Inhaled Anesthetics and Hypoxic Pulmonary Vasoconstriction

Several mechanisms contribute to diminished FRC, reduced oxygenation, and increased PAO₂ -PaO₂ during anesthesia. Inhaled anesthetics contribute to this process by affecting HPV. The influences of anesthetics on HPV have been examined in a variety of experimental models but have yielded conflicting results.

The effects of inhaled anesthetics on HPV are multifactorial and involve direct actions on the pulmonary vasculature combined with indirect effects mediated by the autonomic nervous system, systemic hemodynamics, and humoral actions. In general, most in vitro studies have demonstrated that inhaled anesthetics attenuate HPV to some degree ( Fig. 6-8 ). Inhibition of HPV has been demonstrated with halothane,^{[137] [148] [149] [150] [151] [152]} isoflurane ^{[137] [138]} enflurane, ^{[137] [153]} sevoflurane, ^[138] desflurane,^[139] and nitrous oxide using isolated perfused lungs or an in situ preparation with constant perfusion.^{[154] [155] [156]} Marshall and colleagues^[137] examined the effects of halothane, enflurane, and isoflurane on the HPV response to global hypoxia. All three drugs depressed HPV in a dose-dependent fashion. Similar MAC values (approximately 0.6 MAC) of these agents also depressed HPV by 50% in an in vitro preparation using controlled pulmonary perfusion independent of sympathetic nervous system activity. A later study using isolated rat lungs confirmed the depression of HPV by isoflurane and halothane. The addition of verapamil further reduced HPV by an additional 35% to 40%, suggesting that inhaled anesthetics and Ca²⁺ channel antagonists inhibit HPV through different sites of action.^[157] Halothane reduced the resistance of the middle vascular segment in an atelectatic, hypoxic lung, suggesting a specific, direct action of this agent on small vessels and capillaries.^{[151] [158]}

The effect of hypoxia on PVR was assessed by measuring blood flow to an isolated lobe selectively ventilated with a hypoxic gas mixture and comparing it with total pulmonary blood flow with the remainder of the lung ventilated with 100% oxygen.^{[159] [160]} A significant decrease in flow to the isolated lobe occurred in the presence of localized alveolar hypoxia during constant pulmonary blood flow (i.e., cardiac output), pulmonary artery pressure, and left atrial pressure. Neither halothane nor nitrous oxide administered to the isolated lobe diminished the magnitude of HPV, but a dose-related inhibition was demonstrated during administration of isoflurane. When these experiments were repeated with the anesthetic administered to the remainder of the lung instead of isolated lobar segment, halothane, isoflurane, and enflurane reduced cardiac output, but the effects on blood flow to the isolated segment were almost identical to those obtained when volatile agents were administered to the isolated lobe alone.

The mechanism of the direct inhibitory action of inhaled anesthetics on HPV is unclear but may be related to enhancement of arachidonic acid metabolism ^{[152] [161]} or other endothelium-derived vasodilating factors.^[162] Conversely, other evidence suggests that inhaled anesthetic-induced inhibition of HPV may occur independent of the presence of pulmonary vascular endothelium, NO, or guanylate cyclase.^{[163] [164] [165]}

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Figure 6-8 Concentration-dependent inhibition of hypoxic pulmonary vasoconstriction (HPV) in isolated rabbit lungs by desflurane (solid squares) and halothane (open squares). Values are mean ± SEM and expressed as a percentage of control (*P < .05 versus control HPV). The half-maximum inhibiting effect (ED₅₀ ) values were within the range of 1 to 2 minimum alveolar concentrations (MACs) for rabbits for both agents. (Reproduced from Loer SA, Scheeren TWL, Tarnow J: Desflurane inhibits hypoxic pulmonary vasoconstriction in isolated rabbit lungs. Anesthesiology 83:552, 1995.)

Inhaled anesthetics also disrupt Ca²⁺ homeostasis in vascular smooth muscle and thereby interfere with pulmonary vasoconstriction.^[166] Halothane and isoflurane attenuated endothelium-dependent vasodilation by inhibiting accumulation of cGMP^[165] and a K_ATP channel-mediated interaction between NO and prostacyclin in isolated canine pulmonary artery rings.^{[167] [168]} In contrast, isoflurane modulated the HPV response, at least in part through Ca²⁺ -activated and voltage-sensitive K⁺ but not K_ATP channels in isolated rabbit lungs. Attenuation of HPV by sevoflurane was independent of K⁺ channel function.^[169] Rats with liver cirrhosis exhibit a blunted HPV response and arterial hypoxemia. These cirrhotic rats demonstrate increased NO and reduced endothelin concentration, but the blunted HPV response observed in these animals does not involve these systems and is mediated instead by activation of Ca²⁺ -activated K⁺ channels.^[170] Halothane, isoflurane, enflurane, and desflurane also attenuate K_ATP channel- and endothelin-mediated pulmonary vasodilation in chronically instrumented dogs,^{[171] [172] [173]} in part by inhibiting vasodilatory prostanoids. ^{[167] [174]} The inhibition of pulmonary vasodilation is not a uniform observation during administration of all volatile agents in all circumstances, because isoflurane and halothane, but not enflurane, enhance isoproterenol-mediated vasodilation.^{[175] [176]} Unlike the findings with other volatile agents tested, the sevoflurane-induced pulmonary vasodilation mediated by K_ATP channels is also preserved.^[173] Isoflurane also attenuates hypotension-induced pulmonary vasoconstriction.^[177]

Studies have investigated an apparent biphasic action of volatile anesthetics on isolated pulmonary arterial strips. Dose-dependent increases in force are initially observed with volatile agents after Ca²⁺ release from intracellular stores (associated with protein kinase C activation). Subsequently, a decrease in force (associated with a Ca²⁺ -calmodulin-dependent protein kinase II activation) occurs ( Fig. 6-9 ).^{[178] [179] [180]} Extrapolation of these results in isolated pulmonary artery strips to humans in vivo must be performed cautiously. Nevertheless, the clinical implications of these studies are important and suggest that volatile anesthetics may cause initial pulmonary arterial vasoconstriction before vasodilation. The vasodilatory response may be more profound in patients with low sarcoplasmic reticulum Ca²⁺ stores (i.e., neonates) or those with depressed protein kinase C activity (i.e., primary pulmonary hypertension).

The findings from in vitro studies suggest that volatile anesthetics exert inhibitory actions on HPV, but results from in vivo investigations usually have shown little or no effect. Sykes and associates^[181] examined the effects of one-lung hypoxia on relative pulmonary blood flow distribution measured using xenon in dogs. One lung was ventilated with nitrogen, and the other was ventilated with 100% oxygen. A redistribution of flow to the well-oxygenated lung was found consistent with active HPV. This action was preserved during administration of halothane (inspired concentrations = 3%). In contrast, ether and nitrous oxide profoundly affected the redistribution of pulmonary blood flow in response to hypoxia using the same experimental preparation.^{[182] [183]} Other in vivo investigations have also verified that nitrous oxide markedly attenuates HPV.^{[159] [160] [184]} In contrast, clinically relevant concentrations of halothane, isoflurane, enflurane, sevoflurane, and desflurane appear to have minimal effects on HPV in vivo ( Fig. 6-10 ). ^{[159] [160] [185] [186] [187] [188] [189] [190] [191]} Lennon and Murray^[161] suggested that isoflurane anesthesia may attenuate HPV by inhibiting vasodilatory prostanoids in chronically instrumented dogs. Pulmonary vascular perfusion pressure (determined by the difference between

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Figure 6-9 A, Proposed signaling pathways underlying volatile anesthetic (halothane and isoflurane)-induced contraction and relaxation in pulmonary artery smooth muscle. After Ca²⁺ release from intracellular stores, there are dose-dependent increases in force initially (associated with protein kinase C activation), which is followed by a decrease in force (associated with a Ca²⁺ -calmodulin-dependent protein kinase II activation). High concentrations of halothane may activate a protein kinase C-Ca²⁺ -calmodulin-dependent protein kinase II pathway. B, Example of biphasic (contraction-relaxation) effect of halothane on pulmonary arterial smooth muscle. Halothane dose-dependently enhanced Ca²⁺ -activated peak force as well as late relaxation. 0%, 1%, 2%, and 3%, halothane concentrations; ss, control force at steady state before halothane. (Adapted from Su JY, Vo AC: Ca²⁺ -calmodulin-dependent protein kinase II plays a major role in halothane-induced dose-dependent relaxation in the skinned pulmonary artery. Anesthesiology 97:207, 2002 and from Zhong L, Su JY: Isoflurane activates PKC and Ca²⁺ -calmodulin-dependent protein kinase II via MAP kinase signaling in cultured vascular smooth muscle cells. Anesthesiology 96:148, 2002.)

Figure 6-10 Composite hypoxic pulmonary vasoconstriction (HPV) responses as a function of left pulmonary flow in the same seven chronically instrumented dogs in the conscious state and during sevoflurane and desflurane anesthesia. Neither type of anesthesia affected the magnitude of HPV compared with the response in the conscious state. (Adapted from Lesitsky MA, Davis S, Murray PA: Preservation of hypoxic pulmonary vasoconstriction during sevoflurane and desflurane anesthesia compared to the conscious state in chronically instrumented dogs. Anesthesiology 89:1501, 1998.)