John G. Laffey Permissive hypercapnia — Donall O’Croinin Paul McLoughlin role in protective lung ventilatory strategies Brian P. Kavanagh

Abstract ‘Permissive hypercapnia’ the potential exists for hypercapnia to is an inherent element of accepted exert beneficial effects in the clinical protective lung ventilation. However, context. Direct administration of CO2 there are no clinical data evaluating is protective in multiple models of the efficacy of hypercapnia per se, acute lung and systemic injury. Nev- independent of ventilator strategy. In ertheless, several specific concerns the absence of such data, it is neces- remain regarding the safety of hy- sary to determine whether the poten- percapnia. At present, protective tial exists for an active role for ventilatory strategies that involve hypercapnia, distinct from the dem- hypercapnia are clinically acceptable, onstrated benefits of reduced lung provided the clinician is primarily stretch. In this review, we consider targeting reduced tidal stretch. There four key issues. First, we consider the are insufficient clinical data to sug- evidence that protective lung venti- gest that hypercapnia per se should be latory strategies improve survival and independently induced, nor do out- we explore current paradigms re- come data exist to support the prac- garding the mechanisms underlying tice of buffering hypercapnic these effects. Second, we examine acidosis. Rapidly advancing basic whether hypercapnic acidosis may scientific investigations should better have effects that are additive to the delineate the advantages, disadvan- effects of protective ventilation. tages, and optimal use of hypercapnia Third, we consider whether direct in ARDS. elevation of CO2, in the absence of protective ventilation, is beneficial or Keywords Hypercapnic acidosis · deleterious. Fourth, we address the Mechanical ventilation · Acute lung current evidence regarding the buff- injury · ARDS · Ventilation-induced ering of hypercapnic acidosis in lung injury · Buffering ARDS. These perspectives reveal that

Introduction absence of such data, it is appropriate to investigate whether the potential exists for an active role for ‘Permissive hypercapnia’ is an inherent element of hypercapnia per se, distinct from the demonstrated accepted protective lung ventilatory strategies. However, benefits of reduced lung stretch. This review first the precise role of hypercapnia remains unclear, with no considers the evidence that protective lung ventilatory clinical data comparing the efficacy of protective lung strategies reduce lung injury and improve survival. We ventilatory strategies in the presence and absence of examine current paradigms regarding the mechanisms hypercapnia. Furthermore, it is unlikely that such a trial underlying this protective effect, and the passive role will be carried out, at least in the medium term. In the presently attributed to hypercapnia. We focus on whether 348 198 hypercapnia and/or acidosis may have effects that are humoral immune response in the lung [8–11], although distinct from the effects of protective ventilator param- this is controversial, with conflicting results reported [12]. eters. In addition, the current status of buffering hyper- The potential for intrapulmonary mediators and pathogens capnic acidosis is reviewed. to access the systemic circulation is clear from experi- ments demonstrating translocation of prostaglandins [13], cytokines [14] endotoxin [15], and bacteria [16], across an Protective lung ventilatory strategies — current impaired alveolar-capillary barrier, following high stretch paradigms mechanical ventilation. The potential for mechanical ventilation to induce a systemic cytokine response in It is increasingly clear that mechanical ventilation can the clinical context, and for a protective lung ventilation potentiate or even cause lung injury and worsen outcome strategy to attenuate this response, has been demonstrated in ARDS patients [1, 2]. The likely mechanisms under- [17]. However, the contribution of cytokine release to the lying this ‘ventilator associated lung injury’ (VALI) are pathogenesis of ventilator induced ALI in the clinical increasingly well characterized [3], and several plausible context remains unclear [10, 18]. theories have been proposed. Mechanotrauma, which VALI may be limited by permitting hypoventilation in results from repetitive over-stretching and damage of lung order to reduce mechanotrauma and the resulting inflam- tissue and cyclic recruitment-derecruitment of collapsed matory effects. This invariably involves a reduction in the areas of lung [4–9], plays a pivotal role (Fig. 1). These tidal volume, and generally leads to an elevation in effects may be particularly important, because increased PaCO2, an approach that has been termed “permissive mechanical stress may directly activate the cellular and hypercapnia”. These protective lung ventilation strategies

Fig. 1 Mechanical ventilation may contribute to ALI by causing mechanisms. These include attenuation of key etiologic factors that direct physical injury (baro- and/or volutrauma) to the lung and by lead to ALI, reduction of physical lung damage, inhibition of key activating the inflammatory response, which in turn may lead to aspects of the inflammatory response, and direct protection of multiple organ dysfunction and adverse outcome. Hypercapnic systemic organs. Solid arrows indicate potentiation of effect; acidosis may protect the lung and systemic organs via several broken arrows indicate inhibitory effect 349 199 improve survival in acute respiratory distress syndrome related to systemic injury — as opposed to simply lung (ARDS) patients [1, 19, 20]. The reported levels of PaCO2 injury — it is necessary to examine the effects of and pH (mean maximum PaCO2 67 torr, mean pH 7.2) in hypercapnia on pathophysiologic function in the heart and the study of Hickling et al. [19] reflect typical levels brain as well as the lung. These issues are further observed with institution of this technique. Accordingly, underlined by the fact that hypercapnia has potentially there has been a shift towards greater clinical acceptabil- severe adverse effects in some clinical settings, such as ity of hypercapnia in acute lung injury (ALI) and ARDS. critically elevated intracranial pressure. However, current paradigms attribute the protective effect Clearly, the presence of an acidosis — whether of these ventilatory strategies solely to reductions in lung hypercapnic or metabolic — indicates loss of physiologic stretch, with hypercapnia permitted in order to achieve homeostasis and the presence of disease and/or organ this goal. Accordingly, the potential for hypercapnia to dysfunction. In fact, the extent and severity of acidosis is exert clinically important effects in this context has predictive of adverse outcome in diverse clinical contexts, received little attention to date. including cardiac arrest [27, 28] sepsis [29–31] and in the immediate postpartum neonate [32]. However these data indicate an association rather than a cause and effect Permissive hypercapnia — potential for beneficial relationship, and do not indicate that acidosis is directly effects harmful. The systemic haemodynamic effects of hyper- capnic acidosis are relatively benign, even as the pH falls Protective ventilatory strategies that involve hypoventi- to 7.15, with the typical patient experiencing no change or lation result in both limitation of tidal volume and small increases in cardiac output and blood pressure [33, elevation of systemic PCO2. Of course, lung stretch is 34]. There is a body of evidence in the critical care distinct from elevated PCO2, and by manipulation of literature attesting to the safety of hypercapnic acidosis. respiratory parameters (frequency, tidal volume, dead- In many studies of patients undergoing permissive space, inspired CO2) can to some extent be separately hypercapnia, a pH of well below 7.2 appeared to have controlled in humans. The ARDSnet study [2] demon- been well tolerated [19, 20, 33, 35–39]. The safety of strated that mechanical ventilation of patients with ARDS hypercapnic acidosis is further supported by reports that with a tidal volume of 6 ml kg1 (actually, a complex individuals, both adults [40] and children [41], have protocol involving limitation of tidal volume and plateau survived exposure to extreme levels. Therefore, although pressure [21]) resulted in a 25% reduction in mortality acidosis is common in the setting of critical illness, and when compared with a more traditional tidal volume of may herald an adverse prognosis, it is likely that the 12 ml kg1 and a lower frequency. This study minimized aetiology of the underlying condition resulting in the the potential for hypercapnia and instead permitted acidosis, rather than the acidosis per se, is the key factor increased respiratory rates (respiratory frequency of [34, 42]. Indeed acidosis may constitute a protective 1 29 min ); as a result PaCO2 levels were only modestly adaptation in the context of cellular stress, and may in fact elevated, and pH modestly decreased, in the low stretch constitute beneficial effects in the setting of acute organ group. In fact, the need to substantially reduce tidal injury (Table 1) [42]. volumes in order to improve outcome in ARDS patients The potential for hypercapnia to attenuate to the has recently been questioned [22, 23], and it is increas- deleterious effects of high stretch mechanical ventilation ingly clear that most clinicians (including expert inves- in the clinical context has recently received strong support tigators [24]) seldom use very low tidal volumes in in a preliminary communication [43], where Kregenow practice. An acceptance of more moderate tidal volumes, and co-workers examined mortality as a function of whether by analysis [22], or by observation of actual permissive hypercapnia in patients enrolled in the ARD- current practice [25, 26] may reduce the need for — and Snet study [2]. Using multivariate logistic regression acceptability of — permissive hypercapnia. Therefore, the analysis, and controlling for other co-morbidities and context in which elevated CO2 will be encountered in the severity of lung injury, they demonstrated that permissive future is less likely to be as a passive/permissive hypercapnia reduced mortality in patients randomized to accompaniment of ‘protective’ ventilation. the higher tidal volume (12 ml kg1) [43]. However, there These issues underscore the necessity for (and diffi- was no additional protective effect of permissive hyper- culty in) consideration of the effects of hypercapnia in capnia in patients randomized to receive the lower tidal isolation. If hypercapnia was proven to have independent volume (6 ml kg1) [43]. Nevertheless, the potential for benefit, then deliberately elevating PaCO2 could provide hypercapnia to protect against the deleterious effects of an additional advantage over reducing lung stretch. mechanical ventilation, is clear (Fig. 1). Conversely, in patients managed with conventional per- missive hypercapnia, adverse effects of elevated PaCO2 might be concealed by the generally accepted benefits of lessened lung stretch. Because outcome in ICU might be 350 200

Table 1 Published studies of induced hypercapnic acidosis in capillary isographic pressure, A-a O2 gradient alveolar-arterial models of acute organ dysfunction. ALI acute lung injury, IR oxygen gradient, BALF bronchoalveolar lavage fluid, TNFa tumour ischaemia-reperfusion, Kfc capillary filtration coefficient, Paw peak necrosis factor alpha, NO nitric oxide, NMDA N-methyl-D- airway pressure, Pcap pulmonary capillary pressure, Piso pulmonary aspartate Animal model Injury process Key findings Acute lung injury

Shibata et al. 1998 Ex vivo isolated perfused 1. Lung free radical induced 1. HCA attenuated indices of ALI (Kfc,Paw,Pcap,Piso) [44] (rabbit) lung ALI 2. Lung ischemia — 2. HCA attenuated indices of ALI (Kfc,Paw,Pcap,Piso) reperfusion-induced ALI Laffey et al. 2000 Ex vivo isolated perfused Lung ischemia — Acidosis attenuated indices of ALI (Kfc,Paw,Pcap, [45] (rabbit) lung reperfusion Piso). Hypercapnic acidosis more protective than metabolic acidosis. Buffering of hypercapnic acidosis abolished protec- tive effect. Laffey et al. 2000 In vivo whole animal Lung ischemia — HCA attenuated indices of ALI (lung permeability, [46] (rabbit) model reperfusion A-a O2 gradient, compliance, Paw) and inflammation (BALF TNFa, free radical injury) following uni- lateral lung IR. Potential mechanisms included attenuation of nitro- tyrosine formation, and attenuation of lung apoptosis. Broccard et al. 2001 Ex vivo isolated perfused Ventilator-induced high HCA attenuated indices of ALI (lung permeability, [49] (rabbit) lung lung stretch BALF protein, Kfc). Potential mechanism attenuation of lung NO forma- tion. Sinclair et al. 2002 In vivo whole animal Ventilator-induced high HCA attenuated indices of ALI (lung permeability, [50] (rabbit) model lung stretch A-a O2 gradient, compliance, histologic injury) and inflammation ( BALF neutrophils). Laffey et al, 2003 In vivo whole animal Mesenteric Ischemia- HCA attenuated indices of ALI (lung permeability, [47] (rat) model Reperfusion A-a O2 gradient, compliance, PAW) following Mesen- teric IR. HCA was protective if applied following initiation of mesenteric reperfucion, indicating thera- peutic potential. Laffey et al, 2003 In vivo whole animal Ventilator-induced high HCA attenuated (A-a O2 gradient) while hypocapnic [51] (rabbit) model lung stretch alkalsois worsened (PAW) indices of ALI. Myocardial Injury Nomura et al. 1994 Ex vivo isolated perfused Myocardial ischemia — HCA improved postischemic myocardial function [52] (neonatal lamb) heart reperfusion Metabolic acidosis to an equivalent pH did not improve postischemic function Kitakaze et al. 1997 In vivo whole animal Myocardial ischemia — Acidosis (hypercapnic and metabolic) during reper- [53] (rabbit) model reperfusion fusion decreased myocardial infarct size Neurologic Injury Vannucci et al. 1995 In vivo whole animal Unilateral common carotid HCA decreased histologic brain damage [54] ( rat) model artery occlusion, followed by hypoxia Dose response seen with 6% CO2 more neuroprotec- tive than 9% CO2 Vannucci et al. 1997 In vivo whole animal Unilateral common carotid HCA decreased histologic brain damage [55] (rat) model artery occlusion, followed by hypoxia Mechanisms may include improved cerebral blood flow and attenuation of NMDA receptor activation. Vannucci et al. 2001 In vivo whole animal Unilateral common carotid Severe HCA (15%CO2) worsened histologic brain [73] (rat) model artery occlusion, followed damage by hypoxia 351 201

Hypercapnia and acidosis — be discouraged. Conversely, if hypercapnia per se (and insights from laboratory models not the acidemia) were found to be protective, then further research efforts should be directed to finding It is not currently feasible to examine the direct effects of better buffering strategies in order to maximise the hypercapnic acidosis, independent of ventilator strategy, benefits of hypercapnia. in humans. However, important insights may be gained There is increasing evidence that the protective effects from evaluation of the direct effects of hypercapnia and of hypercapnic acidosis in ALI appear to be a function of acidosis in experimental models of organ injury (Table 1). the acidosis, rather than elevated CO2 per se [45, 61]. Hypercapnia at normal pH caused injury to alveolar epithelial cell monolayers [61] and decreased surfactant Protective effects of hypercapnic acidosis protein A function in vitro [62]. In the isolated lung, the protective effect of hypercapnic acidosis in ischaemia There is an evolving body of evidence suggesting that reperfusion induced ALI was greatly attenuated if the pH hypercapnic acidosis exerts biologically important bene- was buffered towards normal [45]. In fact there appeared ficial effects in experimental models (Table 1). Hyper- to be no significant protective effect detectable with capnic acidosis directly attenuates both primary [44–46] buffered hypercapnia (Table 1). Conversely, normocapnic and secondary [47] ischaemia-reperfusion-induced ALI, (i.e. metabolic) acidosis attenuates primary ischaemia- without reductions in lung stretch. Hypercapnic acidosis reperfusion induced ALI in an ex vivo model, although it also directly protects against free-radical-induced ALI is less effective than hypercapnic acidosis in this model [44] and endotoxin-induced lung injury independent of [45]. ventilation strategy [48]. In addition, hypercapnic acidosis The protective effects of hypercapnic acidosis in attenuates lung injury induced by excessive lung stretch in models of systemic organ injury also appear to be a both ex vivo [49] and in vivo [50, 51] models, by a function of the acidosis. The myocardial protective effects surfactant independent mechanism [51]. of hypercapnic acidosis are also seen with metabolic Hypercapnic acidosis may also protect other vital acidosis both in ex vivo [63] and in vivo [53, 64] models. organs from injury (Table 1). In the heart, reperfusion In cortical brain homogenates, the protective effects of with a hypercapnic acidotic perfusate potentiates recovery hypercapnic acidosis are also seen with metabolic acido- of myocardial function following prolonged ischaemia ex sis, albeit to a lesser extent [57]. Metabolic acidosis vivo [52] and limits myocardial infarct size for in vivo appears to exert protective effects in other models of [53] models. In the brain, hypercapnic acidosis attenuates organ injury. In the liver, metabolic acidosis delays the hypoxic-ischaemic brain injury in the immature rat [54, onset of cell death in isolated hepatocytes exposed to 55]. Hypercapnic acidosis protects the porcine brain from anoxia[65] and to chemical hypoxia [66, 67]. Correcting hypoxia/reoxygenation-induced injury [56]. Hypercapnic the pH to 7.4 abolished the protective effect and in fact acidosis is more effective than comparable degrees of accelerated hepatocyte cell death [67]. Finally, isolated metabolic acidosis in prevention of lipid peroxidation in renal cortical tubules exposed to anoxia have improved cortical homogenates [57]. ATP levels on reoxygenation at acidotic — compared with alkalotic — environmental pH levels [65].

Beneficial effects — acidosis or hypercapnia? Hypercapnic acidosis — underlying mechanisms While it is widely accepted that reduction in pH has profound effects on normal tissue function, it is also clear The models of ALI and ARDS are not precise represen- that hypercapnia per se, in the absence of alterations in tations of the clinical context; indeed most clinical pH, may exert biologically important physiologic effects scenarios differ from each other. Therefore, it is important distinct from those produced by acidosis. Of potential to understand the cellular and biochemical mechanisms importance in the context of acute lung injury, hypercap- underlying the protective effects of hypercapnic acidosis nia per se exerts effects on systemic [58] and pulmonary if we are to be able to apply the findings to the bedside, vascular tone [58, 59] and pulmonary vascular remodel- and particularly, to extrapolate the principles to a variety ing [60] that are increasingly well characterized. Thus, the of disease states. Hypercapnic acidosis attenuates key protective effects of hypercapnic acidosis may be a components of the host inflammatory response, including: function of the acidosis or the hypercapnia per se. This lung neutrophil recruitment [48], pulmonary and systemic issue is of particular relevance when considering the cytokine concentrations [46], cell apoptosis [46, 68], and appropriateness of buffering in the clinical context. If any both free-radical production [44, 45] and free-radical protective effects of hypercapnic acidosis were found to tissue injury [46, 57]. In the brain, hypercapnic acidosis result from the acidosis, then efforts to buffer a hyper- attenuates glutathione depletion and lipid peroxidation capnic acidosis would lessen such protection and should [56]. One promising potential mechanism underlying 352 202 these protective actions of hypercapnic acidosis is atten- reaction of nitric oxide with superoxide radicals, which uation of the activation of the transcription regulator are greatly increased in acute inflammatory states [78– nuclear factor kappa beta (NF-kB) [69]. NF-kB regulates 80]. Peroxynitrite oxidizes a variety of biomolecules the expression of several genes involved in inflammatory including sulfides, thiols, lipids, nucleic acids, transition response and its activation represents a pivotal early step metals and selenoproteins [78–80]. These oxidation in the activation of the inflammatory response. reactions result in altered cellular function and tissue damage. Peroxynitrite also causes nitration of phenolic amino acid residues in proteins, including tyrosine Concerns regarding hypercapnia residues, which leads to alteration of protein function [78, 79, 81, 82]. Two recent in vitro studies demonstrate There are concerns regarding the potential for hypercap- that increased CO2 and a reduction in pH below the nia and/or acidosis to exert deleterious effects that suggest normal physiological value inhibit oxidation by perox- the need for caution when considering its use in the ynitrite while promoting nitration reactions [83, 84]. The clinical context. The potential for hypercapnic acidosis to potential for hypercapnia to promote the formation of exert adverse haemodynamic effects in patients with nitration products from peroxynitrite has been clearly ARDS is clear [70]. However, the potential for detrimen- demonstrated in recent in vitro experiments [61, 62]. tal effects on cardiac output [71] and on the peripheral Peroxynitrite-mediated tissue nitration has been suggested circulation [72] may be overstated. In addition, beneficial to be a key mechanism of tissue damage in inflammatory effects of moderate hypercapnia may be counterbalanced conditions, including ALI [78, 79, 81, 82]. by a potential for adverse effects at higher levels. This is Finally, an important limitation when extrapolating to supported by the experimental evidence demonstrating the clinical context is the relatively short duration of the that protection from the adverse effects of brain ischaemia ALI models in which hypercapnic acidosis has been was better when the inspired CO2 was set at 6% rather studied to date. The common clinical scenario in ARDS than at 9% [54]. Of concern, severe hypercapnia produced patients is that of a more prolonged hypercapnia, during by 15% CO2 has been more recently demonstrated to which time the acidosis may be partially, or even worsen neurologic injury in this context (Table 1) [73]. In completely, compensated. As we have seen, there is isolated hepatocytes, the degree of protection from anoxic reason to believe that the acidosis generated by acute injury conferred by a metabolic acidosis was greater at hypercapnia may be the protective factor in acute models pH 6.9 than at pH 6.6 [65]. Furthermore, acidosis of ALI. The need to study the effects of hypercapnia in attenuates the neutrophil respiratory burst and superoxide ALI models of considerably longer duration is therefore production, which are necessary for neutrophil bacteri- clear. cidal activity [74]. This may impair bacterial killing, In summary, these findings demonstrate that hyper- resulting in unopposed bacterial proliferation, with dele- capnic acidosis, induced by direct administration of CO2, terious consequences, in patients with sepsis induced is protective in multiple models of acute lung and ARDS. systemic organ injury. These protective effects appear to There are reports of lung [75] and intestinal [76] injury be a function of the acidosis rather than the hypercapnia following induction of metabolic acidosis by hydrochloric per se. While significant concerns remain regarding acid infusion in whole animal models. However, it is hypercapnia, in particular, its potential to increase tissue important to recognise that infusion of hyperosmolar nitration, the potential for hypercapnia to attenuate acute solutions of strong acids into whole animal preparations lung and systemic organ injury is clear (Fig. 1). may produce toxic effects close to the infusion site and adverse systemic effects, at least some of which are unrelated to any change in pH [77]. Thus, the effects of Hypercapnia — with or without buffering? infusion of strong acid in any given experiment in vivo is likely to represent the sum of potentially beneficial and Buffering of the acidosis induced by hypercapnia in adverse actions. This contrasts with the situation with ARDS patients remains a common, albeit controversial, hypercapnic acidosis, which is easy to produce, is well clinical practice [85, 86]. Buffering with sodium bicar- tolerated, and does not produce toxic local effects. In ex bonate was permitted in the ARDSnet study [2]. The need vivo experiments, where a changes in pH and/or PCO2 to examine the effects of buffering a hypercapnic acidosis can be produced independently, and without the need for is emphasised by the fact that both hypercapnia and acid infusion close to the tissue, metabolic acidosis is acidosis per se may exert distinct biologic effects. directly protective against ischaemia-reperfusion induced However, as already discussed, there is evidence that ALI [45]. the protective effects of hypercapnic acidosis in ALI are a Of perhaps more concern is the potential for hyper- function of the acidosis, rather than elevated CO2 per se capnia to increase tissue nitration. Peroxynitrite is a [45, 61]. In addition, there are specific concerns regarding potent free radical produced in vivo largely by the the use of bicarbonate to correct an acidosis. These 353 203 concerns have resulted in the removal of bicarbonate consequences of acidosis. In a small, but carefully therapy from routine use in cardiac arrest algorithms [87, performed clinical study in ARDS patients, rapid induc- 88]. The effectiveness of bicarbonate infusion as a buffer tion of a hypercapnic acidosis for a two-hour period is dependent on the ability to excrete CO2, rendering it resulted in significant hemodynamic alterations, including less effective in buffering a hypercapnic acidosis. In fact, decreased systemic vascular resistance, increased cardiac bicarbonate may further raise systemic CO2 levels under output, decreased myocardial contractility, decreased conditions of reduced alveolar ventilation, such as ARDS mean arterial pressure and increased mean pulmonary [89]. While bicarbonate may correct arterial pH, it may arterial pressure [70]. Buffering of the hypercapnic worsen an intracellular acidosis because the CO2 pro- acidosis with THAM rapidly attenuated the haemody- duced when bicarbonate reacts with metabolic acids namic alterations and restored myocardial contractility in diffuses readily across cell membranes, whereas bicar- these patients [70]. bonate cannot [90]. Bicarbonate may exert detrimental In summary, although it is a widely accepted clinical effects when used to buffer a lactic acidosis. The potential practice, there are no long-term clinical outcome data for bicarbonate infusion to augment the production of (e.g., survival, duration of hospital stay) to support the lactic acid has been demonstrated in the experimental and practice of buffering a hypercapnic acidosis. Taken clinical setting [91–97]. Bicarbonate infusion exerted together, the above literature suggests that, in the absence deleterious cardiovascular effects in a model of hypoxia- of correcting the primary problem, buffering a hypercap- induced lactic acidosis [93, 94]. The safety of bicarbonate nic acidosis with bicarbonate is not likely to be of benefit. in diabetic patients has also been questioned. Bicarbonate If the clinician elects to buffer a hypercapnic acidosis, the administration slowed the rate of decrease of ketoacids in rationale for this practice should be clear (e.g. to patients with diabetic ketoacidosis [98]. Of even more ameliorate potentially deleterious haemodynamic conse- concern, bicarbonate administration is associated with a quences of acidosis). THAM may have a role in these four-fold increase in risk of cerebral oedema in children clinical situations. with diabetic ketoacidosis [99]. The administration of sodium bicarbonate constitutes a significant osmolar load, which may exert independent Conclusions beneficial effects independent of any associated changes in pH. Osmolar loads, such as hypertonic saline, may The optimal ventilatory strategy, and the role of ‘permis- improve the haemodynamic profile in hemorrhagic shock sive hypercapnia’ in that strategy, is not yet clear. The [100], attenuate key aspects of the immune response protective effect of reducing lung stretch in improving [100–102] and prevent organ injury in experimental outcome in ARDS patients are beyond doubt. There is models [101–103]. In fact, when compared with an growing evidence to support the contention that hyper- equimolar dose of sodium chloride, bicarbonate admin- capnic acidosis may contribute to the benefits seen with istration does not improve the hemodynamic status of protective lung ventilation. While direct induction of a critically ill patients who have lactic acidosis [104]. A hypercapnic acidosis is protective in multiple models of follow-up study in an in vivo model of lactic acidemia acute lung and systemic organ injury, the potential for found that bicarbonate exerted haemodynamic effects hypercapnia to increase peroxynitrite-mediated tissue (mean arterial pressure, cardiac output, left ventricular nitration is of concern and requires further investigation. contractility), which were indistinguishable from those At present, ventilatory strategies that involve hyper- seen in response to an equimolar dose of sodium chloride capnia are clinically acceptable only provided the clini- [105]. These data give cause for concern about the cian is primarily targeting reduced tidal stretch. There are practice of buffering metabolic acidosis, and comparable insufficient clinical data to suggest that hypercapnia per questions may exist in the setting of hypercapnic acidosis. se should be independently induced, outside the context There may be a role for the use of buffers, such as the of a protective ventilatory strategy. Furthermore, the amino alcohol tromethamine (tris-hydroxymethyl amino- recent questioning of the real benefit of low — versus methane, THAM), in specific situations where the moderate — tidal volume ventilation for adults with physiologic effects of hypercapnic acidosis are of con- ARDS may result in hypercapnia becoming less accept- cern. THAM penetrates cells easily and can buffer pH able in the ventilatory management of ARDS. If that changes and simultaneously reduce PCO2 [106]. Unlike becomes the case, then the clinical study of hypercapnia bicarbonate, which requires an open system for CO2 will become less feasible in the setting of permissive elimination in order to exert its buffering effect, THAM hypercapnia, and will require the deliberate induction of is effective in a closed or semi-closed system [106]. hypercapnia (i.e., ‘therapeutic’ hypercapnia). Pre-clinical THAM rapidly restores pH and acid-base regulation in studies are urgently needed to clarify the advantages, acidaemia caused by CO2 retention [106]. A common disadvantages, and optimal use of hypercapnia in ARDS. rationale for buffering is to ameliorate the haemodynamic 354 204

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