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Published ahead of print on October 18, 2007, doi:10.1164/rccm.200706-906OC
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American Journal of Respiratory and Critical Care Medicine Vol 177. pp. 178-183, (2008)
© 2008 American Thoracic Society
doi: 10.1164/rccm.200706-906OC

Original Article

Acute Hypercapnia Improves Indices of Tissue Oxygenation More than Dobutamine in Septic Shock

Zhen Wang1, Fuhong Su1, Alejandro Bruhn2, Xin Yang3 and Jean-Louis Vincent1

1 Department of Intensive Care, Erasme Hospital, Free University of Brussels, Brussels, Belgium; 2 Department of Intensive Care, Faculty of Medicine, Hospital Clinico, Universidad Catolica of Chile, Santiago, Chile; and 3 Institute of Interdisciplinary Research, Erasme University Hospital, Free University of Brussels, Brussels, Belgium

Correspondence and requests for reprints should be addressed to Dr. Jean-Louis Vincent, M.D., Ph.D., Department of Intensive Care, Erasme Hospital, Route de Lennik 808, 1070-B Brussels, Belgium. E-mail: jlvincen{at}ulb.ac.be


   ABSTRACT
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 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Hypercapnia has similar hemodynamic effects to those of a dobutamine infusion and may have relevance in the management of septic shock.

Objectives: To compare the effects induced by hypercapnia with those of dobutamine in a clinically relevant model of septic shock.

Methods: Fecal peritonitis was induced in 21 anesthetized, invasively monitored, mechanically ventilated female sheep. A combination of Ringer's lactate and 6% hydroxyethyl starch solution was titrated to maintain constant cardiac filling throughout the experiments. Two hours after feces spillage, animals were randomized to one of three groups (each, n = 7): (1) hypercapnia: carbon dioxide given to maintain partial pressure of carbon dioxide between 55 and 65 mm Hg throughout the experiment; (2) dobutamine: dobutamine infused intravenously (7 µg/kg/min); (3) control: no treatment. In the dobutamine and control groups, the partial pressure of carbon dioxide was kept between 35 and 45 mm Hg. All animals were monitored until spontaneous death.

Measurements and Main Results: The animals in the hypercapnia group had significantly lower arterial pH than the other two groups (P < 0.05). Hypercapnic and dobutamine-treated animals developed significantly higher heart rate, cardiac index, and oxygen delivery, and lower lactate concentrations than control animals (P < 0.05). Hypercapnic animals had lower post mortem lung wet/dry ratio than the control animals (P < 0.05). The alveolar–arterial oxygen partial pressure difference and shunt fraction were significantly lower in hypercapnic animals than in the other groups (P < 0.05).

Conclusions: In this clinically relevant ovine model of septic shock, hypercapnia had similar effects to dobutamine on hemodynamic variables and lactic acidosis. Hypercapnia improved tissue oxygenation and reduced lung edema formation more than dobutamine administration.

Key Words: hypercapnic acidosis • sepsis • organ failure • hyperlactatemia



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
Hypercapnia may occur as a result of protective ventilation strategies in patients with respiratory failure, and can have beneficial effects on hemodynamics and outcome.

What This Study Adds to the Field
This study suggests that therapeutic hypercapnia is a safe and promising intervention in septic shock. Hypercapnia improved tissue oxygenation and reduced lung edema formation more than dobutamine administration.

 
Hypercapnia is commonly accepted as a consequence of protective ventilation strategies, in which tidal volume is reduced to minimize the excessive lung stretch in patients with acute lung injury (hence the term "permissive hypercapnia"). Unlike severe and uncompensated hypercapnia, which can be associated with harmful events, such as the development of pulmonary hypertension, elevation of intracranial pressure (1), impairment of myocardial contractility in vitro (2), and prolonged muscular weakness (3), permissive hypercapnia is usually moderate and relatively well tolerated, and may be associated with an independent survival benefit (4). Hypercapnia and respiratory acidosis have been shown to have beneficial effects in diverse pathophysiologic settings, including ischemia reperfusion (5, 6), ventilator-induced lung injury (7, 8), and sepsis (9). Hypercapnia can exert multiple beneficial effects at the systemic, cellular, and molecular levels that may improve ventilation perfusion matching in the injured lungs (10, 11), attenuate cytokine release and free radical production (12), and suppress lactic acidosis (13). Therefore, one may speculate that acute hypercapnia, whether induced by CO2 retention after a reduction in minute ventilation or by adding CO2 to the inspired gas, may be beneficial.

Acute cardiovascular responses to hypercapnia have been well studied in physiologic and pathophysiologic conditions. Hypercapnia has direct inhibitory effects on myocardial contractility in normal and failing hearts (14–16), but these direct effects are counteracted by neuroadrenal stimulation (17, 18), so that the overall effects of hypercapnic acidosis are characterized as increased heart rate and cardiac output, increased pulmonary and decreased systemic vascular tone, and possible venoconstriction (14, 19–21). On the basis of these findings, one may suppose that the acute cardiovascular effects of hypercapnia would be quite similar to those induced by dobutamine, a predominantly β-adrenergic agent. This may be particularly relevant in the presence of hemodynamic instability associated with respiratory failure. However, no study has really addressed this issue.

In a clinically relevant model of septic shock, we investigated the pulmonary and systemic effects of hypercapnia and compared them with those of dobutamine. We selected a large animal model to facilitate vascular catheterization and, therefore, hemodynamic measurements; blood sampling is also more convenient and reliable in such animals. We chose to add CO2 to the inspiratory gas mixture to induce arterial hypercapnia to avoid the additional effects of a change in ventilatory settings. Thus, the effects of hypercapnia could be separated from those of protective ventilation strategies. Some of the results of these studies have been previously reported in the form of an abstract (22).


   METHODS
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 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Complete methodologic details regarding animal preparation, anesthesia, surgical procedure, and measurements are available in the online supplement.

Animal Preparation
The study conformed to the guidelines of animal management established by the animal care committee of the Free University of Brussels. Twenty-one female sheep were fasted for 24 hours before the experiments, with free access to water. The animals were weighed before the experiments and then placed in the supine position. Anesthesia was obtained using midazolam, ketamine hydrochloride, morphine, and rocuronium bromide. The sheep were then intubated endotracheally and mechanically ventilated.

Surgical Procedure
A midline laparotomy was performed and a 1-cm incision made on the surface of the ascending cecum; 1.5 g/kg body weight of feces was collected. The incision was then sutured gently and the surrounding area disinfected with iodine. A plastic tube with a large diameter was placed in the abdominal cavity for later feces injection. A combination of 1 ml/kg/hour hydroxyethyl starch solution and 1 ml/kg/hour Ringer's lactate was infused during the surgical procedure.

Experimental Protocol
After the surgical procedure, the sheep were returned to the prone position and stabilized for a short period to ensure that heart rate, cardiac output, and intravascular pressures remained stable. Feces (1.5 g/kg) were then injected into the abdominal cavity through the drainage tube to induce bacterial peritonitis and the animals were randomized to one of three groups: hypercapnia, dobutamine, and control. In the hypercapnia group, PaCO2 was increased to a level between 55 and 65 mm Hg by adding CO2 at various concentrations from 2 hours after the induction of peritonitis until the end of the experiment. After the desired PaCO2 was reached, the FICO2 was unchanged for the rest of the experiment. In the dobutamine group, dobutamine was administered at a fixed dose of 7 µg/kg/minute from 2 hours after the induction of peritonitis until the end of the experiment. In the dobutamine group and the control group, PaCO2 was maintained between 35 and 45 mm Hg throughout the experiment. In all three groups, PaCO2 was maintained in the desired range by altering the respiratory rate. No antibiotics or antipyretic agents were administered during the experiments.

Monitoring and Measurements
Hemodynamic and respiratory variables were recorded at baseline and for hourly intervals until the end of the experiment. Blood gases were measured instantly with an automated analyzer. Hemoglobin concentration and oxygen saturation were measured with an analyzer adapted for ruminant animals. Inspired CO2 concentrations were continuously recorded with a CO2 analyzer placed at the proximal end of the endotracheal tube. IL-6 levels were measured in the control and hypercapnic groups. All the animals were observed until death. An isolated central lobe in the right lung was excised at the end of the experiments, and the wet/dry weight ratio was determined after sequential weights demonstrated maximal dehydration in a drying oven.

Statistical Analysis
Statistical analyses were performed using JMP 5.0.1 statistical software (SAS Institute, Inc., Cary, NC). A Kolmogorov-Smirnov test was used to verify the normality of distribution of continuous variables. Baseline parameters, survival time, and wet/dry ratio were compared using analysis of variance (with subsequent pairwise comparisons using Student's t test). The analysis of repeated measurements with a mixed-model, followed by a modified, t test with Bonferroni correction was used to evaluate the difference in the evolution of the physiologic variables over time among groups. Survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. Statistical tests were two-tailed and a P value less than 0.05 was considered statistically significant. Data are expressed as mean ± SD.


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Baseline Data
There were no significant differences in baseline body weight, vital signs, or other physiologic variables among the groups (Table 1).


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  		TABLE 1. PHYSIOLOGIC VARIABLES IN THE THREE GROUPS AT BASELINE

 
The mean FICO2 was 4.2% in the hypercapnic group. PaCO2 was significantly higher and arterial pH significantly lower in the hypercapnia group than in the other groups (Figure 1). Animals in the hypercapnia and dobutamine groups had higher heart rates and cardiac outputs than the control group (P < 0.05). Tachycardia was more pronounced in the dobutamine group than in the hypercapnia group (P < 0.05) (Figure 2). There were no significant differences in arterial pressure, pulmonary artery pressure, systemic and pulmonary vascular resistance, or left ventricular stroke work at any time points among the three groups (Figure E1 of the online supplement).


Figure 1
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  		Figure 1. Changes in arterial partial pressure of carbon dioxide (PaCO2) and pH over time in normocapnic animals (control, solid circles), normocapnic animals treated with dobutamine at 7 µg/kg/hour (dobutamine, open diamonds), and hypercapnic animals (hypercapnia, open squares). *P < 0.05 hypercapnia versus control; #P < 0.05 hypercapnia versus dobutamine. The numbers above the abscissa indicate the numbers of surviving animals at the corresponding time point. Data are truncated at 18 hours due to the small number of animals after this time point.

 

Figure 2
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  		Figure 2. Changes in cardiac index and heart rate over time in the normocapnic animals (control, solid circles), normocapnic animals treated with dobutamine at 7 µg/kg/hour (dobutamine, open diamonds), and hypercapnic animals (hypercapnia, open squares). *P < 0.05 hypercapnia versus control; #P < 0.05 hypercapnia versus dobutamine; $P < 0.05 dobutamine versus control. The numbers above the abscissa indicate the numbers of surviving animals at the corresponding time point. Data are truncated at 18 hours due to the small number of animals after this time point.

 
PaO2/FIO2 was higher in the hypercapnic group than in the control group (P < 0.05); the alveolar–arterial oxygen partial pressure difference (PAO2 – PaO2) and the venous admixture (Formula) were lower in the hypercapnic group than in the other two groups (P < 0.05) (Figure 3). However, the changes in airway pressure, respiratory system compliance, and resistance were similar in all groups (Figure E2). There were no differences in core temperature among groups (Figure E3). There were no differences in fluid infusion rates over time among groups, but post mortem lung wet/dry ratio was lower in the hypercapnia group than in the control group (Figure E4).


Figure 3
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  		Figure 3. Changes in PaO2/FIO2, alveolar-to-arterial oxygen tension (PA-aO2), and shunt fraction (Formula) over time in normocapnic animals (control, solid circles), normocapnic animals treated with dobutamine at 7 µg/kg/hour (dobutamine, open diamonds), and hypercapnic animals (hypercapnia, open squares). *P < 0.05 hypercapnia versus control; #P < 0.05 hypercapnia versus dobutamine. The numbers above the abscissa indicate the numbers of surviving animals at the corresponding time point. Data are truncated at 18 hours due to the small number of animals after this time point.

 
The PvO2 was significantly higher in the hypercapnic than in the other two groups (P < 0.05); there was no difference in the SvO2 among groups (Figure 4). The arterial lactate concentration was significantly lower in the hypercapnia and dobutamine groups than in the control group (P < 0.05). Arterial IL-6 levels were lower in the hypercapnic than in the control group (P < 0.05) (Figure 5).


Figure 4
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  		Figure 4. Changes in mixed venous oxygen tension (PO2) and oxygen saturation (SO2) over time in the normocapnic animals (control, solid circles), normocapnic animals treated with dobutamine at 7 µg/kg/hours (dobutamine, open diamonds), and hypercapnic animals (hypercapnia, open squares). *P < 0.05 hypercapnia versus control; #P < 0.05 hypercapnia versus dobutamine. The numbers above the abscissa indicate the numbers of surviving animals at the corresponding time point. Data are truncated at 18 hours due to the small number of animals after this time point.

 

Figure 5
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  		Figure 5. Upper panel: Changes in arterial lactate concentration over time in the normocapnic animals (control, solid circles), normocapnic animals treated with dobutamine at 7 µg/kg/hour (dobutamine, open diamonds), and hypercapnic animals (hypercapnia, open squares). Lower panel: Changes in serum IL-6 levels (presented as the optical density value at 450 nm) over time in the normocapnic animals (control, solid circles) and hypercapnic animals (hypercapnia, open squares). *P < 0.05 hypercapnia versus control; $P < 0.05 dobutamine versus control. The numbers above the abscissa indicate the numbers of surviving animals at the corresponding time point. Data are truncated at 18 hours due to the small number of animals after this time point.

 
There was no significant difference in survival time among the three groups (19.2 ± 2.2 h in the hypercapnic group vs. 18.1 ± 3.1 h in the dobutamine group vs.18.0 ± 2.3 h in the control group, P = 0.36; Figure E5).


   DISCUSSION
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 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
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 DISCUSSION
REFERENCES
 
Our study is the first to investigate the independent effects of acute hypercapnia in experimental septic shock. Because hypercapnia is known to cause neuroadrenal stimulation and vasodilatation, we can expect that these effects would be comparable to those of dobutamine, a commonly used inotropic agent with predominant β1-receptor agonist properties. Indeed, in this acute model of septic shock, hypercapnia induced hemodynamic responses similar to dobutamine, and improved systemic oxygen delivery and suppressed hyperlactatemia, even though these potentially beneficial effects did not translate into a prolonged survival time. Given that all groups were ventilated with the same tidal volume and positive end-expiratory pressure, this limits any potential influence of lung stretch or atelectasis as viable explanations for the observed differences. We kept FICO2 around 4.2% to obtain the desired PaCO2 in the range of 55 to 65 mm Hg.

Hemodynamic Effects
Both hypercapnia and dobutamine induced similar elevations in cardiac output and heart rate. Unlike the inotropic action exerted by a β-receptor agonist, the direct effect of hypercapnia on the heart is to reduce contractility (14–16). However, this effect can be negated by a combination of several mechanisms: First, hypercapnia can initiate a sympathetically mediated release of catecholamines due to neuroadrenal stimulation (14, 23, 24); second, hypercapnic acidosis induces ATP-sensitive K+ channel–mediated vasodilation (25); third, preload may be increased via venoconstriction in acidemia (14, 17). Therefore, cardiac output may increase as a result of increased preload, decreased afterload, and increased contractility. Although some studies have suggested that acidosis rather than increased CO2 concentration may have the predominant beneficial role (14, 15, 26), the evidence indicates that respiratory acidosis is associated with more beneficial effects than a similar degree of metabolic acidosis (27, 28). In our study, systemic vascular resistance decreased more rapidly in the two treatment groups than in the control group, but also decreased late in the control group because decreased vascular tone is one important characteristic of our model of fluid-resuscitated septic shock. Although acute hypercapnic acidosis can increase pulmonary vascular tone by vasoconstriction (6, 15), we did not observe this effect, probably because the hypercapnia was only moderate. Two recent studies (19, 29) showed that hypercapnic acidosis may have beneficial effects on pulmonary hypertension and vascular remodeling induced by chronic hypoxia via antioxidant properties and consequent decreased generation of oxidant-induced pulmonary vasoconstrictors, such as peroxynitrite and endothelin-1. Whether or not these protective mechanisms can develop more acutely could not be explored in this study.

Gas Exchange and Oxygenation
Hypercapnic acidosis obtained by adding CO2 to the inspired gases can have advantages over a reduction in tidal volume, because it can cause a more homogenous hypercapnia and acidotic environment in the lung alveoli (30). Lower tidal volumes may impair gas exchange and increase intrapulmonary shunt in critically ill patients (31, 32). In contrast, inspiring CO2 may improve ventilation/perfusion matching and arterial oxygenation (10, 11, 33, 34) in normal or injured lungs. The lower alveolar-to-arterial oxygen gradient and venous admixture in our study reflect an improvement in ventilation/perfusion matching and less lung edema formation. Our findings differ from those by O'Croinin and colleagues, in which hypercapnia did not reduce the magnitude of the lung injury induced by intratracheal instillation of Escherichia coli (35). It is possible that, in their study, the shorter observation period, the high severity of lung injury induced, and the lack of fluid resuscitation may have limited the beneficial effects of hypercapnia from occurring or being observed. Indeed, hypercapnic acidosis has been demonstrated to enhance hypoxic pulmonary vasoconstriction (17) and to decrease regional pulmonary blood flow heterogeneity (36). Although hypercapnia in our experiments did not influence lung compliance or airway pressure globally, we cannot rule out the possibility that CO2 could have more local bronchodilating effects (37, 38) on dependent areas with altered ventilation/perfusion matching and regional bronchoconstriction.

Another interesting finding was the higher PvO2 but not SvO2 in the hypercapnia group than in the other two groups, probably related to a facilitated release of oxygen in the acidotic environment (Bohr effect), and decreased oxygen demands of the tissues in the acidotic environment. By suppressing hypoxic pulmonary vasoconstriction, an increased PvO2 associated with a high cardiac output can increase the shunt fraction and impair oxygen exchange (32), but dobutamine administration induced similar effects.

In addition to these effects on the lung, some studies (21, 39) have reported that hypercapnia may improve cerebral blood flow and tissue oxygenation. Thus, hypercapnia may be beneficial to the central nervous system in the absence of intracranial hypertension.

Antiinflammatory and Antioxidant Effects
In this study, serum IL-6 concentrations were significantly lower in the hypercapnic animals than the control animals, suggesting an antiinflammatory effect of hypercapnic acidosis. Hypercapnia has been shown to have antiinflammatory effects on the lung (5, 7), the myocardium (40), and other tissues (41) in a context of acute inflammation. Indeed, acidosis can block the activation of nuclear factor (NF)-{kappa}B, by decreasing the phosphorylation and degradation of the inhibitor of NF-{kappa}B (I{kappa}-B) (12). Hypercapnia can attenuate the release of tumor necrosis factor-{alpha} (42) and IL-8 (12) by alveolar macrophages, decrease lung neutrophil infiltration (9), and blunt the expression of intercellular adhesion molecule-1 (12, 43).

Hypercapnia may also attenuate oxidant-induced injury (13) and lipid peroxidation (44). In this regard, CO2 may have some advantage over other antioxidants because of its amphiphilic characteristics. CO2 can rapidly diffuse through all physiologic compartments and permeate into the cells, in which it suppresses the enzymes involved in the generation of free radicals (17). Hence, the antiinflammatory properties of hypercapnic acidosis may have contributed to the reduction in lung edema.

The Effect on Hyperlactatemia
In this study, acute hypercapnia, like dobutamine administration, resulted in lower blood lactate concentrations in the hypercapnia group compared with the control group. Dobutamine administration in septic shock has been found to decrease lactate levels by improving cellular oxygen delivery and facilitating the removal of lactate accumulated in the tissues, including the splanchnic region (45, 46). Furthermore, the lower pH can facilitate oxygen unloading from hemoglobin and thus contribute to reduce cellular hypoxia (47). In addition to the hemodynamic effects, acidosis can decrease cellular lactate production by a decrease in cell metabolism through the inhibition of the glycolytic enzyme phosphofructokinase and an increase in its intracellular uptake by muscle and liver (48).

Limitations
Our study has several limitations. First, we compared only one dose of dobutamine and one level of hypercapnia at a fixed FICO2, so that dose–effect relationships for either dobutamine or CO2 were not established. Hypercapnia with a PaCO2 of around 60 mm Hg seemed clinically relevant, and a FICO2 of 4.1% seems reasonable. Indeed, an FICO2 above 5% may have less beneficial and possibly harmful effects (6, 49, 50). Second, the significant difference in arterial pH between hypercapnic animals and the others could not be maintained throughout the experiments, because metabolic acidosis develops in the late stages of this model, and this may have biased the results. Finally, as the major objective of the study was to distinguish the effects of hypercapnia from other potentially confounding factors, such as antibiotic or vasopressor treatment, therapeutic interventions that would be used clinically were not included in our model.

Conclusions
In summary, this study provides evidence of a potentially beneficial effect of hypercapnia in a clinically relevant model of septic shock due to peritonitis. We show that acute hypercapnia can induce similar hemodynamic effects to the inotropic agent dobutamine and may even have superior effects to dobutamine. These observations are reassuring in terms of the effects of permissive hypercapnia in septic shock and further suggest that acute hypercapnia may be a safe and promising intervention in these conditions.


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

Originally Published in Press as DOI: 10.1164/rccm.200706-906OC on October 18, 2007

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form June 21, 2007; accepted in final form October 17, 2007


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 ABSTRACT
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 METHODS
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 DISCUSSION
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