Evan's syndrome

Hypercapnic acidosis protects against direct lung injury in in vivo and ex vivo models, however, lung injury/acute respiratory distress syndrome commonly occurs after a nonpulmonary etiology. We investigated whether therapeutic hypercapnia (TH)-deliberate elevation of carbon dioxide (CO2) tension-would protect against lung injury after splanchnic ischemia-reperfusion injury in an in vivo model. TH was associated with preservation of lung mechanics, attenuation of protein leakage, and improved oxygenation compared with control conditions. Lung protection was therapeutic as well as prophylactic. Protection was dose-dependent, but inspired CO2 concentrations above 5.0% were associated with little additional lung protection. Before lung injury, increasing F^sub I^sub CO^sub 2^^^ resulted in a dose-dependent increase in Pa^sub O^sub 2^^. Lung protection with hypercapnia occurred despite pulmonary artery pressures that were greater than observed with normocapnia. Reperfusion increased lipid peroxidation (tissue 8-isoprostane concentration) in the bowel, liver, and lung, and caused histologically apparent bowel injury; however, none of these effects was altered by TH. Therefore, TH-induced by adding CO2 to inspired gas-provides consistent protection against lung injury in terms of lung permeability, oxygenation, and lung mechanics after mesenteric ischemia-reperfusion. These data further support the emerging evidence for ongoing physiologic study of TH at the bedside.

Keywords: carbon dioxide; ischemia; reperfusion; acute lung injury

Acidosis, notably hypercapnic acidosis, is protective against organ injury in multiple experimental models (1-9). In critically ill patients, acidosis is an important marker of illness severity (10), and in contemporary practice, hypercapnia reflects either an inability to lower elevated Pa^sub CO^sub 2^^ because of the severity of lung injury and/or adoption of a strategy that permits elevated Pa^sub CO^sub 2^^ to develop (11-13). The latter approach, termed 'permissive hypercapnia', is designed to reduce stretch-induced lung injury due to mechanical ventilation; it limits injurious lung stretch and tolerates the rising carbon dioxide (CO2) as a passive event (12, 13).

The interactions among pulmonary versus systemic organ systems in acute respiratory distress syndrome (ARDS) is increasingly recognized for several reasons. First, the etiology of ARDS may be primary lung injury (e.g., pneumonia, aspiration, lung repcrfusion), and is termed 'pulmonary' ARDS (14). However, approximately 50% of cases of ARDS result from an injury process occurring in an organ remote from the lung (15, 16), and in such cases of 'nonpulmonary' ARDS, lung injury is one manifestation of a multiple organ dysfunction process. second, the distinctions between pulmonary versus nonpulmonary ARDS extend beyond etiology because the syndromes have distinct radiographie, morphologic (17), and physiologic (14) characteristics. Third, the systemic implications of lung ventilatory strategies are becoming clearer, and protective ventilatory regimens are associated with reduced production of pulmonary (18,19) and systemic (15,19) cytokines, in addition to improved patient survival (15, 16). Finally, the interdependence of the lungs and systemic organs in critical illness is further underscored by the recognition that death in patients with ARDS results from systemic effects and not from hypoxemia per se (20). Thus, therapeutic approaches to ARDS must address-and be effective against-systemic as well as pulmonary effects.

Therapeutic hypercapnia (TH)-deliberate elevation of CO2-is consistent with contemporary 'lung-directed' therapies for ARDS (e.g., surfactant, reduced lung stretch, high frequency oscillation, nitric oxide [NO], liquid ventilation). Deliberate elevation of Pa^sub CO^sub 2^^ is protective against ex vivo and in vivo pulmonary (1-3, 7, 8, 21) myocardial (6) and central nervous system (4) ischemia. Therefore, TH may be especially applicable in ARDS with systemic organ dysfunction because in addition to direct administration through the lungs, CO2 undergoes rapid systemic transportation and quickly equilibrates across all physiologic compartments (22). Because hypercapnia directly increases splanchnic perfusion through vasodilation (23), the potential exists for differential effects on mulliorgan injury.

Lung injury, and multiple organ dysfunction, develops after mesenteric ischemia. In addition, experimental models of mesenteric ischemia represent important surrogates of critical illness because gut mucosal perfusion deficits appear to be instrumental in the propagation of multiple organ failure (24) and reflect adverse prognosis in the critically ill (10).

We report that TH protects against lung injury after experimental superior mesenteric artery ischemia-reperfusion (IR). The protection is therapeutic and prophylactic, with plateau dose-response characteristics. These results may have important implications for CO2 effects in lung injury arising from systemic causes.

METHODS

After Institutional Ethics approval (conforming to the guidelines of the Canadian Committee for Animal Care), adult male Sprague-Dawley Rats (380-420 g) were used in all experiments. Anesthesia was induced, and the model of superior mesenteric artery IR as previously reported was modified and used (25, 26). Stable physiologic conditions were obtained before randomization, and animals were excluded where baseline inclusion (i.e., hemoglobin, acid-base status, oxygenation, compliance, hemodynamic status) criteria were not met. Five experimental series were performed.

Experimental Series I

Experimental series I examined pulmonary protection from TH in terms of compliance and permeability to Evan's Blue. Preparations received control (F^sub I^sub CO^sub 2^^^ 0.00) or TH (F^sub I^sub CO^sub 2^^^ 0.05) and either mesenteric IR (n = 6 per group) or sham (n = 4 per group) procedures.

Experimental Series Il

Experimental series II examined effects of timing in three groups: control (Fict,2 0.00 throughout; n = 4 per group); TH applied 15 minutes before reperfusion (TH^sub pre^; F^sub I^sub CO^sub 2^^^ 0.05) or 15 minutes after reperfusion (TH^sub post^; F^sub I^sub CO^sub 2^^^ 0.05). The duration of ischemia was 40 minutes in experimental series I and II, but because 5% CO2 almost completely inhibited the injury effect, the ischemia duration was increased to 60 minutes in scries III to V to magnify the injury and permit demonstration of interval effects of increases in F^sub I^sub CO^sub 2^^^.

Experimental Series III

Experimental series III examined the role of pulmonary artery pressure (Ppa), and preparations (n = 5 per group) were allocated to control (F^sub I^sub CO^sub 2^^^ 0.00) or hypercapnia (F^sub I^sub CO^sub 2^^^ 0.05) followed by mesenteric IR. Five minutes before rcpcrfusion, median stcrnotomy was performed followed by direct cannulation of the main pulmonary artery, allowing Ppa measurement before, during, and after mesenteric artery reperfusion.

Experimental Series IV

Experimental series IV examined dose-response (n = 4 per group) as follows: F^sub I^sub CO^sub 2^^^ 0.00 (control, CON), 0.025 (TH^sub 2.5^), 0.05 (TH^sub 5^), 0.10 (TH^sub 10^), and 0.20 (TH^sub 20^).

Experimental Series V

Experimental series V examined bowel histology and biochemical mechanisms, and was similar to series I, but with the omission of intravenous Evan's Blue. Preparations received control (F^sub I^sub CO^sub 2^^^ 0.00) or hypercapnia (F^sub I^sub CO^sub 2^^^ 0.05) and either mesenteric IR (n = 6 per group) or sham (n = 5 per group) procedures. An additional nonoperated group (n = 4, anesthetized, then killed) was included in this series (control, nonoperated).

In all experimental series, systemic mean arterial pressure, peak airway pressure, arterial blood gas, and rectal temperature were recorded throughout. Static inflation lung compliance was measured at baseline and at completion of the protocol. After exsanguination under general anesthesia, the pulmonary artery was cannulated, the left atrium incised, and the pulmonary vascular bed flushed with normal saline to remove any sequestered pulmonary intravascular blood (25). The heart-lung block was dissected from the thorax, the left and right lungs isolated, and excised, and three samples of lung tissue of approximately 100 mg were taken from the right lung and snap frozen. In the left lung, permeability was assessed by spectrophotometric assessment of the concentration of Evan's Blue in lung homogenate after formamide extraction. Tissue myeloperoxidase (in triplicate) (27) was measured in the bowel, and 8-isoprostane (in duplicate) (28) was measured in the bowel, liver, and lung. Stress-activated protein kinase (SAPK) and mitogen-activated protein kinase (MAPK) were measured in representative samples of lung tissue. Results were standardized for tissue protein concentration. Analysis of variance, Student-Newman-Keuls, or nonparametric testing were used for statistical analysis. Results are expressed as mean ± SEM. Significance was set at p values less than 0.05.

RESULTS

Experimental Series I: Effects against Acute Lung Injury

A total of 20 animals were entered into the study. All passed baseline criteria, and were randomized to the study. All animals survived the experimental protocol.

Arterial blood gases and acid base. Pa^sub CO^sub 2^^ and systemic pH were comparable in all four groups at baseline (Table 1). Before reperfusion, Pa^sub CO^sub 2^^ was significantly lower (and arterial pH significantly higher) in control-IR versus TH-IR groups (Table 1). This pattern was also seen in the control-sham and TH-sham groups. Furthermore, the pH and P^sub CO^sub 2^^ were comparable prereperfusion in the TH-IR and TH-sham groups as well as in the control-IR and control-sham groups. After reperfusion, pH dropped significantly in both IR groups but was not significantly altered in either of the sham groups (Table 1).

Lung injury. TH protected against lung injury secondary to mesenteric IR, attenuating key indices of acute lung injury, including oxygenation, lung compliance, and lung permeability. Pulmonary microvascular permeability was elevated after IR, and this elevation was attenuated with TH (control-IR > TH-IR [asymptotically =] control-sham [asymptotically =] TH-sham) (Figure 1A). After completion of the experiment, final arterial PO^sub 2^ was significantly less (vs. baseline) only in the control-IR group and not the TH-IR or either of the sham groups (Figure 1B). Peak Airway Pressure (Paw) was comparable in all groups at baseline. The increase in Paw ([Delta]Paw: final-baseline) was significantly greater in control-IR versus all other groups (Figure 1C). Static inflation compliance was comparable in all groups at baseline (Figure 1D), and after completion of the experiment, the impairment in static lung compliance (final-baseline static inflation pressure) was significantly greater in control-IR versus TH-IR (and both sham groups) (Figure 1D).

Experimental Series II: TH-Timing of Application

A total of 20 animals were entered into the study. Eight animals failed to pass baseline criteria and were excluded before randomization. Twelve animals were randomized to the study, and all survived the experimental protocol.

The importance of timing of application in relation to the injury process was demonstrated in experimental series II, in terms of compliance and permeability. The impairment of compliance (static inflation pressure: final-baseline) was less when CO2 was administered either 15 minutes before reperfusion (TH^sub pre^) or 15 minutes after reperfusion (TH^sub post^), compared with when CO2 was not administered (control) (Figure 2A). The effects on permeability paralleled the effects on compliance, with Evan's Blue leakage values of 0.50 ± 0.03,0.85 ± 0.20, and 1.13 ± 0.30 for prereperfusion, postreperfusion, and control, respectively (p

Experimental Series III: Ppa

In all, 12 animals were entered into the study. Two animals failed to pass baseline criteria and were excluded before randomization. Ten animals were randomized to the study. All animals survived the experimental protocol.

The effects of TH on Ppa were measured in series III. Ppa was recorded in TH and control groups, before, and for 5 minutes after reperfusion. The elevation in Ppa that occurred in the TH groups was significantly greater that in the control animals (Figure 2B). This suggests that protection against lung injury from hypercapnic acidosis could not have been mediated via a reduction in pulmonary vascular pressure.

Experimental Series IV: Dose-Response

A total of 26 animals were entered into the study. Six animals failed to pass baseline criteria and were excluded before randomization. Twenty animals were randomized to the study. Sixteen animals survived the experimental protocol. Prereperfusion data were used from all animals, whereas postreperfusion data were obtained only from survivors.

Systemic oxygenation. There was a clear dose-response relationship of FI^sub CO^sub 2^^ versus prereperfusion oxygenation (Pa^sub O^sub 2^^) over the FI^sub CO^sub 2^^ range of 0.00 to 0.20 (Figure 2C), with prereperfusion Pa^sub O^sub 2^^ in each group increased directly with increased FI^sub CO^sub 2^^. This effect of hypercapnia on systemic Pa^sub O^sub 2^^ may result from improved V/Q matching (12, 29) and represents the first such demonstration of dose-response.

Lung injury. TH attenuated key indices of injury, including pulmonary permeability; this protective effect of hypercapnia was dose responsive over the FI^sub CO^sub 2^^ range of 0.00 to 0.10 (Figure 2D). However, the relative magnitude of the response diminished at FI^sub CO^sub 2^^ higher than 0.05, indicating the existence of an 'effect 2 ceiling', with reduced incremental benefits at higher FI^sub CO^sub 2^^. Lung permeability (Figure 2D) was a function of FI^sub CO^sub 2^^ (adjusted R^sup 2^ =0.87; p

Experimental Series V: Histologic and Biochemical Data

A total of 26 animals were entered into the study. Four animals failed to pass baseline criteria, and 22 animals were randomized to the study. All animals survived the experimental protocol.

Bowel injury-histology. The extent of histologie primary small bowel injury following mesenteric artery IR injury was significant in both IR groups (compared with sham-operated animals) as assessed by histology scores (Figure 3A). This was further confirmed by lhe finding that tissue myeloperoxidase levels, an index of tissue neutrophil accumulation, were elevated to a comparable degree in both IR groups (TH-IR 4.7 ± 1.3, control-IR 4.5 ± 0.6 pg·mg^sup -1^ protein) versus the two sham groups (TH-sham 2.0 ± 0.7, control-sham 1.9 ± 0.4 pg-mg^sup -1^ protein) (p

Lipid peroxidation-bowel, liver, and lung. The mechanism of bowel injury involves lipid peroxidation, with 8-isoprostane concentration (Figure 3B) in the bowel tissue comparably elevated in both IR groups. There was no effect of CO2 on either the IR or the sham-operated groups. Hepatic lipid peroxidation (tissue 8-isoprostane levels) was elevated in both IR groups versus sham (Figure 3C). Pulmonary lipid peroxidation was also elevated in both IR groups (Figure 3D). Finally, there were no apparent effects of CO2 on representative lung tissue concentrations of phosphorylated P38 MAP-kinase, SAP, or MAPK/Erkl (Figure 4), which may indicate that protection from lung injury was through MAP-kinase independent pathways.

DISCUSSION

This is the first report of TH (deliberate elevation of inspired CO2) in in vivo nonpulmonary ARDS. It confirms the hypothesis that TH is protective against lung injury in experimental nonpulmonary ARDS. It delineates dose-response characteristics, in addition to demonstrating the therapeutic-as well as prophylactic-potential for TH in such injury. The model has direct clinical relevance, particularly in the context of the critically ill patient, where splanchnic ischemia may play an important pathogenic role. The data support both ex vivo (1, 2, 7) and in vivo (3, 8, 9) data demonstrating the efficacy of TH and extend these findings to a model of secondary acute lung injury in a different species. Finally, these data raise concerns about potential mortality with extremes of dose in this model.

Mechanisms of Lung Injury and Protection

TH protected the lungs and systemic organs from secondary injury. These protective effects of TH were seen in the context of comparable degrees of primary injury to the small bowel after mesenteric IR injury. The mechanisms of acute lung injury in this model have been well characterized and include pulmonary neutrophil recruitment (30), increased inducible pulmonary nitric oxide synthase (25), and oxygen-derived free radical injury (25). Hypercapnic acidosis is known to possess potent anliinflammatory properties of relevance in this context, including attenuation of several key leukocyte processes (e.g., Superoxide formation, phospholipase A2 activity, adhesion molecule expression, sodium ion/hydrogen ion exchange, cytokine release, inhibition of xanthine oxidase) (1, 9, 21, 31, 32). Oxidant-induced organ injury plays a key role in critical illness including ARDS, and attenuation of free radical-induced injury appears central to the protective effect of TH after primary lung injury (3). The data provide additional mechanistic insights by which TH might be protective. First, mesenteric reperfusion was associated with higher Ppa in the TH versus control animals. This indicates that protection against lung injury seen with TH was not mediated via reduction of pulmonary artery reperfusion pressures. second, there were no effects of CO2 on lung tissue concentrations of phosphorylated P38MAP kinase, SAPk/jnk, or MAPK-Erkl, suggesting that protection from lung injury was through MAPKindependenl pathways. TH had no impact on the bowel or liver injury in the current study. In addition, the recently recognized mesenteric vasodilatory effect of hypercapnic acidosis mediated through increased expression of smooth muscle potassiumadenosine triphosphate channels (33) is unlikely to play a role in the current results because of the total nature of the mesenteric ischemia achieved. Thus, TH protected against secondary organ injury in the context of similar degrees of primary bowel injury. Finally, recent suggestions from in vitro experiments suggesting that endothelial protection induced by TH might be via inhibition of nuclear factor kappa-B and reduction of downstream cell adhesion and interleukin-8 expression (31) remain to be explored in the in vivo setting.

Deliberate Hypercapnia-Therapeutic or Prophylactic?

The current data strongly support the hypothesis that elevation of systemic CO2 tension exerts both preventive (when given before reperfusion) and therapeutic (when administered after reperfusion) effects. For oxidant-mediated injury, this is important, because many 'antioxidant' strategies are only effective if present before the injury (34). In the clinical context, the reperfusion event may be identified but not always predicted in a timely manner (e.g., reperfusion after trauma, or resuscitation after cardiac arrest). Alternatively, reperfusion may be occurring but is not clinically detectable (e.g., splanchnic microperfusion deficits). In either situation, the administration of TH may be particularly efficacious. Of course, in clinical situations where a reperfusion is predictable (e.g., intraoperative aortic cross clamp and release) and can be defined, the benefits would be maximal. The details of timing of postreperfusion administration are important. In the current model, the timing was 15 minutes after reperfusion. In terms of relative timing, this constitutes 25% of the total reperfusion time and is quite different from, e.g., application within seconds or 1 to 2 minutes after reperfusion. Therapeutic' versus prophylactic administration both resulted in significant benefit, compared with nonadministration, in the current study, suggesting that relatively late application might be efficacious in other scenarios.

TH-Dose-Response

This study documented the dose-response characteristic for TH in this model. The findings-that the protective effect increased with increasing dose-were as expected, although we did not have a clear a priori idea of optimal testing ranges. Several important phenomena were identified. First, although increasing dose was associated with greater effect, an 'effect ceiling' was apparent, and there appears to be little value in increasing inspired CO2 to values above 5%, which may increase the potential clinical utility-and acceptability-of the technique. Second, although lung permeability appeared to be progressively protected with increasing Fic02, there was one death (in four animals) in animals exposed to 10% inspired CO2, and three deaths (in four animals) in those exposed to 20% inspired CO2. It is important to note that while substantially elevated, these higher doses are associated with Pa^sub CO^sub 2^^ and pH values are within the ranges described in published series of critically ill patients, in whom permissive hypercapnia was associated with a survival advantage (35, 36).

Overall, this pattern of effect is consistent with physiologic expectations, as an upper effective ceiling is expected. The importance of dose-response issues is underscored by findings in other studies. Increasing levels of Pa^sub CO^sub 2^^ were associated with improved-but at higher doses, worsened-neurologic outcome in a neonatal rabbit stroke model (4). In addition, spontaneously breathing rat pups have a greatly increased mortality rate in the context of elevated inspired CO2 (37). Regardless of the actual mechanisms of protection from CO2, most biologic mechanisms demonstrate a point beyond which advantages are outweighed by harmful effects. Although we do know that extreme elevations of CO2 can be tolerated in humans with complete recovery (38), the responses to high levels of CO2 may not be predictable in specific illnesses.

TH and Systemic Oxygenation

In the dose-response series, prereperfusion Pa^sub O^sub 2^^ was positively correlated with FI^sub CO^sub 2^^, confirming, in a dose-response fashion, the ability of TH to increase Pa^sub O^sub 2^^ (29, 39). Systemic oxygénation, reflecting arterial O2 content and Q, is globally increased by elevated Pa^sub CO^sub 2^^ (12, 40).

Relevance of the Experimental Model

The model is highly relevant to the clinical context, given the increasing recognition of the role of extrapulmonary injury in clinical ARDS, both as etiologic factors (16) and as causes of death (20). Selection of IR in the small bowel recognizes the pivotal role of the gut mucosal microcirculation in systemic organ failure. Stimulation of the inflammatory response due to enteric hypoperfusion may cause or further exacerbate organ dysfunction in the critically ill (41). In fact, splanchnic hypoperfusion has been described as a 'motor' of multiple organ dysfunction syndrome, principally due to the potential for endotoxin translocation after ischemic compromise of mucosal barrier integrity. Indeed, endotoxin may play an important in the development of lung injury in bowel IR (42).

Limitations of Current Findings

There are several limitations of the current study that limit immediate extrapolation to the clinical scenario. First, we have not demonstrated whether the in vivo protective effects of TH in this model are a function of the acidosis or hypercapnia per se. However, we have demonstrated previously in our ex vivo lung preparation, that the protection is reflected in part, by the degree of extracellular acidosis (2). Furthermore, buffering hypercapnic acidosis in ex vivo perfused lungs is associated with loss of protection (2). Second, it is possible that significant species variability exists. Caution must therefore be exercised with extrapolation from the current model. Third, the issue of duration is important. This is because the current model -and indeed the vast majority of in vivo experimental laboratory models -uses time courses of injury that are far shorter and more acute than are seen in most clinical scenarios. Although the model is comparable, in timing, to several cardiovascular surgical procedures (e.g., aortic surgery, cardiopulmonary bypass), care must be exercised before extrapolating to other critical care disease contexts. Fourth, the experiments do not differentiate between epithelial versus endothelial leak. However, previous work from our group demonstrated protective effects of TH on endothelial fluid flux (1,2), and Evan's Blue-used in the current study-is an excellent and inert marker of overall alveolar-capillary albumin leak, a key issue in reperfusion acute lung injury (43). Nonetheless, the data in the current manuscript do not include alternative corroboration of the effects on pulmonary edema. Finally, this study has not fully delineated dose-response closer to the 5% CO2 concentration, the dose that appears to offer the best balance between safety and efficacy in this model. These issues need detailed investigation before translation to the clinical context can be considered.

Significance

Our results provide evidence of in vivo lung protection after remote IR injury. These data should further enhance-and guide-the clinical acceptability of testing TH as an option in critically ill patients, if future mechanistic and translational studies confirm benefit.

Conflict of Interest Statement: J.G.L has no declared conflict of interest; R.P.J. has no declared conflict of interest; D.E. has no declared conflict of interest; A.K.T. has no declared conflict of interest; M.P. has no declared conflict of interest; T.L. has no declared conflict of interest; J.B.M. has no declared conflict of interest; A.R. has no declared conflict of interest; D.S. has no declared conflict of interest; C.McK. has no declared conflict of interest; B.P.K. has no declared conflict of interest.

Acknowledgment: The authors are grateful to Jason Liu, Lily Morikawa, Emira Ovcina, and Helena Frndova for technical expertise, and to A. C. Bryan, M.D. for his insightful comments.

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John G. Laffey, Robert P. Jankov, Doreen Engelberts, A. Keith Tanswell, Martin Post, Thomas Lindsay, J. Brendan Mullen, Alex Romaschin, Derek Stephens, Colin McKerlie, and Brian P. Kavanagh

The Lung Biology Programme and the Departments of Critical Care Medicine, Paediatrics and Physiology, The Research Institute, The Hospital for Sick Children; and The University of Toronto, Canada

(Received in original form August 17, 2001; accepted in final form July 24, 2003)

Supported by Physicians Services Inc., and the Canadian Institutes of Health Research. B.P.K. is the recipient of a Premier's Research Excellence Award from the Ontario Ministry of Ministry of Energy, Science and Technology, and of a New Investigator Career award from the Canadian Institutes of Health Research.

Correspondence and requests for reprints should be addressed to Brian P. Kavanagh, M.D., Department of Critical Care Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, MSG 1×8 Canada. E-mail: brian.kavanagh@ sickkids.ca

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Am J Respir Crit Care Med Vol 168. pp 1383-1390, 2003

DOI: 10.1164/rccm.2108078

Internet address: www.atsjournals.org

Copyright American Thoracic Society Dec 1, 2003
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