Carbon dioxide (CO2) is an end product of aerobic cellular respiration.1 PaCO2 is determined by tissue CO2 production, minute ventilation, and dead space to tidal volume fraction.2 In healthy persons, PaCO2 is maintained by physiologic mechanisms within a narrow range (35–45 mm Hg). Because CO2 is in equilibrium with carbonic acid (H2CO3) in the arterial blood, hypercapnia can drive arterial pH down, a condition termed hypercapnic acidosis
The hydration–dehydration reaction proceeds most rapidly in the red blood cells because of the presence of the enzyme, carbonic anhydrase.1
Elevated values for PaCO2 are encountered in many clinical situations (Table 1).1 In recent years, the number of hypercapnic patients has increased by the use of smaller tidal volumes to limit lung stretch and injury during mechanical ventilation, so-called permissive hypercapnia.2 Hypercapnic acidosis itself may also have lung-protective effects because of its anti-inflammatory actions, which has prompted calls by at least one authority for the addition of CO2 to the inspired gas.3 Hypocapnic alkalosis, whether produced deliberately (to reduce intracranial pressure in head trauma), accidentally (during excessive mechanical ventilation), or related to a disease, anxiety, or a drug effect is also frequently observed in anesthesia practice.1,4 An appreciation of the cardiac responses to variations in PaCO2 is necessary for optimal clinical management in the perioperative and critical care settings.
This review discusses, from a historical perspective: (1) the effects of CO2 on coronary blood flow and the mechanisms underlying these effects (Table 2); (2) the role of locally produced CO2 in metabolic control of coronary blood flow, that is, oxygen supply/demand matching; and (3) the direct and reflexogenic actions of CO2 on myocardial contractile function. Clinically relevant issues are addressed, including the role of increased myocardial tissue PCO2 (PmCO2) in the decline in myocardial contractility during coronary hypoperfusion and the increased vulnerability to CO2-induced cardiac depression in patients receiving a β-blocking drug or with otherwise compromised inotropic reserve. The potential use of real-time measurements of PmCO2 to monitor the adequacy of myocardial perfusion in the perioperative period is discussed. For simplicity sake, hypercapnic acidosis and hypocapnic alkalosis are referred to as hypercapnia and hypocapnia, respectively, throughout this review.
EFFECT OF CO2 IN THE CORONARY CIRCULATION
In 1907, Barcroft and Dixon5 provided the first evidence that the coronary circulation may be responsive to CO2, finding a strong relation between myocardial CO2 production and coronary blood flow in the isolated canine heart-lung preparation. On the basis of their findings, these investigators wrote “liberation of metabolic products from the heart, of which carbonic acid is the chief, controls the vaso-motor changes in the coronary arterioles.” Shortly thereafter, in 1913, Markwalder and Starling6 using the same preparation demonstrated for the first time that hypercapnia (inspired 12% CO2 gas) increased coronary blood flow. Subsequent animal studies confirmed this response and demonstrated further that the increase in coronary blood flow during hypercapnia was accompanied by a decrease in the coronary arteriovenous O2 difference (with attendant increases in coronary sinus PO2 and oxygen saturation; Table 3).7–16 The increases in coronary sinus PO2 were disproportionate to those in oxygen saturation because of a rightward shift of the oxyhemoglobin dissociation curve, now known as “the Bohr effect.” A rightward shift of the curve reflects a decrease in hemoglobin oxygen affinity, resulting in an enhanced diffusion of oxygen into the tissue. The Bohr effect originates from the ability of hemoglobin to bind both H+ and CO2 and to form a carbamino compound, which can allosterically alter the affinity of the hemoglobin-binding sites for oxygen.17 Studies have demonstrated that coronary blood flow is linearly correlated to PaCO2 over a wide range of values (10–90 mm Hg).18
The decrease in myocardial oxygen extraction during hypercapnia is a sign of “luxuriant perfusion,” and it provides evidence that the increase in coronary blood flow was due to direct relaxation of the smooth muscle of the coronary arterioles, that is, resistance vessels, and not secondary to an increase in myocardial oxygen demand.19 The increase in coronary sinus PO2 during hypercapnia reflects an increase in myocardial PO2.20 The potency of hypercapnia as coronary vasodilator is evidenced by its ability to overcome the direct vasoconstrictor effect of increased myocardial PO2.19
Only few studies of limited scope have evaluated the effects of hypercapnia in the human coronary circulation, but the results have been essentially consistent with those obtained in animal models. In 1998, Kazmaier et al.21 found that moderate hypercapnia (+10 mm Hg) increased myocardial blood flow (argon tracer technique) by 15% in anesthetized patients (age 63 ± 9 years) with angiographically verified coronary artery disease. This increase in myocardial blood flow was accompanied by no change in global myocardial oxygen consumption and by a reduction in myocardial oxygen extraction. Subsequent studies extended the vasodilator effect of moderate hypercapnia to the coronary circulation of young healthy volunteers (Fig. 1).22,23 However, in a limited study in elderly, healthy, male volunteers, Yokoyama et al.24 found that hypercapnia caused an increase in myocardial blood flow (positron emission tomography scanning), which was proportional to the increase in cardiac workload, assessed by the rate pressure product, thus implying no direct coronary vasodilator effect. Possible explanations for this divergent finding are the imposition of an extremely mild degree of hypercapnia (PaCO2, 43.1 ± 2.7, pHa, 7.385 ± 0.019) and the use of a relatively insensitive hemodynamic index to estimate myocardial oxygen demand.
Studies in dogs12,25–27 and humans28,29 have demonstrated that hypocapnia has the opposite effects of hypercapnia, that is, coronary vasoconstriction and a decrease in coronary blood flow accompanied by an increase in oxygen extraction (Table 4). A leftward shift of the oxyhemoglobin curve exacerbates the decrease in intracapillary PO2, thus impairing diffusion of oxygen into the tissue.
Case et al.27 demonstrated in anesthetized dogs that extreme hyperventilation (PaCO2 approximately 10 mm Hg) can cause severe coronary vasoconstriction (as reflected in coronary sinus PO2 values of <9 mm Hg) with a corresponding myocardial oxygen extraction of approximately 90%. A decrease in coronary sinus PO2 of this magnitude is associated with insufficient myocardial oxygenation and lactate production,30 changes which could lead to impaired cardiac function. These findings suggest that excessive hyperventilation should be avoided and, if encountered clinically, treated expeditiously, especially in the patient in whom myocardial oxygen supply is already compromised by coronary insufficiency, hypoxemia, or hemodilution.
Is the Coronary Vasodilation Because of CO2 or H+?
Several studies have attempted to separate the roles of increased arterial PCO2 and reduced pH in the coronary vasodilation during hypercapnia.25,31,32 Two experimental approaches have been used. In one approach, the effect of correction of pH with a buffer on the hypercapnia-induced increases in coronary blood flow was assessed. In another, the effect of hypercapnia on coronary blood flow was compared with a same decrease in pH caused by an acid, such as hydrochloric acid. The findings from these studies were inconsistent. This may be due to the more rapid inward diffusion of highly soluble CO2 molecules into vascular smooth muscle compared with H+ influx, and the different times at which measurements of coronary blood flow were obtained. Because of the free diffusibility of CO2 across cell membranes, an increase in extracellular CO2 causes a decrease in intracellular pH (Equation 1). H+ is likely to be ultimately responsible for relaxation of the coronary vascular smooth muscle. The precise roles of arterial CO2 and H+ in the coronary vasodilation during hypercapnia remain unresolved.
Molecular Mechanisms Mediating CO2-Induced Changes in Coronary Vasomotor Tone
Several molecular mechanisms have been proposed to account for the vasodilator effect of hypercapnia in the coronary circulation.
In 1979, van den Bos et al.33 observed, in anesthetized dogs, that the increase in coronary blood flow caused by inspired CO2 was abolished by pretreatment with the β-adrenergic receptor antagonist, sotalol. Thus, they concluded that the coronary vasodilation by hypercapnia was due to sympathoadrenergic stimulation and not to a direct vasodilator effect. However, this conclusion has been contradicted by studies indicating that the increases in coronary blood flow during either systemic10,31 or selective intracoronary15 hypercapnia persisted after treatment with propranolol. It is now commonly accepted that the coronary vasodilation during hypercapnia occurs independently of the β-adrenergic receptors.
Nitric oxide (NO) is produced in the vascular endothelium from the amino acid L-arginine in a reaction requiring calcium-/calmodulin-dependent NO synthase (NOS).34 NO diffuses from the endothelium to the vascular smooth muscle cell, where it stimulates guanylyl cyclase activity and the production of guanosine 3′,5′-cyclic monophosphate, which has a vasorelaxing action.34 Using a canine preparation, our laboratory demonstrated that pretreatment with a NOS inhibitor (Fig. 2) obtunded hypercapnia-induced coronary vasodilation, implying a role for NO released from the vascular endothelium in the response.16 This effect was evident under constant-pressure or constant-flow conditions, suggesting that the release of NO was through a direct effect and not secondary to an increased flow rate (shear stress). A role for NO during hypercapnia-induced coronary vasodilation was also demonstrated in isolated crystalloid-perfused mouse35 and guinea pig hearts.36 The stimulus for the activation of endothelial NOS may be calcium mobilization secondary to an increase in H+ concentration.37,38
ATP-Sensitive and Voltage-Dependent Potassium Channels
Opening of the ATP-sensitive potassium channels (KATP channels) causes hyperpolarization of vascular smooth muscle cells.39 Hyperpolarization inhibits Ca2+ entry through voltage-dependent Ca2+ channels, leading to vasodilation. Ishizaka and Kuo40 showed that the inhibitor of the KATP channels, glyburide, blunted HCl-induced dilation of isolated porcine coronary arterioles. Phillis et al.41 and Heintz et al.35 obtained similar results during hypercapnia in isolated rat and mouse hearts, respectively. Heintz et al. also demonstrated that combining glyburide with a NOS inhibitor abolished the hypercapnia-induced increase in coronary flow in the mouse heart, implying that, together, these mechanisms accounted for the entire vasodilator effect (Fig. 3). However, findings in vascular smooth muscle cells from rat coronary arteries have suggested that the voltage-dependent potassium channels (Kv channels) may also play a role.42 In light of the apparent involvement of endothelium-derived NO and the KATP channels, it would be of interest to study the effect of hypercapnia on coronary blood flow in patients in whom endothelial function is impaired, for example, obstructive sleep apnea,43–45 and in patients with diabetes mellitus treated with glyburide.
Because the coronary vasomotor response to CO2 is a continuum, it is reasonable to surmise that the coronary vasoconstrictor effect of hypocapnia may involve reduced activity of NO and a closure of the KATP and Kv channels. Implicit in this assumption is that these pathways are operative under normocapnic conditions, which has been shown to be the case.46–49
Role of Locally Produced CO2 in Metabolic Regulation of Coronary Blood Flow
The myocardium has a limited anaerobic capacity and is dependent on a continuous delivery of oxygen from the coronary circulation. Myocardial oxygen consumption is normally high relative to coronary blood flow; thus, O2 extraction is large (70%–80%), resulting in a low value for coronary sinus PO2 of 20 mm Hg or less.19 The absence of an appreciable oxygen extraction reserve renders the myocardium essentially dependent on increases in blood flow to meet increases in oxygen demand, and thus cardiac work. This is accomplished by a local metabolic mechanism that couples the level of myocardial oxygen consumption to the tone of the coronary resistance vessels. The importance of the local metabolic mechanism cannot be overstated. If coronary blood flow does not increase adequately to satisfy an increase in cardiac work demand, myocardial ischemia will ensue, with the risk of impaired contractile function, hypotension, arrhythmias, and death.
Current concepts of metabolic regulation depend on a feed-forward mechanism (Fig. 4).50 In such a mechanism, a vasodilating metabolite is produced at a rate proportional to the rate of oxidative metabolism. Metabolites that have been proposed are reactive oxygen species, that is, hydrogen peroxide, which are formed in the mitochondrial respiratory chain, and CO2, which is generated in the decarboxylation reactions of the citric acid cycle. As alluded to earlier, a role for CO2 in local metabolic control of coronary blood flow was hypothesized as early as 1907 by Barcroft and Dixon.5 Much later, in 1991, Broten et al.51 determined that an increase in PmCO2 (estimated from coronary sinus PCO2 values) could account for approximately 16% of the steady-state increases in coronary blood flow during pacing-induced increases in myocardial oxygen consumption in canine hearts. The vasodilator response initiated by locally produced CO2 is mediated by the secondary mechanisms described earlier, including endothelium-derived NO and the KATP and Kv channels (Fig. 4). Increases in PmCO2 may also contribute to the arteriolar dilation downstream from a coronary stenosis. In this setting, the increases in PmCO2 are due to multiple factors, including the addition of CO2 generated by the weakly contracting myocardium, CO2 produced from buffering of H+ (resulting from lactic acid) by endogenous HCO3−, and an impaired washout of CO2 from the tissue. The arteriolar dilation in response to a coronary stenosis reduces the available vasodilator reserve and the capacity of the coronary circulation to respond effectively to increases in myocardial oxygen demand. Although endogenous adenosine was once considered the primary metabolite coupling coronary blood flow to myocardial oxygen demand, the current thought is that adenosine becomes involved in local coronary vasomotor regulation only when the stimulus for its production, low tissue PO2, is present.50
Effect of Hypercapnia in the Obstructed Coronary Circulation
“Coronary steal” refers to small-vessel dilation and an increase in blood flow to an area of already well-perfused myocardium, leading to a decrease in blood flow to another area of myocardium with borderline perfusion and limited coronary reserve because of an upstream stenosis.52 Coronary steal can be intercoronary or transmural. Coronary steal has been observed when pharmacologic vasodilators, such as isoproterenol and adenosine, were administered IV in dogs with collateral-dependent myocardium53 and when drug-induced vasodilator therapy was used in patients with angina pectoris.54 Because hypercapnia is clearly a coronary vasodilator, it would theoretically be capable of producing coronary steal. However, the only study to date on this topic, in a swine model of chronic, single-vessel coronary artery obstruction, yielded negative results.55 Although inhalation of high CO2 gas (maximal PaCO2 of 127 mm Hg) caused marked increases in myocardial blood flow (measured with radioactive microspheres), there was no effect on either the intercoronary or the transmural flow ratio. These findings do not rule out a change in these ratios when multivessel disease renders the coronary anatomy more steal prone.56
Chemoreflex Control of Coronary Vasomotor Tone
Although the direct vasomotor effect of CO2 likely predominates during arterial hypercapnia, there is evidence of chemoreflex pathways involving the autonomic nervous system. Chemoreceptors, sensitive to CO2, are present centrally on the ventrolateral surface of the medulla oblongata57 and peripherally in the carotid and aortic bodies.58,59 In a study in chronically instrumented, conscious dogs, Murray et al.60 demonstrated that stimulation of the carotid chemoreceptors by injection of nicotine into the carotid artery caused a biphasic change in coronary vascular tone; first vasodilation, then vasoconstriction (Fig. 5). The coronary vasodilation had a minor component secondary to a chemoreceptor-mediated activation of the coronary vagal fibers and a major component that followed an increase in depth of respiration (and activation of lung receptors) involving a withdrawal of α-adrenergic constrictor tone. The subsequent coronary vasoconstriction was due to an increased α-adrenergic constrictor tone mediated by both the cardiac sympathetic nerves and the circulating catecholamines. In contrast to the findings from Murray et al.,60 Ehrhart et al.61 found no coronary vasomotor responses when the carotid bodies of anesthetized, open-chest dogs were perfused selectively with hypoxic and hypercapnic blood. This discrepancy in findings is likely due to methodologic differences, including the stimulus used to activate the carotid body chemoreceptors and the absence or presence of anesthesia. Whether chemoreceptor-mediated, autonomic nerve pathways modulate coronary blood flow during arterial hypercapnia must be considered an open question.
Effect of CO2 on Coronary Open Capillary Density
Open capillary density affects the blood-tissue diffusion distance and the available surface area for gas exchange.52 Alterations in open capillary density are important in maintaining oxygen supply/demand balance in the myocardium. A study in beating rat hearts demonstrated that hypercapnia caused small and functionally insignificant decreases in intercapillary distance, as measured by stop-motion microcinematography.62 These results are in accord with work showing that the coronary precapillary sphincters are chiefly controlled by the partial pressure of oxygen to which they are exposed.63 CO2 seems to have a differential effect on the smooth muscle controlling the caliber of the arteriolar resistance vessels versus the precapillary sphincters.
Hypocapnia-Induced Coronary Arterial Spasm
In 1959, Prinzmetal et al.64 proposed the existence of a variant form of angina pectoris, which is characterized by reduced myocardial oxygen supply at rest, and not, as in the case of classic angina, an imbalance between myocardial oxygen supply and demand resulting from an increase in oxygen demand in the presence of a flow restriction. Subsequent angiographic findings demonstrated a role for large arterial coronary spasm in the pathogenesis of variant angina.65,66 The susceptibility to coronary spasm has been attributed to endothelial dysfunction combined with a hyperreactivity of vascular smooth muscle cells.67 Potential triggers of coronary spasm include the autonomic nervous system (both the sympathetic and the parasympathetic nerve supply), abnormal platelet activation causing the release of thromboxane A2 and serotonin, endothelin-1, and hyperventilation.67 In patients with documented variant angina, hyperventilation was shown to induce coronary artery constriction, demonstrated angiographically, and abnormal ST-T segment changes identical to those of ischemia.68–70 Addition of 4.9% CO2 to the inspired air reversed the abnormal electrocardiographic changes caused by hyperventilation, providing proof that hypocapnia played a key role in the genesis of these changes.69 Hyperventilation has been shown to be a reliable diagnostic test for variant angina.71 Variant angina can severely impair myocardial oxygenation, which can predispose to malignant cardiac arrhythmias, resulting in sudden death or, if prolonged, in acute myocardial infarction.67 Thus, it is necessary that patients with variant angina be identified and that their PaCO2 be vigilantly monitored and tightly controlled.
EFFECT OF CO2 ON CARDIAC FUNCTION
The earliest report of an action of CO2 on cardiac muscle was in 1879 by Klug,72 who observed that an excess of carbonic acid in the blood reduced the amplitude of contractions of the frog heart and eventually produced diastolic arrest. One year later, Gaskell73 found that a saline solution of lactic acid had a similar effect. In 1910, Jerusalem and Starling74 extended the cardiac depressant effect to hypercapnia, in demonstrating that administration of a gas mixture containing 20% CO2 caused marked depression of myocardial contractility in an isolated mammalian (cat) heart-lung preparation. A direct inhibitory effect of CO2 on cardiac performance was subsequently confirmed in a variety of in vitro preparations.75–81 Cardiac performance was found to vary inversely with PCO2 over the range 25 to 75 mm Hg in the isometric papillary muscle preparation from the cat.81 Foëx and Fordham82 showed that the initial stage of depression resulting from exposure of cat papillary muscle to high CO2 was followed by a significant degree of spontaneous recovery during the next hour (Fig. 6). It was hypothesized that this phenomenon may be attributable to a buffering ability in cardiac cells, which returned intracellular pH toward normal in the face of a continued extracellular acidosis. In vivo this mechanism would presumably act in conjunction with an increased sympathetic activity (see later) to moderate the cardiac depression caused by elevated PaCO2.
The mechanisms that normalize pH in cardiac cells are complex and have been described in detail elsewhere.83–85 In brief, regulation of pH in the cardiac cell is accomplished by a combination of intracellular buffering of H+ ions and specific sarcolemmal ion transport mechanisms, which extrude excess acid or alkali from the cell. Both extrinsic and intrinsic intracellular buffering mechanisms have been described.85 Extrinsic buffering comprises of the reversible hydration of CO2 (Equation 1). Intracellular HCO3− is considered an extrinsic buffer because it is formed from CO2 which, because of its high membrane permeability, readily equilibrates with the extracellular compartment. Intrinsic buffering refers to the noncarbonic intracellular solutes, including histidine groups on intrinsic proteins and cytoplasmic dipeptides, such as homocarnosine, N-acetylanserine, and N-acetylcarnosine, that accept H+ ions.85 The 2 prominent sarcolemmal ion transport mechanisms are Na+–HCO3− cotransport,85 and Na+–H+ exchange.86
Studies have shown that the magnitude and rate of the decrease in myocardial contractility because of intracellular acidosis depend on how the acidosis is produced. In 1926, Smith,75 using an isolated cardiac muscle preparation, was the first to demonstrate that the negative inotropic effect of extracellular acidosis was greater and more rapid if it were produced by an increase in PCO2 (respiratory acidosis) than by an infusion of an acid, such as HCl (metabolic acidosis). This finding was corroborated by later studies.80,87–90 Using an isolated crystalloid-perfused Langendorff preparation, Tang et al.89 demonstrated a >60% reduction in contractile function within the first minute after an increase in perfusate PCO2 from 34 to 114 mm Hg, but only a minimal reduction in contractile function after a selective increase in H+ concentration (Fig. 7). These results supported the concept that the negative inotropic effect was due to intracellular, rather than extracellular, acidosis. CO2 can readily diffuse across the myocardial cell membrane and reduce intracellular pH (via dissociation of carbonic acid to H+ and HCO3−), whereas cell membranes are relatively impermeable to extracellular H+. The reduction in myocardial contractility during intracellular acidosis is caused by the ability of H+ to affect multiple steps in the excitation–contraction coupling pathway, including the delivery of Ca2+ to the myofilaments and the response of the myofilaments to Ca2+.91
Despite the well-established direct cardiac depressive action of hypercapnia, inhalation of high CO2 gases caused transient and minimal effects on cardiac performance in conscious dogs92 and increases in cardiac output in healthy awake volunteers.93–96 Asmussen96 proposed that the increase in cardiac output during CO2 breathing was due to the ability of hyperventilation to promote venous return. However, this theory was refuted by findings demonstrating (1) that, with PaCO2 held constant, hyperventilation resulted in no significant change in circulatory variables, including cardiac output,93 and (2) that increases in cardiac output during CO2 administration were the same during spontaneous breathing and controlled ventilation in volunteers.95
It is now well accepted that the direct cardiac depressive effect of hypercapnia is opposed in vivo by a positive inotropic pathway comprising central and peripheral chemoreceptors and the sympathoadrenal system. The first investigators to bring attention to the chemoreceptor/sympathoadrenal reflex pathway were Itami in 191297 and Cathcart and Clark in 191598 in studies focusing on peripheral vasoconstrictor responses during hypercapnia. In 1957, Honig and Tenney99 presented evidence extending this chemoreflex pathway to the regulation of cardiac function. Plethysmographic measurements of lower extremity blood volume and ballistic measurements of stroke force were obtained. In their studies in humans, Honig and Tenney showed that breathing 6% CO2 gas caused an increase in stroke force accompanied by a reduction in intrathoracic blood volume, which suggested that the improved cardiac function was due to humoral or nervous factors rather than to increased cardiac filling. A bioassay demonstrated an increase in circulating catecholamines, a finding confirmed by others.100,101 In the companion canine studies, Honig and Tenney demonstrated that transection of the spinal cord and ablation of the peripheral chemoreceptors (both aortic and carotid bodies) resulted in a decrease, rather than an increase, in stroke force during hypercapnia. A role for the peripheral chemoreceptors in the cardiac response during hypercapnia was also suggested by Vatner and Rutherford,102 who observed an increase in left ventricular systolic ventricular contractility (dP/dtmax) during selective activation of the carotid bodies by nicotine in conscious, chronically instrumented dogs. This positive inotropic effect was abolished with propranolol, indicating a role for the cardiac β-adrenergic receptors. Interestingly, the positive inotropic effect was greater when ventilation was fixed, that is, in the absence of the attenuating influence of the pulmonary inflation reflex. Walley et al.103 reevaluated the effect of hypercapnia on cardiac function in fentanyl-anesthetized dogs, using a sophisticated afterload-insensitive index of myocardial contractility, the left ventricular end-systolic pressure-volume relation (Fig. 8).104,105 These investigators found that hypercapnia caused a decrease in myocardial contractility, although cardiac output was maintained by an increase in venous return. The latter effect could reflect a redistribution of blood flow through low-resistance vascular beds, for example, the cerebral circulation,106 and/or an increase in tone of the venous capacitance vessels via a chemoreflex activation of the sympathoadrenal system.107 In keeping with the studies described earlier, Walley et al.103 also found that β-receptor blockade caused a more pronounced reduction in myocardial contractility and prevented the increase in cardiac output during hypercapnia. Taken together, the findings to date suggest that the net change in cardiac performance during hypercapnia depends on the balance between the direct inhibitory effect of CO2 and the compensatory adjustments mediated by the chemoreflex-sympathoadrenal pathways. Studies have shown that anesthetic drugs, both volatile and IV, as well as spinal anesthesia, obtund the cardiostimulatory effects of sympathetic arousal during hypercapnia, which would unmask the direct cardiodepressive effect.94,95 An exception is ketamine, an IV sedative-hypnotic drug, that enhances sympathetic nervous system activity and increases heart rate, arterial pressure, and myocardial contractility.108
CO2 and Right Ventricular Function
In contrast to its direct vasodilator effect in the coronary circulation, hypercapnia causes vasoconstriction in the pulmonary circulation.109–113 Studies in isolated vascular smooth muscle preparations have suggested that this differential reactivity of the coronary and pulmonary circulations may be due, at least in part, to opposite, tissue-specific effects on the Kv channels, that is, K+ current is increased in coronary vascular smooth muscle and decreased in pulmonary vascular smooth muscle.42,114
An increase in afterload because of pulmonary vasoconstriction and the resulting hypertension can precipitate right ventricular contractile dysfunction, especially in patients in whom right ventricular performance is already compromised and contractile reserve is limited.115 When right ventricular emptying is impaired, right ventricular end-diastolic volume increases to occupy the available pericardial space. This can decrease compliance of the left ventricular wall, impede chamber filling, and reduce the effectiveness of the Frank-Starling mechanism on left ventricular performance.
Afterload is the tension or stress in the wall of the ventricular wall during ejection. It is well accepted that aortic pressure can provide a reasonable estimate of left ventricular afterload. However, because of the more dynamic and pulsatile nature of right ventricular ejection, it has been suggested that right ventricular afterload would be more accurately characterized from measurements of pulmonary artery input impedance.116,117 These measurements require a waveform analysis of pulmonary artery pressure and flow as a function of time.117 This methodology is complicated and requires expensive high-fidelity technology.117 Thus, most investigations of the effects of CO2 on right ventricular dynamics have estimated changes in afterload from measurements of pulmonary arterial pressure. The one exception is a study in healthy anesthetized goats, which, interestingly, demonstrated that hypercapnia (PaCO2, 69.3 ± 4.1 mm Hg; pHa, 7.223 ± 0.027) caused modest increases in both pulmonary vascular resistance (+22%) and mean pulmonary arterial pressure (+15%) but did not alter right ventricular afterload, as assessed from measurements of input impedance.116
In the immediate period following coronary artery bypass graft surgery, right ventricular function is frequently depressed.118 Viitanen et al.119 demonstrated that in such patients, moderate hypercapnia (PaCO2, 49.8 ± 2.9 mm Hg) induced by hypoventilation increased pulmonary vascular resistance and mean pulmonary artery pressure. This was associated with right ventricular end-diastolic and end-systolic dilation and a reduced right ventricular ejection fraction (Fig. 9). However, stroke volume was maintained, at least in part, because an augmentation of preload, that is, the Frank-Starling mechanism, was sufficient to overcome the adverse effects of a presumed increase in afterload and high tissue CO2 on cardiac performance. An enhanced right ventricular contractility via activation of the sympathoadrenal system may have also contributed to the maintained stroke volume during hypercapnia. The compensatory reserve of the right ventricle may be exceeded in patients with more compromised right ventricular function or under conditions of more severe hypercapnia.
Rose et al.120 demonstrated in conscious, chronically instrumented dogs, that both acute and chronic hypercapnia caused right ventricular dysfunction in the setting of pulmonary hypertension, that is, an increased afterload, produced by a pulmonary artery constrictor. This was reflected in an exaggerated rise in right ventricular end-diastolic pressure. β-Adrenergic blockade accentuated the hypercapnia-induced increase in right ventricular end-diastolic pressure during an increased afterload, attesting to the compensatory role of the sympathoadrenal system in opposing the direct cardiac depressive action of hypercapnia.
Cardiac Protective Effect of Hypercapnic Acidosis
Studies in animal models have suggested that hypercapnic acidosis may be protective in a number of organs, including the heart.121–127 Acidosis, either alone or combined with hypercapnia, when induced transiently during early reperfusion, improved the functional recovery of stunned myocardium and reduced myocardial infarct size.121,122,125,127 Conversely, transient alkalosis abolished the cardioprotection of postconditioning produced by intermittent reperfusion127 or helium administration.128 Possible mechanisms for the cardioprotective effects of hypercapnic acidosis are (1) a reduction in Ca2+ loading by an H+-induced inhibition of Ca2+ uptake and by H+ competing for intracellular Ca2+ binding sites,129 (2) an attenuation of inflammatory processes and reduction in free radical production,3 (3) an increase in blood flow and a reduction in energy expenditure resulting in a more favorable balance between O2 supply and demand (see earlier), and (4) an inhibition to mitochondrial permeability transitioning pore formation, which is a change in reperfused cells that rapidly produces death by necrosis and apoptosis.127,128 It has been shown that inhibition of mitochondrial permeability transitioning pore formation involves an activation of the mitochondrial KATP channels.130 As described earlier, hypercapnia has been demonstrated to activate these channels in the coronary circulation. An extrapolation of the experimental findings relating to the cardioprotective effects of transient hypercapnia to patients requires that several issues be clarified, including possible species-related differences, the long-term effects of the exposure to hypercapnia, and the level of PaCO2 providing the maximal benefit.
Intramyocardial CO2 During Ischemia
PmCO2 was measured directly for the first time in the 1970s using a Teflon membrane-vacuum spectrometer system131 and later a microelectrode with a more rapid response.132,133 The findings revealed that (1) there was a strong relationship between PmCO2 and coronary sinus PCO2, reflecting the free diffusibility of CO2 through tissue membranes (Fig. 10A); (2) the addition of CO2 generated by the myocardium resulted in PmCO2 being approximately 20 mm Hg higher than PaCO2 (normally 40 mm Hg; Fig. 10A); (3) a coronary artery occlusion caused an immediate increase in PmCO2 from the baseline value of approximately 60 mm Hg, reaching a maximal value of >400 mm Hg after 20 minutes (Fig. 10B); (4) a progressive reduction in coronary blood flow caused an increase in PmCO2, which paralleled the increase in intramyocardial ST segment voltage (Fig. 10C). The rapidity of the increase in PmCO2 was sufficient to explain the immediate decrease in myocardial contractility during ischemia. The increase in PmCO2 during myocardial ischemia is the combined result of continued metabolic production of CO2, buffering of the accumulating lactic acid by intracellular HCO3−, and an impaired washout.
Current investigators have developed, and are testing, a conductometric PmCO2 sensor for potential clinical use.134,135 The idea is to use the measurements of PmCO2 as a means to assess in real-time the adequacy of myocardial perfusion in the perioperative period. The validation studies in swine models have, to date, yielded promising results. The PmCO2 sensors have been shown to provide reliable and continuous detection of myocardial ischemia, as confirmed from measurements of tissue PO2 and pH, the lactate/pyruvate ratio, and regional contractile function. The PmCO2 sensors are sterile, disposable, and durable, being able to tolerate the wide pressure variations in the myocardium. Because they are small (0.7 mm in diameter), the sensors are easily inserted and removed without significant tissue trauma. This technology, if approved for clinical use, could be a valuable cardiac monitoring tool in cardiac anesthesia and postoperative care.
A review of the literature over >100 years reveals that PaCO2, and the attendant changes in pH, can have profound influence on coronary blood flow and myocardial contractile function, in both physiologic and pathophysiologic situations. CO2 has a direct coronary vasodilator effect and, when produced locally, plays an integral role in matching coronary blood flow to the prevailing myocardial oxygen demand. Because hypocapnia is a coronary vasoconstrictor, can induce coronary artery spasm in patients with variant angina, and can impair unloading of oxygen by hemoglobin, it has the potential to produce tissue hypoxia, especially in the patient in whom myocardial oxygen supply is already jeopardized. Hypercapnia has a direct cardiodepressive action, which is normally offset in vivo by a concurrent activation of chemoreflex-sympathoadrenal pathways. Clinicians should be wary of high PaCO2 values in patients receiving a β-adrenergic receptor antagonist or with otherwise compromised inotropic reserve. Hypercapnic pulmonary vasoconstriction can result in afterload stress and reduced right ventricular performance in post-coronary artery bypass graft patients. Animal studies have demonstrated that increases in PmCO2 correlate with metabolic, electrophysiologic, and contractile indices of coronary hypoperfusion. Small PmCO2 sensors are being developed, which, if approved for clinical use, could provide a means for early detection of myocardial ischemia in the perioperative setting. Animal studies have demonstrated that transient exposure of reperfused myocardium to high CO2/low pH conditions can reduce tissue injury and contractile dysfunction. The clinical applicability of the latter findings needs to be determined.
Name: George J. Crystal, PhD.
Contribution: This author wrote the article.
Attestation: George J. Crystal approved the manuscript.
This manuscript was handled by: Martin J. London, MD.
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