Carol A. Hirshman

Wheezing during induction of general anesthesia in patients with and without asthma : a randomized, blinded trial

BackgroundPatients with asthma who require general anesthesia and tracheal intubation are at increased risk for the development of bronchospasm during induction. The incidence of wheezing during induction with different intravenously administered agents is unknown. A randomized, double-blinded prosp

Mechanism of Action of Inhalational Anesthesia on Airways

To separate reflex from direct actions of anesthetics on airways, we studied the effects of halothane and isoflurane (1.5 MAC) on Ascaris antigen-induced (a mixed reflex and direct stimulus) and methacholine-induced (a direct acting stimulus) airway constriction in Basenji-Greyhound dogs. Prior to aerosol challenge, pulmonary resistance (RL) and dynamic compliance (Cdyn) were not different during control (thiopental), halothane, and isoflurane anesthesia. RL was 1.93 · 0.15 (mean · SE), 1.81 · 0.23 and 2.1 cm 0.12 cm H2. l−1.s during thiopental, halothane, and isoflurane, respectively. Cdyn was 116 · 8, 106 · 16 and 110 · 9 ml/cmH3O during thiopental, halothane, and isoflurane anesthesia, respectively. In control studies (thiopental), Ascaris antigen increased RL by 9·4 · 2.44 fold and decreased Cdyn to 0.29 · .02 times the prechallenge value. Both halothane and isoflurane anesthesia significantly attenuated the increase in RL provoked by Ascaris antigen challenge and halothane significantly attenuated the decrease in Cdyn. During halothane and isoflurane anesthesia, Ascaris antigen increased RL by 3.8 · 0.96 and 3.5 · 0.57 fold, respectively, and decreased Cdyn to 0.48 · 0.09 and 0.38 · .07 times the prechallenge value, respectively. In control studies (thiopental anesthesia), methacholine produced dose-related increases in RL and decreases in Cdyn. Both halothane and isoflurane attenuated the increase in RL and the decrease in Ccyn provoked by methacholine with halothane being more effective than isoflurane with regards to Cdyn. The mechanism of action of halothane and isoflurane on airways is similar and complex, involving depression of airway reflexes as well as direct effects on airway smooth muscle.

Anesthesia for Laser Surgery

Laser surgery offers several advantages to the surgeon and patient: microscopic precision, a bloodless operative field, and complete sterility. While the majority of procedures pose few problems beyond protection of the eyes of operating room personnel and patients, microlaryngeal surgery with the CO2 laser requires very careful anesthetic management. A preoperative visit to determine the degree of existing airway obstruction is mandatory in deciding the safest anesthetic technique. Continued communication and cooperation between the surgeon and anesthesiologist throughout the procedure will help minimize the conflicting needs for airway access and ventilation. We feel the best approach to the anesthetic management of patients undergoing laser airway surgery is to have several alternatives available at the time of induction of anesthesia. For adult patients wrapped tubes, metal tubes, and a jet injector should be on hand. The options are more limited in children. The smallest metal tubes available have external diameters of 6 mm (Norton tube) or 7 mm (Porch tube), which are too large to use in these younger patients. Small wrapped, uncuffed tubes or Venturi ventilation through a small-gauge needle are most often used. Regardless of the technique, constant vigilance throughout the procedure is required to detect complications early. Wrapped tubes, metal tubes, insufflation using no tube, and jet ventilation using a needle or metal tube reduce the fire hazard but each method substitutes its own set of problems. Before adopting any approach, we strongly recommend that the equipment selected be tested for flammability with the laser before its use in patients. If, in spite of precautions, ignition of equipment does occur, immediately interrupt the flow of oxygen and nitrous oxide as most materials do not burn readily in air. Then remove the offending material. We have reviewed selected aspects of the management of the patient undergoing laser surgery, outlined the principles of laser technology, and listed the many surgical procedures employing lasers. Also, recommendations on anesthetic management of microlaryngeal surgery with the CO2 laser with emphasis on currently available measures to prevent problems were reviewed in light of our own experience with this technique along with a summary of the literature on laser surgery. An understanding of the fundamental principles and applications of lasers will hopefully lead to safer patient care.

Actin reorganization in airway smooth muscle cells involves Gq and Gi-2 activation of Rho

Extracellular stimuli induce cytoskeleton reorganization (stress-fiber formation) in cells and Ca2+ sensitization in intact smooth muscle preparations by activating signaling pathways that involve Rho proteins, a subfamily of the Ras superfamily of monomeric G proteins. In airway smooth muscle, the agonists responsible for cytoskeletal reorganization via actin polymerization are poorly understood. Carbachol-, lysophosphatidic acid (LPA)-, and endothelin-1-induced increases in filamentous actin staining are indicative of actin reorganization (filamentous-to-globular actin ratios of 2.4 +/- 0.3 in control cells, 6.7 +/- 0.8 with carbachol, 7.2 +/- 0.8 with LPA, and 7.4 +/- 0.9 with endothelin-1; P < 0.001; n = 14 experiments). Although the effect of all agonists was blocked by C3 exoenzyme (inactivator of Rho), only carbachol was blocked by pertussis toxin. Although carbachol-induced actin reorganization was blocked in cells pretreated with antisense oligonucleotides directed against Galphai-2 alone, LPA- and endothelin-1-induced actin reorganization were only blocked when both Galphai-2 and G(q)alpha were depleted. These data indicate that in human airway smooth muscle cells, carbachol induces actin reorganization via a Galphai-2 pathway, whereas LPA or endothelin-1 induce actin reorganization via either a Galphai-2 or a Gqalpha pathway.

Carbachol-induced actin reorganization involves Gi activation of Rho in human airway smooth muscle cells

To determine whether M2 muscarinic receptors are linked to the monomeric G protein Rho, we studied the effect of carbachol on actin reorganization (stress fiber formation) in cultured human airway smooth muscle cells that expressed mainly M2 muscarinic receptors by dual- fluorescence labeling of filamentous (F) and monomeric (G) actin. F-actin was labeled with FITC-labeled phalloidin, and G-actin was labeled with Texas Red-labeled DNase I. Carbachol stimulation induced stress fiber formation (increased F-actin staining) in the cells and increased the F- to G-actin ratio 3.6 ± 0.4-fold (mean ± SE; n = 5 experiments). Preincubation with pertussis toxin, Clostridium C3 exoenzyme, or tyrosine kinase inhibitors reduced the carbachol-induced increase in stress fiber formation and significantly decreased the F- to G-actin ratio, whereas a mitogen-activated protein kinase inhibitor, a phosphatidylinositol 3-kinase inhibitor, and a protein kinase C inhibitor were without effect. This study demonstrates that in cultured human airway smooth muscle cells, muscarinic-receptor activation induces stress fiber formation via a pathway involving a pertussis-sensitive G protein, Rho proteins, and tyrosine phosphorylation.To determine whether M2 muscarinic receptors are linked to the monomeric G protein Rho, we studied the effect of carbachol on actin reorganization (stress fiber formation) in cultured human airway smooth muscle cells that expressed mainly M2 muscarinic receptors by dual-fluorescence labeling of filamentous (F) and monomeric (G) actin. F-actin was labeled with FITC-labeled phalloidin, and G-actin was labeled with Texas Red-labeled DNase I. Carbachol stimulation induced stress fiber formation (increased F-actin staining) in the cells and increased the F- to G-actin ratio 3.6 +/- 0.4-fold (mean +/- SE; n = 5 experiments). Preincubation with pertussis toxin, Clostridium C3 exoenzyme, or tyrosine kinase inhibitors reduced the carbachol-induced increase in stress fiber formation and significantly decreased the F- to G-actin ratio, whereas a mitogen-activated protein kinase inhibitor, a phosphatidylinositol 3-kinase inhibitor, and a protein kinase C inhibitor were without effect. This study demonstrates that in cultured human airway smooth muscle cells, muscarinic-receptor activation induces stress fiber formation via a pathway involving a pertussis-sensitive G protein, Rho proteins, and tyrosine phosphorylation.

Inhibitory Effects of Thiopental, Ketamine, and Propofol on Voltage-dependent Calcium sup 2+ Channels in Porcine Tracheal Smooth Muscle Cells

Background Intravenously administered anesthetics directly inhibit airway smooth muscle contraction. Because many anesthetic agents affect membrane ion channel function and sustained contraction of airway smooth muscle requires the influx of Calcium2+ through voltage‐dependent Calcium2+ channels, it was hypothesized that intravenous anesthetics inhibit airway smooth muscle voltage‐dependent Calcium2+ channels.

Hypoxic Ventilatory Drive in Dogs during Thiopental, Ketamine, or Pentobarbital Anesthesia

The ventilatory responses to isocapnic hypoxia and hypercapnia were studied in seven chronically tracheostomized dogs awake and during anesthesia with pentobarbital (30 mg/kg, iv), ketamine, or thiopental (10 and 15 mg/kg, respectively, followed by infusion). Isocapnic hypoxic ventilatory drive (HVD) was expressed as the parameter A such that the higher the A, the greater the hypoxic drive. HVD(A) was significantly reduced from 259 ± 28 (mean ± SEM) in awake dogs, to 96 ± 14 after pentobarbital, 161 ± 27 after thiopental, and 213 ± 23 after ketamine. Hypercapnic ventilatory drive (HCVD) as measured by S (slope of the VE – PAco2 response curve) was significantly reduced from 1.3 ± .32 in awake dogs to 0.4 ± .13 after pentobarbital, 0.5 ± .12 after thiopental, and 0.6 ± .11 after ketamine. In addition, hypercapnia-induced augmentation of hypoxic drive was markedly diminished by the two barbiturates but was unaffected by ketamine. Therefore, ketamine at this dose level afforded greater protection during exposure to hypoxia than did barbiturates.

A mechanism for rapacuronium-induced bronchospasm: M2 muscarinic receptor antagonism.

Background A safe and effective ultra-short-acting nondepolarizing neuromuscular blocking agent is required to block nicotinic receptors to facilitate intubation. Rapacuronium, which sought to fulfill these criteria, was withdrawn from clinical use due to a high incidence of bronchospasm resulting in death. Understanding the mechanism by which rapacuronium induces fatal bronchospasm is imperative so that newly synthesized neuromuscular blocking agents that share this mechanism will not be introduced clinically. Selective inhibition of M2 muscarinic receptors by muscle relaxants during periods of parasympathetic nerve stimulation (e.g., intubation) can result in the massive release of acetylcholine to act on unopposed M3 muscarinic receptors in airway smooth muscle, thereby facilitating bronchoconstriction. Methods Competitive radioligand binding determined the binding affinities of rapacuronium, vecuronium, cisatracurium, methoctramine (selective M2 antagonist), and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; selective M3 antagonist) for M2 and M3 muscarinic receptors. Results Rapacuronium competitively displaced 3H-QNB from the M2 muscarinic receptors but not from the M3 muscarinic receptors within clinically relevant concentrations. Fifty percent inhibitory concentrations (mean ± SE) for rapacuronium were as follows: M2 muscarinic receptor, 5.10 ± 1.5 &mgr;m (n = 6); M3 muscarinic receptor, 77.9 ± 11 &mgr;m (n = 8). Cisatracurium and vecuronium competitively displaced 3H-QNB from both M2 and M3 muscarinic receptors but had affinities at greater than clinically achieved concentrations for these relaxants. Conclusions Rapacuronium in clinically significant doses has a higher affinity for M2 muscarinic receptors as compared with M3 muscarinic receptors. A potential mechanism by which rapacuronium may potentiate bronchoconstriction is by blockade of M2 muscarinic receptors on prejunctional parasympathetic nerves, leading to increased release of acetylcholine and thereby resulting in M3 muscarinic receptor–mediated airway smooth muscle constriction.

Comparison of low concentrations of halothane and isoflurane as bronchodilators

Background: Although high concentrations of all currently used inhalational anesthetics are thought to be good bronchodilators, studies using traditional measures of airway tone fail to show differences in airway responsiveness during halothane, enflurance, and Isoflurane use. Using a more sensitive technique, the authors compared the ability of halothane and Isoflurane to dilate histamine-constricted airways at equivalent MAC concentrations. Methods:Responses of histamine-constricted individual airways to Increasing doses of halothane and Isoflurane were directly measured using high-resolution computed tomography (HRCT). Fifteen studies were performed in five dogs. All dogs were Initially anesthetized with thiopental 15 mg/kg followed by a 10-rng - kg-1 - h-1 maintenance dose. Following tracheal intubation, the lungs were mechanically ventilated (15 ml/kg, 15 bpm). The airways were constricted with intravenous histamine 200 µg/min. On alternate days, the dogs subsequently received Increasing concentrations of either halothane or Isoflurane (0.6,1.1, and 1.7 MAC). On a separate day, the dogs received atropine 0.2 mg/kg after the histamine infusion and the study was repeated. Results:Histamine decreased airway area 34 ± 2.5% (mean ± SEM). All preconstricted airways showed a significant dosedependent dilation to halothane and isoflurane at concentrations of 0.6,1.1, and 1.7 MAC. Halothane significantly dilated airways to a greater extent than isoflurane at 0.6 and 1.1 MAC (P <0.001). This effect was most pronounced In airways less than 3 mm In diameter. At 1.7 MAC, there was no significant difference between the two agents (P =0.42). Atropine (0.2 mg/kg) reversed the airway constriction elicited by Intravenous histamine. The histamine-preconstricted airways area Increased 370 ± 34% (P <0.0001) after atropine. Conclusions:Halothane and Isoflurane dilate histamineconstricted airways In a dose-dependent manner. However, at low concentrations, halothane was a more effective bronchodilator than isoflurane at equivalent MAC doses.

Neuromuscular relaxants as antagonists for M2 and M3 muscarinic receptors

BACKGROUND Neuromuscular relaxants such as pancuronium bind to M2 and M3 muscarinic receptors as antagonists. Blockade of muscarinic receptors in atria of the M2 subtype mediates tachycardia. In the lung, blockade of M2 receptors on parasympathetic nerves potentiates vagally induced bronchospasm, whereas blockade of M3 receptors on bronchial smooth muscle inhibits bronchospasm. The current study was designed to quantify the affinity of a series of neuromuscular relaxants for the M2 and M3 muscarinic receptors, which were individually stably transfected in Chinese hamster ovary cell lines. METHODS Competitive radioligand binding assays determined the relative binding affinities of the neuromuscular relaxants pancuronium, succinylcholine, mivacurium, doxacurium, atracurium, rocuronium, gallamine, and pipecuronium for the muscarinic receptor in the presence of a muscarinic receptor antagonist (3H-QNB) in membranes prepared from cells individually expressing either the M2 or M3 muscarinic receptor. RESULTS All muscle relaxants evaluated displaced 3H-QNB from muscarinic receptors. The relative order of potency for the M2 muscarinic receptor (highest to lowest) was pancuronium, gallamine, rocuronium, atracurium, pipecuronium, doxacurium, mivacurium, and succinylcholine. The relative order of potency for the M3 muscarinic receptor (highest to lowest) was pancuronium, atracurium, pipecuronium, rocuronium, mivacurium, gallamine, succinylcholine, and doxacurium. CONCLUSIONS All neuromuscular relaxants studied had affinities for the M2 and M3 muscarinic receptor, but only pancuronium and gallamine had affinities within the range of concentrations achieved with clinical use. The high affinities of gallamine and pancuronium for the M2 muscarinic receptor are consistent with a mechanism of M2 receptor blockade in relaxant-induced tachycardia.