Section 2: Scientific Principles
Part A: Inhaled Anesthetics
Chapter 5B: Pulmonary Pharmacology

Inhaled Anesthetics and Hypoxic Pulmonary Vasoconstriction

Many mechanisms exist, such as pulmonary atelectasis and diminished functional residual capacity relative to closing capacity of the lung, that cause a decrease in oxygenation and an increase in P(A-a)O2 during anesthesia. The effects of numerous inhaled anesthetics on HPV have been examined in a variety of animal and experimental models, with conflicting results. Experiments and results are summarized in Table 5B–1.

TABLE 5B–1. Effects of Inhaled Anesthetic on Airway Resistance

The effect of inhalational anesthetics on HPV is multifactorial, involving direct pulmonary vascular actions and indirect cardiovascular, autonomic, and humoral actions. In general, most in vitro studies have demonstrated some degree of attenuation of HPV with all inhalational anesthetics (Fig. 5B–26). Inhibition of HPV has been demonstrated with halothane, 71, 79, 80, 81, 82, 83  isoflurane 71, 72  enflurane, 71, 84  sevoflurane, 72  desflurane, 73  and nitrous oxide, using isolated perfused lungs or an in situ preparation with constant perfusion. 85, 86, 87  Marshall et al 71  examined the effects of halothane, enflurane, and isoflurane on the HPV response to global hypoxia. All three drugs dose-dependently depressed HPV, and similar MAC values (approximately 0.6 MAC) depressed HPV by 50 percent in an in vitro preparation allowing for control of lung perfusion and eliminating any effect of the sympathetic nervous system. A more recent study in isolated rat lungs confirmed depression of HPV by both isoflurane and halothane, but the addition of verapamil reduced HPV by an additional 35 to 40 percent, implying an additive effect and different sites of action. 88  Furthermore, halothane reduced the resistance of the middle vascular segment in atelectatic and hypoxic lung, suggesting a direct action on small vessels and capillaries. 82, 89

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FIGURE 5B–26 Concentration-dependent inhibition of hypoxic pulmonary vasoconstriction (HPV) in rabbit lungs by desflurane (closed circles) and halothane (open circles). Values are mean ± SEM and expressed as a percentage of control. *P < 0.05 versus control HPV. The half-maximum inhibiting effect (ED50) values were within the range of 1 and 2 MAC (for rabbits) for both agents. (From Loer et al73 )

With the left lower lobe of a dog lung selectively ventilated with an hypoxic gas mixture and the remainder of the lung ventilated with 100 percent oxygen, the effect of hypoxia on PVR was assessed by measuring blood flow to the isolated lobe and comparing it with total pulmonary blood flow. 90, 91  A significant decrease in flow to the isolated lobe occurred in the presence of localized alveolar hypoxia during constant pulmonary blood flow (cardiac output), pulmonary artery pressure, and left atrial pressure. Neither halothane nor nitrous oxide administered to the isolated lobe diminished the magnitude of HPV, although a dose-related inhibition could be demonstrated in the presence of isoflurane. These experiments were also performed with the anesthetic agent administered to the whole animal and to the isolated lung segment. Whereas halothane, isoflurane, and enflurane diminished cardiac output, the effects on blood flow to the isolated segment were almost identical to those obtained when administration of anesthetic gas was confined to the isolated lobe alone.

The mechanism of the direct inhibitory action of volatile anesthetics on HPV is unclear but may be related to enhancement of arachidonic acid metabolism 83, 92  or other endothelial-derived vasodilating factors. 93  However, volatile anesthetic-induced inhibition of HPV is not dependent on the presence of pulmonary vascular endothelium, nitric oxide, or guanylate cyclase. 94, 95, 96  Volatile anesthetics may also disrupt Ca2+ homeostasis, which is intimately involved in pulmonary vasoconstriction. Interestingly, halothane and isoflurane, in isolated canine pulmonary artery rings, attenuated endothelium-dependent vasodilation by inhibiting accumulation of cGMP 96  and an ATP-sensitive potassium channel-mediated interaction between nitric oxide and prostacyclin. 97  Halothane and enflurane also attenuate ATP-sensitive potassium channel–mediated pulmonary vasodilation in chronically instrumented dogs. 98  In contrast, isoflurane enhanced isoproterenol-mediated vasodilation. 99 

Findings from in vitro studies suggest that volatile anesthetics exert inhibitory actions on HPV, but results from in vivo investigations have been surprisingly inconclusive. Sykes et al 100  examined the effects of one-lung hypoxia on relative pulmonary blood flow distribution in dogs, as measured using xenon. 133  One lung was ventilated with nitrogen, and the other was ventilated with 100 percent oxygen. A redistribution of flow to the well-oxygenated lung was found, indicating active HPV, which was preserved in the presence of halothane at inspired concentrations of up to 3 percent. In contrast, using the same experimental preparation, ether and nitrous oxide profoundly affected the redistribution of pulmonary blood flow in response to hypoxia. 101, 102  Other in vivo investigations have also determined that nitrous oxide markedly attenuates HPV. 90, 91, 103  Halothane, isoflurane, and enflurane may have minimal or no effects on HPV in vivo.90, 91, 104, 105, 106, 107  Recently, Lennon and Murray 92  have shown that isoflurane anesthesia attenuates HPV in chronically instrumented dogs as compared with the response measured in the same animal in the conscious state. Pulmonary vascular pressure (pulmonary arterial pressure–left atrial pressure) versus pulmonary blood flow relationships were generated in the absence of baseline anesthesia and acute surgical trauma to demonstrate flow dependency of the HPV. Unlike the case of isoflurane, inhibition of HPV was not observed using the same preparation in the presence of sevoflurane or desflurane. 108