotaxis55 and the release of IL-8 following stimulation by LPS.56 Such effects also occur in vivo; lung neutrophil recruitment is inhibited during ventilator-induced25 and endotoxininduced32 lung injury. Free radical generation and activity In common with most biological enzymes, the enzymes that produce oxidising free radicals function optimally at physiological pH. Generation of oxidants by both basal and stimulated neutrophils appears to be regulated by ambient CO2 levels; oxidant generation is reduced by hypercapnia and increased by hypocapnia.56 The production of superoxide by stimulated neutrophils in vitro is decreased at acidic pH.57 In the brain, hypercapnic acidosis attenuates glutathione depletion and lipid peroxidation,40 which reflect free radical activity and tissue damage, respectively. In the lung, hypercapnic acidosis reduces free radical tissue injury following ischaemia–reperfusion22 and attenuates production of the higher oxides of NO (e.g. NO2, NO3) following both ventilator-induced24 and endotoxin-induced32 injury. Hypercapnic acidosis inhibits injury mediated by xanthine oxidase, and directly inhibits the enzyme.20 There are concerns regarding the potential for hypercapnia to potentiate tissue nitration by peroxynitrite, a potent free radical. Buffered hypercapnia promotes the formation of nitration

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Figure 2 Hypercapnia suppresses the degradation of IkB-a (panel A) but not IkB-b (panel B) following exposure to lipopolysaccharide, thereby inhibiting the nuclear translocation of NF-kB and downstream cytokine production. The effects of isocapnic acidosis and buffered hypercapnia (panel C) on IkB-a degradation were intermediate between normocapnic control and hypercapnic acidosis conditions. BH, buffered hypercapnia; HA, hypercapnic acidosis; IA, isocapnic acidosis; LPS, lipopolysaccharide; NC, normocapnia; NF-kB, nuclear factor kappa-B. (Reproduced with permission, Takeshita K, et al. Am J Respir Cell Mol Biol 2003; 29: 124–32.)

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sample size limits the conclusions that can be drawn from this study. A prospective multi-centre study of extremely premature neonates in Denmark (1994–1995) reported that a ventilatory strategy incorporating PHC, early use of nasal continuous positive airway pressure and surfactant significantly reduced the incidence of CLD.63

CLD in premature neonates may be lowered if barotrauma is reduced by the acceptance of higher PaCO2.60 Conversely, the presence of hypocapnia at 48 and 96 hours of life in neonates with respiratory failure has been demonstrated to be the best predictor of BPD.61 In the first randomized controlled trial of PHC, Mariani et al. reported beneficial effects of hypercapnia in infants with neonatal respiratory distress syndrome.59 Preterm infants (birth weight 8547163 g, gestational age 2671.4 weeks) were randomly allocated to a target PaCO2 of 35–45 mmHg or 45–55 mmHg for the first 96 hours of life. Infants randomised to the higher PaCO2 required less intensive ventilation and were weaned from mechanical ventilation significantly faster. The total number of days on assisted ventilation was 2.5 (1.5–11.5) in the PHC group and 9.5 (2.0–22.5) in the control group (p ¼ 0.17), and the number of infants requiring assisted ventilation during the first 96 hours was lower (po0.005) in the PHC group (Figure 3). No obvious adverse effects were seen, though such a small study would not detect a low incidence of adverse effects. A larger, multi-centre trial of PHC randomised extremely low birth weight infants (501–1000 g) mechanically ventilated before 12 hours of life to a target PaCO2 of below 48 mmHg (routine) or above 52 mmHg (PHC group), and a tapered course of dexamethasone or a saline placebo, using a 2  2 factorial design, for the first 10 post-natal days.62 Unfortunately, the trial was stopped early, because of unanticipated non-respiratory adverse events related to the dexamethasone therapy. There was a trend towards a lower incidence of death and CLD in the PHC group. Importantly, only 1% of the PHC group required mechanical ventilation at 36 weeks’ gestational age, compared with 16% in the routine group (po0.01). However, the reduced

Persistent pulmonary hypertension of the newborn (PPHN) PPHN is a complication of neonatal sepsis, aspiration of meconium or severe neonatal respiratory failure, or occurs in an idiopathic form in term or near-term neonates. Traditional management has emphasised hyperventilation to reduce pulmonary arterial pressure. To achieve a significant effect with a resultant increase in oxygenation, extreme reduction of PaCO2 (420 mmHg) resulting in a pH of more than 7.60 has been advocated.64 However, the resultant hypocapnia has been clearly associated with adverse neurological outcome in the survivors of PPHN, in terms of sensorineural hearing loss and low psychomotor developmental scores.65,66 In marked contrast to this traditional approach, Wung et al.67 described lower than previous mortality, and a reduced incidence of CLD, in 15 neonates with persistent foetal circulation in severe respiratory failure. PaCO2 was allowed to increase as high as 60 mmHg, while hyperventilation and muscle relaxants were avoided. All of the neonates survived, and only one developed CLD as defined by a need for supplemental oxygen beyond 30 days of life.67 In a more recent study, Marron et al.68 reported 100% survival in a case series of 34 infants with severe PPHN and severe respiratory failure at birth managed with PHC. Subsequent detailed neurological and audiological testing of 27 of these patients revealed a good neurological outcome, with average IQ in the normal range, no cases of sensorineural hearing loss, and a relatively low incidence of neurological abnormalities not attributable to birth asphyxia. Only two infants developed BPD, and neither required supplemental oxygen at follow-up.68 Congenital diaphragmatic hernia Permissive hypercapnia is playing an increasing role in the ventilatory management of infants with congenital diaphragmatic hernia.69 This contrasts sharply with traditional management strategies, which involved aggressive hyperventilation with the aim of producing systemic alkalinisation. However, high levels of barotrauma, poor long-term respiratory outcomes and poor survival rates led to the recognition that it is the hypoplastic lung that is the major pathophysiological defect. Accordingly, avoidance of barotrauma has assumed increasing importance, and ventilation strategies involving PHC are increasingly used in this clinical setting. A retrospective analysis of the effect of three treatment protocols on the outcome in high-risk infants with congenital diaphragmatic hernia reported that prioritizing PHC was associated with a substantial increase in survival, reduced barotrauma, and reduced morbidity at 6 months. In contrast, earlier introduction of high-frequency oscillatory ventilation (which readily controls PaCO2) appeared to have a minimal impact. Despite limitations of this study, the finding of a clear survival benefit with a treatment protocol in which PHC appears to be the sole addition is persuasive.70

Figure 3 Duration of mechanical ventilation in neonates with respiratory failure randomised to conventional therapy or permissive hypercapnia. (Reproduced with permission from Mariani G et al. Pediatrics 1999; 104: 1082–8.)

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Congenital heart disease Control of CO2 has traditionally played an integral role in the management of patients with complex congenital heart defects. In the context of single ventricle physiology, pulmonary vascular resistance can be controlled by inducing alveolar hypoxia or alveolar hypercapnia. The potential of hypercapnia to improve brain and other systemic organ oxygenation is increasingly recognised. In neonates with severe congenital heart defects, low cerebral blood flow has been associated with periventricular leucomalacia and adverse neurological outcome.71 These deficits in cerebral blood flow were reversible when CO2 was administered.71 Furthermore, addition of inspired CO2 increased cerebral oxygenation and mean arterial pressure compared with reducing FiO2 in hypoplastic left heart syndrome72 and following cavopulmonary connection,73 respectively. Hypoventilation has also been shown to improve systemic oxygenation after bidirectional superior cavopulmonary connection, potentially via a hypercarbia-induced decrease in cerebral vascular resistance, thereby increasing cerebral, superior vena caval and pulmonary blood flow.74 A more detailed recent study showed that, without altering tidal volume or mean airway pressure, addition of CO2 to the inspired gas resulted in improved cerebral blood flow and systemic oxygenation following cavopulmonary connection.75 Taken together, these studies raise the possibility that inhaled CO2 might have a future therapeutic role in this context.

trials), these dats show no discernable relationship between level of hypercapnia and survival. The database of the largest of these studies80 has been subsequently analysed to determine whether, in addition to the effect of tidal volume, there might also have been an independent effect of hypercapnic acidosis.84 Mortality was examined as a function of PHC on the day of enrolment, and using multivariate analysis and controlling for other co-morbidities and the severity of the lung injury. It was found that PHC reduced mortality in patients randomised to the higher tidal volume, but not in those receiving lower tidal volumes.84 If these data are supported, there may be a good case for concluding that hypercapnic acidosis directly attenuates ventilator-associated lung injury, rather than simply being a side effect tolerated to reduce lung stretch.

Balancing risks and benefits Although hypercapnia and acidosis exert a myriad of biologically important effects, in practice there are few complications. Nevertheless, in certain clinical contexts, the potential deleterious effects of hypercapnia must be carefully considered. PHC and the immature brain Rapid changes in CO2 levels in very low birth weight infants may lead to substantial fluctuations in cerebral blood flow, and predispose to intraventricular haemorrhage in the immature brain.85 In one study of very low birth weight infants, hypercapnia was associated with progressive loss of cerebral autoregulation.86 As a consequence, fluctuations in blood pressure in premature neonates in the presence of hypercapnia may increase the risk of intraventricular haemorrhage. This risk may be reduced by avoiding abrupt changes in PCO2, and by modest rather than severe hypercapnia (or hypocapnia). Reassuringly, neither Mariani et al.,59 nor Carlo et al.62 found any increase in intraventricular haemorrhage rates in their randomised controlled trials of PHC in preterm infants with respiratory failure. Hypercapnia may protect the immature brain. As discussed above, there is laboratory evidence that hypercapnia may directly protect the immature brain from hypoxicischaemic injury.42,43 Of potentially more importance, PHC may indirectly protect the developing brain by avoiding accidental hypocapnia. Preterm infants exposed to severe hypocapnia (PaCO2o15 torr (o2 kPa)), even of relatively short duration, develop considerable long-term neurological abnormalities,87 probably due to reduced cerebral perfusion. In addition, abrupt termination of hyperventilation can result in reactive cerebral hyperaemia, and precipitate intracranial haemorrhage.88

Acute severe asthma Although much of the current research on ventilatory strategies involving PHC concentrates on its therapeutic potential in lung injury, its use was first described in patients with status asthmaticus.76 PHC facilitates reduction of dynamic hyperinflation during mechanical ventilation in acute severe asthma, by allowing increased expiratory time, reduced inspiratory flow rate, and reduced tidal volume. This reduces the end-inspiratory lung volume and the risk of auto-PEEP. Others have supported the case for morbidity and mortality being reduced when PHC is used in patients with severe asthma who require mechanical ventilation,77 and modest PHC (mean highest levels 62 mmHg) is routinely used in patients with acute severe asthma admitted to ICUs in mainland Europe.78 ARDS The potential for protective lung ventilation strategies, with varying degrees of PHC, to improve survival in patients with acute lung injury and ARDS was suggested initially by Hickling et al.5,79 Two studies by this group, one retrospective79 and one prospective,5 strongly indicated that a low tidal volume approach was beneficial. Of the five prospective randomized controlled trials of protective ventilation strategies4,80–83 conducted in the last decade, two showed an impact of ventilatory strategy on mortality,4,80 though three did not.81–83 To some extent, PHC developed in all of the trials, though there was much variability. In the four major trials, the post-randomization ranges of PaCO2 (mean7SD, mmHg) in the control (i.e. higher tidal volume) groups were 35.878.0,80 36.071.5,4 41.077.582 and 46.0710.81 In contrast, the post-randomisation ranges of PaCO2 in the protective (i.e. lower tidal volume) groups were 40.0710,80 58.073.0,4 59.571582 and 54.5719.81 Thus, though it is clear that ventilation strategy can affect mortality (in the positive

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PHC and intracranial pressure (ICP) regulation A key concern regarding PHC is the potential for hypercapniainduced increases in cerebral blood flow to critically elevate ICP in situations where intracranial compliance is diminished.89 However, clinical conditions predisposing to intracranial hypertension constitute a relative rather than an absolute contraindication to PHC. Consideration should be given to the insertion of an ICP monitor or a jugular venous oximetry catheter, which can facilitate the gradual titration (or avoidance) of PHC in patients with a brain injury. The successful use of such an approach was described in the management of a child with

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acidosis91 because the CO2 produced when bicarbonate reacts with metabolic acids diffuses readily across cell membranes, whereas bicarbonate cannot.92

Conclusion Ventilatory strategies involving hypercapnia are widely used in critically ill neonates and children, with the aim of realising the benefits of reduced lung stretch. The potential for hypercapnia to directly contribute to the beneficial effects of protective lung ventilatory strategies is clear from experimental studies demonstrating protective effects in models of acute lung and systemic organ injury. These findings raise the possibility that hypercapnia might be induced for therapeutic effect in certain clinical contexts. However, concerns persist regarding the potential deleterious effects of hypercapnia and/or acidosis, and the need for caution before extrapolation to clinical settings must be emphasised. The optimal ventilatory strategies, and the precise contribution of hypercapnia to them, remains unclear. At present, clinicians must continue to decide the benefits and costs of avoiding high tidal volumes and the associated hypercapnia in individual patients. A clearer understanding of the effects and the mechanisms of action of hypercapnia is central to determining ~ its safety and therapeutic utility.

Figure 4 Chest radiograph and brain CT scan of a child with both acute respiratory distress syndrome and cerebral oedema, illustrating the ‘trade-off’ involved in instituting permissive hypercapnia to protect against ventilator-associated lung injury. (Reproduced with permission, Tasker RC and Peters MJ. Intensive Care Med 1998; 24: 616–9.)

meningococcal septicaemia complicated by both significantly elevated ICP and severe acute lung injury (Figure 4).89 PHC and pulmonary vascular resistance Clinical conditions predisposing to pulmonary hypertension should be considered a relative rather than an absolute contraindication to PHC strategies. As discussed above, PHC is increasingly used in the setting of severe neonatal respiratory failure resulting in persistent fetal circulation and pulmonary hypertension.67 In addition, laboratory studies have shown that hypercapnic acidosis may retard the development of hypoxiainduced pulmonary hypertension in newborn rodents.23 Concerns about significant pulmonary hypertension can be most rationally dealt with by assessing the degree of pulmonary hypertension or its sequelae (e.g. right ventricular failure, tricuspid regurgitation, increased right to left shunting) and the effect of hypercapnia on pulmonary vascular resistance, and titrating the degree of hypercapnia accordingly. In this context, monitoring by transthoracic echocardiography or the placement of a pulmonary artery catheter may be indicated.

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The role of buffering Buffering of the acidosis induced by hypercapnia remains a common, albeit controversial clinical practice. Buffering with sodium bicarbonate was permitted in the ARDS Network tidal volume study.80 The need to consider the effects of buffering of hypercapnic acidosis is emphasized by the fact that both hypercapnia and acidosis per se may have distinct biological effects. However, as discussed above, there is evidence that the protective effects of hypercapnic acidosis in ARDS are a function of the acidosis rather than the elevated CO2 per se.21,51 Buffering may simply ablate any protective effects, while not addressing the primary problem. There are specific concerns regarding sodium bicarbonate, the buffer used most commonly in clinical settings. The effectiveness of bicarbonate infusion as a buffer depends on the ability to excrete CO2, rendering it less effective in buffering hypercapnic acidosis. Indeed, bicarbonate may further raise PaCO2 when alveolar ventilation is limited, such as in ARDS.90 Although bicarbonate may correct arterial pH, it may worsen intracellular

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Traditional approaches to the management of CO2 in neonates and children have focused on deleterious effects of hypercapnia Mechanical ventilation strategies involving high lung stretch are directly injurious to the lung Protective ventilatory strategies aimed at reducing lung stretch generally require tolerance of ‘permissive’ hypercapnia There is increasing evidence from laboratory studies that hypercapnia may attenuate lung and systemic organ injury The potential for deleterious physiological effects of hypercapnia when intracranial compliance is reduced, or where increases in pulmonary vascular resistance may be deleterious, must be considered; however, these are not absolute contraindications to the careful use of PHC in these patients There is increasing evidence supporting the use of PHC in neonatal respiratory failure, congenital diaphragmatic hernia, acute respiratory distress syndrome, persistent pulmonary hypertension, congenital heart disease and severe asthma There is no evidence to support the clinical practice of buffering hypercapnic acidosis with bicarbonate

intracellular acidosis. Clin Sci 1997; 93: 593–8.

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