Controversies involving hypercapnic acidosis in acute respiratory distress syndrome

Nardelli, Liliane; Rocco, Patricia Rieken Macedo; Garcia, Cristiane Sousa Nascimento Baez

doi:10.1590/S0103-507X2009000400011

Abstracts

Acute respiratory distress syndrome is characterized by a diffuse inflammatory reaction of lung parenchyma induced by a direct insult to the alveolar epithelium (pulmonary acute respiratory distress syndrome) or an indirect lesion through the vascular endothelium (extrapulmonary acute respiratory distress syndrome). The main therapeutic strategy for acute respiratory distress syndrome is the ventilatory support. However, mechanical ventilation can worsen lung injury. In this context, a protective ventilatory strategy with low tidal volume has been proposed. The use of low tidal volume reduced the mortality rate of acute respiratory distress syndrome patients, but result in hypercapnic acidosis. The current article presents a review of literature on the effects of permissive hypercapnia in acute respiratory distress syndrome. To that end, we carried out a systematic review of scientific literature based on established criteria for documental analysis including clinical and experimental articles, using as data bases MedLine, LILACS, SciELO, PubMed, Cochrane. Hypercapnic acidosis has been considered by some authors as a modulator of the inflammatory process of acute respiratory distress syndrome. However, clinical and experimental studies on the effects of hypercapnic acidosis have shown controversial results. Therefore it is important to better elucidate the role of hypercapnic acidosis in acute respiratory distress syndrome.

Acute respiratory distress syndrome; Permissive hypercania; Hipercapinic acidosis; Inflammation

A síndrome do desconforto respiratório agudo é caracterizada por uma reação inflamatória difusa do parênquima pulmonar induzida por um insulto direto ao epitélio alveolar (síndrome do desconforto respiratório agudo pulmonar) ou indireto por meio do endotélio vascular (síndrome do desconforto respiratório agudo extrapulmonar). A principal estratégia terapêutica da síndrome do desconforto respiratório agudo é o suporte ventilatório. Entretanto, a ventilação mecânica pode agravar a lesão pulmonar. Nesse contexto, uma estratégia ventilatória protetora com baixo volume corrente foi proposta. Tal estratégia reduziu a taxa de mortalidade dos pacientes com síndrome do desconforto respiratório agudo, porém acarretou acidose hipercápnica. O presente artigo apresenta uma revisão da literatura acerca dos efeitos da acidose hipercápnica na síndrome do desconforto respiratório agudo. Para tal, realizou-se uma revisão sistemática da literatura científica conforme critérios já estabelecidos para análise documental incluindo artigos experimentais e clínicos sobre o tema, usando-se como bases de dados MedLine, LILACS, SciElo, PubMed, Cochrane. A acidose hipercápnica é defendida por alguns autores como moduladora do processo inflamatório da síndrome do desconforto respiratório agudo. Entretanto, estudos clínicos e experimentais acerca dos efeitos da acidose hipercápnica têm demonstrado resultados controversos. Logo, é fundamental a realização de mais pesquisas para elucidar o papel da acidose hipercápnica na síndrome do desconforto respiratório agudo.

Síndrome do desconforto respiratório agudo; Hipercapnia permissiva; Acidose hipercápnica; Inflamação

REVIEW ARTICLE

^IMaster in Science, Laboratory of Pulmonary Investigation Researcher, Carlos Chagas Filho Biophysics Institute (IBCCF), Universidade Federal do Rio de Janeiro (UFRJ) - Rio de Janeiro (RJ), Brazil

^IIPhD, Associate Professor, Universidade Federal do Rio de Janeiro (UFRJ) - Rio de Janeiro (RJ), Brazil

^IIIPost-Doctor, Laboratory of Pulmonary Investigation Researcher, Carlos Chagas Filho Biophysics Institute (IBCCF), Universidade Federal do Rio de Janeiro (UFRJ) - Rio de Janeiro (RJ), Brazil

Author for correspondence

ABSTRACT

Acute respiratory distress syndrome is characterized by a diffuse inflammatory reaction of lung parenchyma induced by a direct insult to the alveolar epithelium (pulmonary acute respiratory distress syndrome) or an indirect lesion through the vascular endothelium (extrapulmonary acute respiratory distress syndrome). The main therapeutic strategy for acute respiratory distress syndrome is the ventilatory support. However, mechanical ventilation can worsen lung injury. In this context, a protective ventilatory strategy with low tidal volume has been proposed. The use of low tidal volume reduced the mortality rate in acute respiratory distress syndrome patients, but result in hypercapnic acidosis. The current article presents a literature review on the effects of permissive hypercapnia in acute respiratory distress syndrome. To that end, we carried out a systematic review of scientific literature based on established criteria for documental analysis including clinical and experimental articles, using as databases MedLine, LILACS, SciELO, PubMed, and Cochrane. Hypercapnic acidosis has been considered by some authors as an inflammatory process modulator in acute respiratory distress syndrome. However, clinical and experimental studies on hypercapnic acidosis effects have shown controversial results. Therefore it is important to better elucidate the role of hypercapnic acidosis in acute respiratory distress syndrome.

Keywords: Acute respiratory distress syndrome; Permissive hypercania; Hipercapinic acidosis; Inflammation

INTRODUCTION

The benefit of ventilating a patient with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) using protective ventilatory strategy is a consensus in the literature^(1,2), because the inappropriate adjustment of ventilator may induce and/or exacerbate pulmonary and systemic inflammation^(3,4) leading to multiple organ dysfunction^(5,6) and contributing to a worse prognosis in ALI/ARDS patients. If on one hand, protective ventilatory strategy with low tidal volume of 6 ml/kg and limited plateau pressure (30-35 cmH₂O) reduces the stress, on the other hand it causes a condition referred to as permissive hypercapnia, with consequent respiratory acidosis.^(1,2)

The effects of hypercapnic acidosis in ALI/ARDS are not completely understood. There are evidences that hypercapnic acidosis may, by itself, reduce lung injury by modulating the inflammatory process.⁽⁷⁾ However, experimental studies have shown controversial results, with some studies showing no improvement⁽⁸⁾ and others presenting worsening of lung injury.⁽⁹⁾ The controversies of the experimental studies may be attributed to: (1) the hypercapnia induction method, either by changing ventilatory parameters⁽⁸⁾ or administration of a carbogenic gas mixture in the inspiratory extremity of the ventilator circuit;^(7,9) and (2) the ALI/ARDS model used. In addition, it is important to emphasize that the human body tolerance to hypercapnic acidosis is so far unknown.

For years, hypercapnic acidosis was treated with sodium bicarbonate, being its use recommended by ADRSNet which describes the importance of buffering acidosis and partial hypercapnia correction for a better ALI/ARDS patients' survival.⁽²⁾ However, the impact of the buffering hypercapnic acidosis with sodium bicarbonate in ALI/ADRS patients' mortality remains to be clarified.

This paper discusses controversies on hypercapnic acidosis as well as the possible therapeutic effects of ALI/ARDS buffering.

The CO₂chemistry

The main ventilation function is to eliminate carbon dioxide (CO₂), the end-product of aerobic cell breath (Figure 1). CO₂ molecules are eliminated by the cell while hydrogen (H⁺) molecules are captured by NAD molecules, which become NADH₂ (hydrogen ions carrier). In some reactions, ADP molecules are phosphorilated generating ATP molecules, in which a relevant portion of cellular energy is stored. The NADH₂ carrier delivers the H⁺ ions to a cytochrome chain at the mitochondrial crest, releasing energy. The H⁺ ions react with oxygen molecules (O₂) to form water (H₂O).

The CO₂ released by the cell into the extracellular environment is transported by blood to the lungs dissolved in the plasma with bicarbonate ions (HCO₃^-) and bound to hemoglobin (carbamino-hemoglobin) and other carbamin compounds. Only a minor portion of cells CO₂ (10%) is transported dissolved in the plasma, while most of it (90%) enters the erythrocytes. Inside the erythrocytes, CO₂ combines with water to form carbonic acid which dissociates into H⁺and HCO₃^-. Unlike plasma, this chemical reaction inside the erythrocyte is catalyzed by carbonic anhydrase (Figure 2).

Usually, alveolar ventilation is adjusted to keep arterial carbon dioxide partial pressure (PaCO₂) around 35-45 mmHg. PaCO₂ changes are detected by central and peripheral chemoreceptors. When the alveolar ventilation is increased (hyperventilation) or decreased (hypoventilation) in relation to CO₂ production, there is a respiratory acid-base imbalance. When the CO₂ elimination is insufficient in relation to its tissue production rate, PaCO₂ increases, as well as the H⁺ and HCO₃^- ions concentration, according to the Henderson-Hasselbalch equation, resulting in respiratory acidosis.⁽¹⁰⁾

Hypercapnia in ALI/ARDS: from the bench to clinical practice

Experimental studies

Experimental studies have reported controversial results regarding hypercapnia effects in ALI/ARDS. Hypercapnia-induced respiratory acidosis may improve, mitigate, and eventually worsen lung injury (Chart 1). Since the results differ according to the model used to induce ALI/ARDS, the exposed data will be initially discussed according to this line.

Hypercapnia in ALI/ARDS induced by ischemia-reperfusion

Some experimental studies on ALI induced by ischemia-reperfusion showed a protective effect of hypercapnic acidosis.^(7,11) However, there are some doubts related to the protective role of hypercapnic acidosis, i.e., if the beneficial effects were related to CO₂ or to the acid pH, as hypercapnic acidosis buffering did not protect the lungs from ischemia-reperfusion induced ALI⁽⁷⁾ Furthermore, these studies were performed ex vivo, thus limiting the understanding of the role of systemic hypercapnic acidosis.

To overcome such limitations, Laffey et al. done in vivo studies using ALI models induced by ischemia-reperfusion.^(12,13) They initially evaluated in rabbits the effects of mechanical ventilation with a N₂ balanced 12% CO₂ and 75% O₂ gas mixture for 90 minutes in a experimental pulmonary ischemia-reperfusion.⁽¹²⁾ They observed an improvement in lung function and a reduction in alveolar-capillary permeability, suggesting a beneficial effect of hypercapnic acidosis. They also evaluated the effects of therapeutic hypercapnia (increase in inhaled CO₂) in an ALI model induced by mesenteric ischemia-reperfusion and showed that pulmonary microvascular permeability, compliance and oxygenation changes were mitigated, but the results were not significant.⁽¹³⁾ Based on these results, we can speculated that mechanical and gas exchange parameters might not be ideal for assessing the effects of CO₂, especially if its action was more at the cellular and molecular levels. Despite this, it should be highlighted that this experimental model is highly relevant for the clinical context since extrapulmonary ALI/ARDS presents high mortality rate.⁽¹⁴⁾ It is important to say that, in none of these in vivo ALI/ARDS models induced by ischemia-reperfusion, hypercapnic acidosis buffering was used in order to separate CO₂and pH effects, thus, determining which parameter is responsible for the protective effect.

Hypercapnia in ALI/ARDS induced by pneumonia (pulmonary ALI/ARDS) and sepsis (extrapulmonary ALI/ARDS)

In a model of ALI induced by intratracheal instillation of E. coli lipopolysaccharide (LPS), hypercapnia induced by inhalation of a high CO₂ concentration-containing gas mixture yielded gas exchange improvement and lung inflammation reduction associated with a decrease in nitric oxide (NO) end-products, nitrite and nitrosothiol in the bronchoalveolar lavage fluid (BALF) and lung tissue.⁽¹⁵⁾ In contrast, in an E. coli LPS ALI model, Lang et al. evidenced that hypercapnia induced by changes in respiratory frequency worsened lung injury, increasing BALF cells and proteins content, and lung wet-to-dry weight ratio.⁽⁹⁾ In addition, NO synthase expression and NO metabolites formation were higher in LPS groups under hypercapnic conditions. Although both studies differ according to animal model and hypercapnia induction method, these data requires careful analysis.

Since 2005 Laffey's group carried out some studies to better understand the mechanisms of hypercapnic acidosis induced by CO₂inhalation in an ALI model induced by E. coli intratracheal instillation^(8,16-18), however their results were also controversial.

Laffey's group also evaluated the influence of antibiotic therapy (100 mg/kg of intravenous ceftriaxone). In contrast to his findings in experimental ALI induced by E. coli LPS⁽¹⁵⁾, when ALI was induced by intratracheal instillation of living bacteria, the severity of lung injury was not modulated by hypercapnic acidosis, neither in the presence nor absence of antibiotics.⁽⁸⁾ These differences could be attributed to the experimental model used. Furthermore, it is important to highlight that the degree of lung injury in the study of O'Croinin et al. may have not been severe enough to allow hypercapnic acidosis effects.

In 2008, the same researchers analyzed the effects of 5% CO₂ inhalation during 48 hours in an ALI model induced by intratracheal instillation of E. coli.⁽¹⁶⁾ They observed that hypercapnic acidosis worsened lung injury and increased bacterial colonies count.⁽¹⁶⁾ Although the interleukin (IL)-1β levels in BALF and the content of macrophages and neutrophils in the lung were similar both in normo- or hypercapnia ALI groups, neutrophil phagocytic function was significantly worsened in the hypercapnic group. The use of antibiotics in the presence of hypercapnia reduced the bacterial colonies count, as well as the infection extension and inflammatory mediators' levels compared to those seen in normocapnic animals. Therefore, prolonged hypercapnic acidosis may be immunosuppressive and worsen the bacterial pneumonia if not treated. This brings up a dilemma for clinicians as, if on one hand the protective ventilatory strategies with tidal volume reduction and permissive hypercapnia are indicated for ALI/ARDS, on the other hand, the benefits that it provides are uncertain. Attention should be paid to the fact that the studies O'Croinin et al.^(8,16) showed that hypercapnic acidosis may compromise the host response to bacterial invasion, allowing a greater bacterial growth and worsening lung injury. However, it is important to say that the duration of therapeutic hypercapnia also needs to be better investigated, in order to be safely used in clinical practice, since longer exposure periods (2 days)⁽¹⁶⁾ led to adverse effects, worsening lung injury and increasing bacterial growth.

Undoubtedly, the studies of Ni Chonghaile et al. have contributed to a better comprehension of the effects of the interaction between the antibiotic and hypercapnic acidosis in ALI/ARDS.^(17,18) Using the same ALI model induced by intratracheal instillation of E. coli, they demonstrated that, without antibiotic therapy, hypercapnic acidosis reduced lung peak pressure and compliance. However, with antibiotic therapy, which substantially reduces the content of bacteria in the lung, hypercapnic acidosis significantly attenuated the extent of histological injury induced pneumonia.⁽¹⁷⁾ This study showed the therapeutic potential of hypercapnic acidosis, since the effects of therapeutic hypercapnia were evaluated after pneumonia be installed (6 hours after intratracheal instillation of E. coli). This is important because in the clinical practice therapeutic intervention occurs only after the lung disease is established.

In fact, neutrophils are fundamental in ALI/ARDS pathogenesis. In this line, recently, Ni Chonghaile et al.⁽¹⁸⁾reported that in the absence of neutrophil depletion, hypercapnic acidosis protected against pneumonia-induced ALI, attenuating the increase in airway pressure and the reduction in lung compliance and arterial oxygen partial pressure (PaO₂), without changing the histological lesion. The lack of some other parameters as mean airway pressure, inspiratory flow, and inspiratory:expiratory times rate has limited the understanding of the functional effects. Furthermore, the use of a 2 cmH₂O PEEP does not appropriately reflects the clinical scenario, because these patients need higher PEEP levels.

The negative findings of Laffey et al. regarding therapeutic hypercapnia in ALI induced by intratracheal instillation of E. coli LPS⁽¹⁵⁾ were contrary to those of Liu et al.⁽¹⁹⁾who submitted rabbits, instead of rats, to mechanical ventilation during 4 hours with moderate hypercapnia (~55-60 mmHg). They observed that lung injury worsens with an increase in reactive nitrogen species and neutrophil content in BALF. Furthermore, hypercapnia also increased in vitro and in vivo neutrophil adhesion associated with a raise in vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin and chemokines. It is important to highlight that these studies^(15,19) differ according to the method to induce hypercapnia, since in the study of Laffey et al.⁽¹⁵⁾ hypercapnia was induced by increasing the CO₂ inspired fraction, and in the Liu et al.⁽¹⁹⁾'s study by the respiratory rate reduction.

Finally, more recently, Costello et al. published a study investigating whether acute hypercapnic acidosis induced by adding CO₂ to the inspired air would protect against the pulmonary and systemic organ lesions induced by severe sepsis induced by cecal ligation and perforation.⁽²⁰⁾ In early sepsis, hypercapnic acidosis, when compared to normocapnia, attenuated the hypotension development and severity, and reduced the lactate accumulation, the central venous oxyhemoglobin levels, neutrophil infiltration and the lung wet-to-dry weight ratio. In prolonged sepsis, hypercapnic acidosis reduced the histological scores of lung injury. Despite the positive findings, hypercapnic acidosis did not change the pulmonary and systemic bacterial load, both in early and late sepsis.

The high relevance of these studies comes, mostly, from the use of in vivo animal models. Each study has its particular relevance, as the findings add and complete each other aiming to complete the hypercapnic acidosis regulating mechanisms puzzle, a still very controversial subject in the literature.

Hypercapnia in ventilator-induced lung injury

Ventilator-induced lung injury (VILI), reviewed by Nardelli et al.⁽²¹⁾ is an important component of ALI/ARDS pathogenesis, and may contribute to the high mortality rate.⁽²²⁾ The protective strategy with low tidal volume and pressure limitation had a positive impact on mortality rate reduction,^(1,2) but it may cause a CO₂ increase leading to a hypercapnic acidosis. Moreover, during mechanical ventilation, airway and alveoli epithelial cells and other lung parenchyma cells as fibroblasts and macrophages, undergo a variety of mechanical forces that activate several cell signaling cascades (revised by Garcia et al.),⁽²³⁾ some of which show pH or PCO₂ dependence. To better understand the role of hypercapnic acidosis in VILI, Broccard et al. evaluated, in isolated rabbit lungs, the effects of two distinct gas mixtures administration: the first with 5% CO₂and the second with 25% CO₂.⁽²⁴⁾ They observed a reduction in the severity of VILI associated with a decrease in BALF protein concentration. In addition, high pressures mechanical ventilation increased the BALF nitric oxide (NOx) end-products contents, which were attenuated by hypercapnia. Although Broccard et al.⁽²⁴⁾'s study is an ex vivo model, the results showed that hypercapnic acidosis has a protective effect in VILI. In vivo studies have corroborated Broccard et al.⁽²⁴⁾'s findings, showing that hypercapnic acidosis is protective in VILI.^(25,26)

In these VILI models, it is also unknown if the hypercapnic acidosis protective effect ^(24-26) is related to either low pH or increased CO₂. In this context, Caples et al. evaluated the effects of buffering hypercapnic acidosis with bicarbonate or tris-hydroxymethyl aminomethane (THAM) in isolated rat lungs under non-protective mechanical ventilation.⁽²⁷⁾ The authors found worsening of repair process under hypercapnia acidosis, confirming the previous findings by Doerr et al.⁽²⁸⁾ Hypercapnic acidosis buffering, both with bicarbonate or TAM, protected against mechanical ventilation-associated pulmonary cell damage, suggesting a pH-dependent protective mechanism.

Hypercapnia effects in the microcirculation

Hypercapnia may affect the local and systemic arterial blood flow distribution, as well as blood oxygenation and tissues oxygen uptake, since respiratory acidosis: 1) right-shifts the hemoglobin dissociation curve, increasing the venous blood partial pressure of oxygen (PvO₂) and, consequently, the O₂ uptake in ischemic tissues, 2) reduces the intrapulmonary shunt by potentiating the hypoxic pulmonary vasoconstriction and directly acting on airways, and 3) increases the cardiac output, further increasing the PvO₂ and venous blood oxygen content (CvO₂).⁽²⁹⁾

Hypercapnia effects on microcirculation appear to be pH-dependent. In this context, Cardenas et al. showed that the changes in the cardiac output, organs blood flow and intracranial pressures during hypercapnia may be attenuated by acidosis correction with sodium bicarbonate, with no adverse hemodynamic effects.⁽³⁰⁾

Additionally, the time of hypercapnia exposure also appears to modulate the effects on the microcirculation, since Kiefer et al. demonstrated that acute PCO₂ changes have no relevant effects on splanchnic perfusion and metabolism.⁽³¹⁾

It is important to better understand the effects of hypercapnia on the microcirculation since microcirculatory disorders may compromise tissues nutrients and oxygen supply, leading to organ failure.

Hypercapnia effects in the diaphragm

Patients with respiratory failure may have hypercapnic acidosis in two main circumstances: short term (acute) or chronic. Hypercapnic acidosis that occurs in acute respiratory failure can be result from any injury to the lung parenchyma (pulmonary edema and massive pulmonary embolism),⁽³²⁾ airway,⁽³³⁾ pleura, chest wall, neuromuscular (spinal cord injury) or central nervous system (drug overdose).⁽³⁴⁾ Chronic hypercapnic acidosis is seen in mechanically ventilated patients with limited plateau pressure and tidal volume ("protective strategy").^(35,36) Although hypercapnia effects on pulmonary function⁽³⁵⁾and hemodynamics⁽³⁰⁾ have being evaluated, few studies evaluated in vivo hypercapnia effects on diaphragm function.^(37,38) It was observed that hypercapnic acidosis caused a reduction in diaphragm strength, however no study evaluated the recovery of diaphragm contractile properties, fundamental for the weaning process. Recently, Jaber et al. evaluated the diaphragm contractility under hypercapnic conditions and after PaCO₂ normalization.⁽³⁹⁾ The authors showed that a short-term exposure to hypercapnic acidosis reduced diaphragm contractility proportionally to the level of hypercapnia, being this change partially reverted 60 minutes after the exposure was discontinued. This is an interesting finding, because it may explain why asthmatic patients or compensated obstructive pulmonary disease did not recover immediately their diaphragm strength after a respiratory failure episode. However, caution should be taken into account to extrapolate these results to a real setting, since the study was only performed on healthy diaphragms.

Clinical trials

Since 2000, the randomized multicenter trial comparing ventilated patients with 12 ml/kg versus 6 ml/kg tidal volume has been the mainstay for successive experimental studies regarding mechanical ventilation in ALI/ARDS.⁽²⁾ Tidal volume reduction induces the increment of PaCO₂ leading to permissive hypercapnia. This hypercapnic acidosis, according to the ARDSNet protocol, was buffered by sodium bicarbonate, suggesting that this buffering was fundamental for these patients improved prognosis. In this context Kregenow et al. performed multiple logistic regression using the ARDSNet trial data, and found that hypercapnic acidosis was associated to reduced mortality in the high tidal volume patients group.⁽⁴⁰⁾ A meta analysis of six trials involving 1297 adult ALI/ARDS patients compared low volume or low airway pressure ventilation versus ventilation with tidal volumes between 10 and 15 ml/kg. The clinical heterogeneity and the differences between follow-up time and the degree of plateau pressures in the two trials make interpreting trial results more difficult. The long term effects on mortality are unknown, however the clinical benefit of hypercapnic acidosis may not be ruled out.⁽⁴¹⁾

Hypercapnia buffering

Several buffers are responsible for maintaining body pH, among them the bicarbonate buffer which is highly relevant not only for buffering H⁺ ions, but also for the components concentration being independently changeable: [CO₂] by respiration, and [HCO₃] by liver and kidneys, being thus called a "open buffer system". CO₂ is a conjugate acid which is membrane permeable and, by diffusion, overcomes the lipid layer; HCO₃^- is a base which moves through membrane only helped by specific transporter proteins.

Some experimental protocol mentioned on this review did not include the hypercapnic acidosis buffering, thus leading to doubt regarding if the protective effects seen were due to the increased CO₂ or the pH drop. There is one single ex vivo study conducted in rabbits, ventilated with 5% CO₂ and 95% O₂, where the authors performed a bicarbonate hypercapnic acidosis buffering. The authors concluded that hypercapnic acidosis entailed beneficial effect, and that buffering attenuated these effects, suggesting that the protective effect is related to the acidosis and not to CO₂.⁽⁷⁾ This finding is very interesting considering pulmonary vascular tonus, since hypercapnia, itself, is a potent vasodilator, while acidosis acts as a pulmonary vasoconstrictor. Hypercapnic acidosis results in pulmonary vasoconstriction, showing that the pulmonary vascular tonus is more sensitive to pH than to CO₂. This may suggest that direct pH and PCO₂ effects are independent. Since it was an ex vivo study⁽⁷⁾ it neglects the hemodynamic changes from systemic circulation limiting the understanding of these data. Therefore, in vivo studies are required.

In a critical patient, acidosis promotes systemic changes, and the main organism defense is constituted by bicarbonate/carbonic acid buffering system (Figure 3). Bicarbonate links to excessive hydrogen producing CO₂ which reaches the lungs to be eliminated; this process would continue until pH is normalized, if not limited by progressive bicarbonate levels reduction. Cavaliere et al. studied the acid-base balance changes and the CO₂ elimination induced by bicarbonate infusion in 10 patients, and found that during bicarbonate infusion the doses used increased the total CO₂ blood contents, while no tissue retention was found, since hemodynamics remained steady as well as the arterial-venous TCO₂ difference.⁽⁴²⁾In the venous blood, bicarbonate infusion increased the CO₂ transportation capacity, probably by the pH increment effect. CO₂ elimination only increased after a given bicarbonate amount was infused.

COMMENTS

Permissive hypercapnia has been tolerated and used in ALI/ARDS. Therefore, it is essential to better understand the effects of hypercapnic acidosis, as well as CO₂ and/or pH levels separately. There is still insufficient knowledge on hypercapnic acidosis benefits on respiratory system and distal organs to allow it to be consolidated in the therapeutic arsenal of ALI/ARDS. Additionally, it is unclear whether hypercapnic acidosis should or not be buffered, and additional studies are necessary to clarify this issue.

ACKNOWLEDGEMENTS

Financial support by Centers of Excellence Program (PRONEX-FAPERJ), Brazilian Council for Scientific and Technological Development (CNPq), Rio de Janeiro State Research Supporting Foundation (FAPERJ), Coordination for the Improvement of Higher Education Personnel (CAPES), and INCT-INOFAR.

REFERENCES

1. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338(6):347-54.
2. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342(18):1301-8.
3. Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest. 1997;99(5):944-52.
4. Ranieri VM, Suter PM, Tortorella C, De Tullio R, Dayer JM, Brienza A, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1999;282(1):54-61.
5. Slutsky AS, Tremblay LN. Multiple system organ failure. Is mechanical ventilation a contributing factor? Am J Respir Crit Care Med. 1998;157(6 Pt 1):1721-5.
6. Ranieri VM, Giunta F, Suter PM, Slutsky AS. Mechanical ventilation as a mediator of multisystem organ failure in acute respiratory distress syndrome. JAMA. 2000;284(1):43-4.
7. Laffey JG, Engelberts D, Kavanagh BP. Buffering hypercapnic acidosis worsens acute lung injury. Am J Respir Crit Care Med. 2000;161(1):141-6.
8. O'Croinin DF, Hopkins NO, Moore MM, Boylan JF, McLoughlin P, Laffey JG. Hypercapnic acidosis does not modulate the severity of bacterial pneumonia-induced lung injury. Crit Care Med. 2005;33(11):2606-12.
9. Lang JD, Figueroa M, Sanders KD, Aslan M, Liu Y, Chumley P, Freeman BA. Hypercapnia via reduced rate and tidal volume contributes to lipopolysaccharide-induced lung injury. Am J Respir Crit Care Med. 2005;171(2):147-57.
10. Kellum JA. Determinants of plasma acid-base balance. Crit Care Clin. 2005;21(2):329-46.
11. Shibata K, Cregg N, Engelberts D, Takeuchi A, Fedorko L, Kavanagh BP. Hypercapnic acidosis may attenuate acute lung injury by inhibition of endogenous xanthine oxidase. Am J Respir Crit Care Med. 1998;158(5 Pt 1):1578-84.
12. Laffey JG, Tanaka M, Engelberts D, Luo X, Yuan S, Tanswell AK, et al. Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion. Am J Respir Crit Care Med. 2000;162(6):2287-94.
13. Laffey JG, Jankov RP, Engelberts D, Tanswell AK, Post M, Lindsay T, et al. Effects of therapeutic hypercapnia on mesenteric ischemia-reperfusion injury. Am J Respir Crit Care Med. 2003;168(11):1383-90.
14. Montgomery AB, Stager MA, Carrico CJ, Hudson LD. Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis. 1985;132(3):485-9.
15. Laffey JG, Honan D, Hopkins N, Hyvelin JM, Boylan JF, McLoughlin P. Hypercapnic acidosis attenuates endotoxin-induced acute lung injury. Am J Respir Crit Care Med. 2004;169(1):46-56.
16. O'Croinin DF, Nichol AD, Hopkins N, Boylan J, O'Brien S, O'Connor C, et al. Sustained hypercapnic acidosis during pulmonary infection increases bacterial load and worsens lung injury. Crit Care Med. 2008;36(7):2128-35.
17. Chonghaile MN, Higgins BD, Costello J, Laffey JG. Hypercapnic acidosis attenuates lung injury induced by established bacterial pneumonia. Anesthesiology. 2008;109(5):837-48. Erratum in: Anesthesiology. 2009 Mar;110(3):689.
18. Ni Chonghaile M, Higgins BD, Costello JF, Laffey JG. Hypercapnic acidosis attenuates severe acute bacterial pneumonia-induced lung injury by a neutrophil-independent mechanism. Crit Care Med. 2008;36(12):3135-44.
19. Liu Y, Chacko BK, Ricksecker A, Shingarev R, Andrews E, Patel RP, Lang JD Jr. Modulatory effects of hypercapnia on in vitro and in vivo pulmonary endothelial-neutrophil adhesive responses during inflammation. Cytokine. 2008;44(1):108-17.
20. Costello J, Higgins B, Contreras M, Chonghaile MN, Hassett P, O'Toole D, Laffey JG. Hypercapnic acidosis attenuates shock and lung injury in early and prolonged systemic sepsis. Crit Care Med. 2009;37(8):2412-20.
21. Nardelli LM, Garcia CSNB, Pássaro CP, Rocco PRM. Entendendo os mecanismos determinantes da lesão pulmonar induzida pela ventilação mecânica: [revisão]. Rev Bras Ter Intensiva. 2007;19(4):469-74.
22. Han B, Lodyga M, Liu M. Ventilator-induced lung injury: role of protein-protein interaction in mechanosensation. Proc Am Thorac Soc. 2005;2(3):181-7.
23. Garcia CS, Prota LF, Morales MM, Romero PV, Zin WA, Rocco PR. Understanding the mechanisms of lung mechanical stress. Braz J Med Biol Res. 2006;39(6):697-706.
24. Broccard AF, Hotchkiss JR, Vannay C, Markert M, Sauty A, Feihl F, Schaller MD. Protective effects of hypercapnic acidosis on ventilator-induced lung injury. Am J Respir Crit Care Med. 2001;164(5):802-6.
25. Sinclair SE, Kregenow DA, Lamm WJ, Starr IR, Chi EY, Hlastala MP. Hypercapnic acidosis is protective in an in vivo model of ventilator-induced lung injury. Am J Respir Crit Care Med. 2002;166(3):403-8.
26. Park CM, Lim SC, Kim YI, Kim KS, Oh IJ, Kim SO, Kim YC. Does hypercapnic acidosis, induced by adding CO2 to inspired gas, have protective effect in a ventilator-induced lung injury? J Korean Med Sci. 2005;20(5):764-9.
27. Caples SM, Rasmussen DL, Lee WY, Wolfert MZ, Hubmayr RD. Impact of buffering hypercapnic acidosis on cell wounding in ventilator-injured rat lungs. Am J Physiol Lung Cell Mol Physiol. 2009;296(1):L140-4.
28. Doerr CH, Gajic O, Berrios JC, Caples S, Abdel M, Lymp JF, Hubmayr RD. Hypercapnic acidosis impairs plasma membrane wound resealing in ventilator-injured lungs. Am J Respir Crit Care Med. 2005;171(12):1371-7.
29. Hickling KG, Joyce C. Permissive hypercapnia in ARDS and its effect on tissue oxygenation. Acta Anaesthesiol Scand Suppl. 1995;107:201-8.
30. Cardenas VJ Jr, Zwischenberger JB, Tao W, Nguyen PD, Schroeder T, Traber LD, et al. Correction of blood pH attenuates changes in hemodynamics and organ blood flow during permissive hypercapnia. Crit Care Med. 1996;24(5):827-34.
31. Kiefer P, Nunes S, Kosonen P, Takala J. Effect of an acute increase in PCO2 on splanchnic perfusion and metabolism. Intensive Care Med. 2001;27(4):775-8.
32. Bouchama A, Curley W, Al-Dossary S, Elguindi A. Refractory hypercapnia complicating massive pulmonary embolism. Am Rev Respir Dis. 1988;138(2):466-8.
33. Mutlu GM, Factor P, Schwartz DE, Sznajder JI. Severe status asthmaticus: management with permissive hypercapnia and inhalation anesthesia. Crit Care Med. 2002;30(2):477-80.
34. Gupta R, Haydock T. Severe hypercapnia caused by acute heroin overdose. Ann Emerg Med. 2004;43(5):665-6.
35. Hickling KG. Permissive hypercapnia. Respir Care Clin N Am. 2002;8(2):155-69, v.
36. Hickling KG, Walsh J, Henderson S, Jackson R. Low mortality rate in adult respiratory distress syndrome using low-volume, pressure-limited ventilation with permissive hypercapnia: a prospective study. Crit Care Med. 1994;22(10):1568-78.
37. Schnader JY, Juan G, Howell S, Fitzgerald R, Roussos C. Arterial CO2 partial pressure affects diaphragmatic function. J Appl Physiol. 1985;58(3):823-9.
38. Yanos J, Wood LD, Davis K, Keamy M 3rd. The effect of respiratory and lactic acidosis on diaphragm function. Am Rev Respir Dis. 1993;147(3):616-9.
39. Jaber S, Jung B, Sebbane M, Ramonatxo M, Capdevila X, Mercier J, Eledjam JJ, Matecki S. Alteration of the piglet diaphragm contractility in vivo and its recovery after acute hypercapnia. Anesthesiology. 2008;108(4):651-8.
40. Kregenow DA, Rubenfeld GD, Hudson LD, Swenson ER. Hypercapnic acidosis and mortality in acute lung injury. Crit Care Med. 2006;34(1):1-7.
41. Petrucci N, Iacovelli W. Lung protective ventilation strategy for the acute respiratory distress syndrome. Cochrane Database Syst Rev. 2007;(3):CD003844. Review.
42. Cavaliere F, Pennisi MA, Mura LA, Proietti R. Variazione dell'equilibrio acido-base e dell'eliminazione di CO₂ indotte dall'infusione di bicarbonato. Minerva Anestesiol. 2000;66(9):627-33.