Permissive hypercapnia (acceptance of raised concentrations of carbon dioxide in mechanically ventilated patients) may be associated with increased survival as a result of less ventilator-associated lung injury. Conversely, hypocapnia is associated with many acute illnesses (eg, asthma, systemic inflammatory response syndrome, pulmonary oedema), and is thought to reflect underlying hyperventilation. Accumulating clinical and basic scientific evidence points to an active role for carbon dioxide in organ injury, in which raised concentrations of carbon dioxide are protective, and low concentrations are injurious. We hypothesise that therapeutic hypercapnia might be tested in severely ill patients to see whether supplemental carbon dioxide could reduce the adverse effects of hypocapnia and promote the beneficial effects of hypercapnia. Such an approach could also expand our understanding of the pathogenesis of disorders in which hypocapnia is a constitutive element.

The possibility that systemic carbon dioxide tension may have a role in protection against organ injury has not been considered in the clinical context. Although hypercapnic acidosis may indicate tissue dysoxia and predict adverse outcome, it is not necessarily harmful per se. In fact, it may be beneficial. There is increasing evidence that respiratory (and metabolic) acidosis can exert protective effects on tissue injury, and furthermore, that hypocapnia may be deleterious. We discuss current insights into the effects of carbon dioxide on organ injury, and propose an integrated concept of the mechanism of action of carbon dioxide in acute disease processes. We draw on this evidence to propose the concept of "therapeutic hypercapnia"--ie, the prevention of hypocapnia, and the induction of hypercapnia--whereby increased partial pressure of carbon dioxide in arterial blood (PaCO2) might be a goal of therapy in critical illness, rather than something to be avoided.

Lung injury and "permissive" hypercapnia

One of the most important concepts in the care of critically ill patients is the recognition that mechanical ventilation--the supportive therapy commonly used in respiratory failure--can worsen, or even cause, lung injury, by repetitive over-stretching of lung tissue.(1) If hypoventilation is allowed in an effort to limit lung stretch, carbon dioxide tension increases. Such "permissive hypercapnia" may be associated with increased survival in acute respiratory distress syndrome (ARDS);(2) this association is supported by outcome data from a 10-year study.(3) Although explanations for this apparent decline in mortality remain speculative, recognition of the potential impact of ventilator-induced lung injury has led to the suggestion that the adoption of "protective" ventilatory strategies may have been a factor. However, attribution of any improvements solely to the emergence of new ventilatory strategies may be premature. Death in ARDS results largely from multisystem organ failure, not hypoxia.(4) Furthermore, improved survival may be attributable to non-ventilatory issues, such as improvements in resuscitation, fluid management, sepsis diagnosis or treatment, supportive measures for organ dysfunction, nutritional support, staff training, or other unidentifiable clinical factors.

Nevertheless, permissive hypercapnia resulting from protective ventilatory strategies,(5) has been identified as an important technique in the management of patients with ARDS.(1) Such an approach assumes that the hypercapnic acidosis generated reflects the underlying protective hypoventilatory strategy rather than having any direct therapeutic role per se. The possibility that hypercapnic acidosis may exert clinically important organ protection has received little attention.

Targeting of normal PaCO2

Arbitrary targeting of physiological norms has traditionally been used as the optimum goal in the management of patients. However, the reason for applying this approach does not seem to be based on outcome. In fact, targeting of normal oxygen partial pressure in neonates may have contributed to retinopathy of prematurity and bronchopulmonary dysplasia;(6) targeting of normal packed-cell volume in critically ill adults may worsen mortality,(7) and targeting of normal blood pressure in acute trauma is associated with lower survival.(8) Therefore, empirical targeting of normal values, although intuitively appealing, may not always be the best approach. There are also good reasons why targeting of normal (or lower than normal) values for PaCO2 in critically ill patients may be harmful.

Role of hypocapnia in disease

Acute injury can be caused by hyperventilation; hyperventilation causes hypocapnic alkalosis; and hyperventilation and hypocapnic alkalosis frequently coexist in lung (or other organ) injury. Although separation of these entities is difficult, the association of hyperventilation, hypocapnia, and worsened lung injury is well documented.(9) In fact, hypocapnia and hyperventilation may be independent causes of bronchopulmonary dysplasia.(9) Possible mechanistic insights into the direct effect of hypocapnia are provided by studies showing that hypocapnia increases microvascular permeability in tracheal mucosa,(10) decreases lung compliance,(11) and increases dysfunctional surfactant production.(12) Furthermore, hypocapnia shifts the oxyhaemoglobin dissociation curve leftwards, restricting oxygen off-loading at the tissue level; local oxygen delivery may be further impaired by hypocapnia-induced vasoconstriction.

In non-pulmonary organs, the differentiation between the effect of altered ventilation and that of altered PaCO2 is more clear-cut. For example, prophylactic hyperventilation to produce hypocapnia in acute head injury (a traditional therapy) is associated with a worsened neurological outcome.(13) In addition, hypocapnia before neonatal-extracorporeal-membrane oxygenation increases sensorineural hearing loss in children.(14) Hypocapnia is also a pathogenetic factor in pontosubicular necrosis,(15) a pattern of acute brain injury seen in infants with perinatal anoxia. Experimentally, ischaemic stroke in animals is worse in the presence of hypocapnia.(16) Long-term neurological sequelae from exposure to extreme altitude are associated not with exposure to a low oxygen concentration, but rather with the generation of extremely low PaCO2.(17)

Effects of acidosis

In the myocardium, intracellular acidosis is more rapidly increased when the extracellular acidosis is due to hypercapnia as opposed to a metabolic source;(18)raised PCO2 results in rapid inward diffusion of highly soluble carbon dioxide molecules, and lowering of the intracellular pH through subsequent dissociation into H+ and HCO3- ions. This decrease in pH occurs more rapidly than is possible by inward equilibration of the H+ ions associated with metabolic acidosis. Decreases in myocardial contractility, and thereby oxygen consumption, are far more sensitive to increases in extracellular PCO2 than to increases in H+.(18)

Brain homogenates develop far fewer free radicals and less lipid peroxidation when pH is lowered by carbon dioxide than when it is lowered by hydrochloric acid.(19)

Finally, greater inhibition of tissue lactate production occurs when lowered pH is due to carbon dioxide than when it is due to hydrochloric acid.(20)

Protective mechanisms in hypercapnia and acidosis

An association between hypoventilation, hypercapnia, and improved outcome has been established in human beings.(2,5,21) In lambs, ischaemic myocardium recovers better in the presence of hypercapnic acidosis than metabolic acidosis.(22) Hypercapnic acidosis has also been shown to protect ferret hearts against ischaemia,(23) rat brain against ischaemic stroke,(16) and rabbit lung against ischaemia-reperfusion injury.(24) Hypercapnia attenuates oxygen-induced retinal vascularisation,(25) and improves retinal cellular oxygenation in rats.(26) "pH-stat" management of blood gases during cardiopulmonary bypass, involving administration of large amounts of additional carbon dioxide for maintenance of temperature-corrected PaCO2, results in better neurological and cardiac outcome.(27)

Oxygenation

Hypercapnia results in a complex interaction between altered cardiac output, hypoxic pulmonary vasoconstriction, and intrapulmonary shunt, with a net increase in PaO2 (figure).(28) Because hypercapnia increases cardiac output, oxygen delivery is increased throughout the body.(28) Regional, including mesenteric, blood flow is also increased,(29) thereby increasing oxygen delivery to organs. Because hypercapnia (and acidosis) shifts the haemoglobin-oxygen dissociation curve rightwards, and may increase packed-cell volume,(30) oxygen delivery to tissues is further increased. Acidosis may reduce cellular respiration and oxygen consumption,(31) which may further benefit an imbalance between supply and demand, in addition to greater oxygen delivery. One hypothesis(32) is that acidosis protects against continued production of further organic acids (by a negative feedback loop) in tissues, providing a mechanism of cellular metabolic shutdown at times of nutrient shortage--eg, ischaemia.

Inflammation

Acidosis attenuates the following inflammatory processes (figure): leucocyte superoxide formation,(33) neuronal apoptosis,(34) phospholipase A2 activity,(35) expression of cell adhesion molecules,(36) and neutrophil Na+/H+ exchange.(37) In addition, xanthine oxidase (which has a key role in reperfusion injury) is inhibited by hypercapnic acidosis.(24) Furthermore, hypercapnia upregulates pulmonary nitric oxide(38) and neuronal cyclic nucleotide production,(39) both of which are protective in organ injury. Oxygen-derived free radicals are central to the pathogenesis of many types of acute lung injury, and in tissue homogenates, hypercapnia attenuates production of free radicals and decreases lipid peroxidation.(19) Thus, during inflammatory responses, hypercapnia or acidosis may tilt the balance towards cell salvage at the tissue level.

Calcium flux

Acidotic reperfusion of myocardial cells prevents the decrease in Ca2+ responsiveness of the contractile proteins that characterises stunned myocardium.(23) Acidosis may prevent intracellular calcium overload by preventing cellular influx of Ca2+, increasing intracellular binding, and decreasing sarcoplasmic release (figure).(18) This reduces contractility and oxygen demand, possibly explaining the protective effect of acidosis during myocardial ischaemia.(20,23)

Hypocapnia and hypercapnia--is there a balance?

There are several issues of importance. First, the likelihood of there being an effective upper limit of hypercapnia is high because most physiological systems are saturable. Second, although high doses of carbon dioxide seem to be well tolerated, dose-response data have not been well characterised for efficacy. Third, there may exist a point at which benefits are counterbalanced by adverse effects. Adverse effects such as narcosis and coma can occur in any patient, given sufficiently high concentrations of carbon dioxide. In addition, lethal adverse effects may develop at much lower concentrations in vulnerable patients (eg, those with raised intracranial pressure or the inability to buffer carbon dioxide adequately). However, we know from several case series that human beings, and animals, can tolerate exceptionally high concentrations of carbon dioxide, and when adequately ventilated, can recover rapidly and completely. Therefore, high concentrations (if tolerated) may not necessarily cause harm. Finally, although we believe that hypocapnia may be generally undesirable, the life-saving role of acute hyperventilation in the context of impending brainstem herniation should never be forgotten.

Hypothesis

We suggest that, in the setting of acute organ injury, hypercapnia is protective (compared with normocapnia or hypocapnia). Conversely, we suggest that hypocapnia in this setting worsens organ injury (compared with hypercapnia or normocapnia). Although hypocapnia has been assumed to occur as a consequence of many disorders (eg, asthma, systemic inflammatory response syndrome, high-altitude pulmonary oedema, and ventilator-induced lung injury), we propose that hypocapnic alkalosis may be pathogenetic. We suggest a potentially novel strategy--therapeutic hypercapnia--whereby hypercapnia could be intentionally produced in critically ill patients to provide organ protection. Specifically, we contend that administration of carbon dioxide may be beneficial through prevention of hypocapnia, generation of hypercapnia, or both. It is not yet clear whether the range of hypocapnia-normocapnia-hypercapnia represents a therapeutic (or pathogenetic) continuum. However, we contend that the same disease or types of injuries that are adversely affected by hypocapnia would be protected by hypercapnia (and vice versa). From the published studies reviewed, and from the pathological mechanisms assessed, we postulate that changes in carbon dioxide concentration might affect acute inflammation,(33-36) tissue ischaemia,(16) ischaemia-reperfusion,(20,24) and other metabolic,(12,21,32) or developmental(14) processes.

Hypothesis testing

Before testing in human beings, the effects of these hypotheses can be investigated in several models.

Laboratory testing

These experiments could be done in isolated organ systems, in in-vivo single-organ systems, and finally in whole-animal models of multisystem organ failure. The experimental models should include acute and chronic disease processes, and encompass significant pathogenetic variety. Promising models of injury appear to involve tissue ischaemia or ischaemia-reperfusion. From the mechanistic point of view, the chosen models should enable specific assessment of protection afforded by alterations in oxygenation, inflammatory mediators, free-radical generation, and nitric oxide or calcium flux. In any case, the mechanisms, and the therapeutic benefit of their effects, should be well characterised before testing in human beings.

Target populations of patients

The ideal prospective target population for trials of therapeutic hypercapnia would be best identified by future preclinical studies. Most laboratory experimental work to date has focused on acute processes, but this does not preclude a role for therapeutic hypercapnia in chronic disease states in human beings. Target populations could turn out to be those in whom hypocapnia is common. Therapeutic hypercapnia may therefore affect the natural course of disorders in which hypocapnic alkalosis is a constitutive component.

Dose-response relations

Although high doses of carbon dioxide seem to be well tolerated in human beings, a full description of human dose-response data would need to be characterised in preclinical models.

These concerns constitute major, but not ultimately insurmountable, impediments to testing of this clinical hypothesis. Furthermore, the potential for attenuation of possible beneficial effects of hypercapnia by adverse effects of extreme hypercapnia, would be a central issue in future clinical testing.

Conclusion

Re-evaluation of our traditional concepts of hypercapnia and hypocapnia may be valuable. Basic research on this topic during the past decade has not been incorporated into contemporary clinical therapy. The need to document the effects of changes in PaCO2 and pH on organ function, particularly during injury, is clear. We argue that the recent shift in thinking about hypercapnia must now be extended to therapeutic use of carbon dioxide. Our understanding of the biology of disorders in which hypocapnia is a cardinal element would require fundamental reappraisal if hypocapnia is shown to be independently harmful. In summary, in critically ill patients, future therapeutic goals involving PaCO2 might be expressed as: "keep the PaCO2 high; if necessary, make it high; and above all, prevent it from being low".

Acknowledgments

We thank J F Boylan, A C Bryan, and A S Slutsky for helpful comments.

Lancet 1999; 354: 1283-86

Department of Anaesthesia and Medical-Surgical Intensive Care Unit, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada (J G Laffey MB, B P Kavanagh MB)

Correspondence to: Dr Brian P Kavanagh, Department of Critical Care, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada (e-mail: bpk@sickkids.on.ca)

References

(1) Slutsky AS. Mechanical ventilation. American College of Chest Physicians' Consensus Conference. Chest 1993; 104: 1833-59.

(2) 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: 1568-78.

(3) Milberg JA, Davis DR, Steinberg KP, Hudson LD. Improved survival in patients with acute respiratory distress syndrome (ARDS): 1983-1993. JAMA 1995; 273: 306-09.

(4) Montgomery AB, Stager MA, Carrico CJ, Hudson LD. Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Resp Dis 1985; 132: 485-89.

(5) Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338: 347-54.

(6) Saugstad OD. Bronchopulmonary dysplasia and oxidative stress: are we closer to an understanding of the pathogenesis of BPD? Acta Paediatr 1997; 86: 1277-82.

(7) Hebert PC, Wells G, Blajchman MA, et al. A multicentre, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999; 340: 409-17.

(8) Bickell WH, Wall MJ, Pepe PE, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med 1994; 331: 1105-09.

(9) Garland JS, Buck RK, Allred EN, Leviton A. Hypocarbia before surfactant therapy appears to increase bronchopulmonary dysplasia risk in infants with respiratory distress syndrome. Arch Ped Adolesc Med 1995; 149: 617-22.

(10) Reynolds AM, Zadow SP, Scicchitano R, McEvoy RD. Airway hypocapnia increases microvascular leakage in the guinea pig trachea. Am Rev Resp Dis 1992; 145: 80-84.

(11) Cutillo A, Omboni E, Perondi R, Tana F. Effects of hypocapnia on pulmonary mechanics in normal subjects and in patients with chronic obstructive lung disease. Am Rev Respir Dis 1974; 110: 25-33.

(12) Oyarzun MJ, Donoso P, Quijada D. Role of hypocapnia in the alveolar surfactant increase induced by free fatty acid intravenous infusion in the rabbit. Respiration 1986; 49: 187-94.

(13) Muizelaar JP, Marmarou A, Ward JD, et al. Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized trial. J Neurosurg 1991; 75: 731-39.

(14) Graziani LJ, Gringlas M, Baumgart S. Cerebrovascular complications and neurodevelopmental sequelae of neonatal ECMO. Clin Perineonatol; 1997; 24: 655-75.

(15) Hashimoto K, Takewuchi Y, Takashina S. Hypocarbia as a pathogenic factor in pontosubicular necrosis. Brain Dev 1991; 13: 155-57.

(16) Vannucci RC, Towfighi J, Heitjan DF, Brucklacher RM. Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: an experimental study in the immature rat. Pediatrics 1995; 95: 868-74.

(17) Hornbein TF, Townes BD, Schoene RB, Sutton JR, Houston CS. The cost to the central nervous system of climbing to extremely high altitude. N Engl J Med 1989; 321: 1714-19.

(18) Orchard CH, Kentish JC. Effects of changes of pH on the contractile function of cardiac muscle. Am J Physiol 1990; 258: C967-81.

(19) Rehncrona S, Hauge HN, Siesjo BK. Enhancement of iron-catalyzed free radical formation by acidosis in brain homogenates: difference in effect by lactic acid and CO2. J Cereb Blood Flow Metab 1989; 9: 65-70.

(20) Abu Romeh S, Tannen RL. Amelioration of hypoxia-induced lactic acidosis by superimposed hypercapnea or hypochloride acid infusion. Am J Physiol 1986; 250: F702-F709.

(21) Wung JT, James LS, Kilchevsky E, James E. Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics 1985; 76: 488-94.

(22) Nomura F, Aoki M, Forbess JM, Mayer JE. Effects of hypercarbic acidotic reperfusion on recovery of myocardial function after cardioplegic ischemia in neonatal lambs. Circulation 1994; 90: 321-27.

(23) Kitakaze M, Weisfeldt ML, Marban E. Acidosis during early reperfusion prevents myocardial stunning in perfused ferret hearts. J Clin Invest 1988; 82: 920-27.

(24) 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 Resp Crit Care Med 1998; 158: 1578-84.

(25) Holmes JM, Duffner LA, Jappil JC. The effect of raised carbon dioxide on developing rat retinal vasculature exposed to elevated oxygen. Curr Eye Res 1994; 13: 779-82.

(26) Berkowitz BA. Adult and newborn rat inner retinal oxygenation during carbogen and 100% oxygen breating: comparison using magnetic resonance imaging delta PO2 mapping. Invest Opthalmol Vis Sci 1996; 37: 2089-98.

(27) du Plessis AJ, Jonas RA, Wypij D, et al. Perioperative effects of alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants. J Thorac Cardiovasc Surg 1997; 114: 991-1000.

(28) Hickling KG, Joyce C. Permissive hypercapnia in ARDS and its effects on tissue oxygenation. Acta Anaesthesiol Scand 1995; 107: 201-08.

(29) Cardenas VJ, Zwischenberger JB, Tao W, et al. Correction of blood pH attenuates changes in hemodynamics and organ blood flow during permissive hypercapnia. Crit Care Med 1996; 24: 827-34.

(30) Tobarti D, Mangino MJ, Garcia E, Estrada M, Totapally BR, Wolfsdorf J. Acute hypercapnia increases the oxygen-carrying capacity of the blood in ventilated dogs. Crit Care Med 1998; 26: 1863-67.

(31) Hillered L, Ernster L, Siesjo BK. Influence of in vitro lactic acidosis and hypercapnia on respiratory activity of isolated rat brain mitochondria. J Cereb Blood Flow Metab 1984; 4: 430-37.

(32) Hood VL, Tannen RL. Protection of acid-base balance by pH regulation of acid production. N Engl J Med 1998; 339: 819-26.

(33) Allen DB, Maguire JJ, Mahdavian M, et al. Wound hypoxia and acidosis limit neutrophil bacterial killing mechanisms. Arch Surg 1997; 132: 991-96.

(34) Xu L, Glassford AJ, Giaccia AJ, Giffard RG. Acidosis reduces neuronal apoptosis. Neuroreport 1998; 9: 875-79.

(35) Wang H, Harrison-Shostak DC, Lemasters JJ, Herman B. Contribution of pH-dependent group II phospholipase A2 to chemical hypoxic injury in rat hepatocytes. Faseb J 1996; 10: 1319-25.

(36) Serrano CV, Fraticelli A, Paniccia R, et al. pH dependence of neutrophil-endothelial cell adhesion and adhesion molecule expression. Am J Physiol 1996; 271: C962-70.

(37) Gewirtz AT, Seetoo KF, Simons ER. Neutrophil degranulation and phospholipase D activation are enhanced if the Na+/H+ antiport is blocked. J Leukocyte Biol 1998; 64: 98-103.

(38) Yamaguchi K, Takasugi T, Fujita H, et al. Endothelial modulation of pH-dependent pressor response in isolated perfused rabbit lungs. Am J Physiol 1996; 270: H252-58.

(39) Parfenova H, Leffler CW. Effects of hypercapnia on prostanoid and cAMP production by cerebral microvascular cell cultures. Am J Physiol 1996; 270: C1503-10.

Localisation initiale
http://www.findarticles.com/cf_0/m0833/9186_354/56218619/print.jhtml