PULMONARY BLOOD FLOW DISTRIBUTION AND HYPOXIC PULMONARY VASOCONSTRICTION IN PENTOBARBITAL-ANESTHETIZED HORSES DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Phillip Lerche, BVSc MS ***** The Ohio State University 2006 Dissertation Committee: Approved by Dr William W Muir III, Adviser Dr Robert L Hamlin ________________________ Dr John AE Hubbell Adviser Graduate Program in Veterinary Clinical Sciences ABSTRACT Anesthetized horses commonly develop undesirable hypoxemia when dorsally recumbent. The major reason for this is development of ventilation/perfusion (V/Q) mismatching associated with atelectasis of dependent lung tissue. Improving ventilation frequently does not improve oxygenation, suggesting that pulmonary blood flow distribution is abnormal during anesthesia. Perfusion is normally matched to ventilation by hypoxic pulmonary vasoconstriction (HPV). This mechanism causes pulmonary arterioles to constrict in areas where alveolar oxygen (O 2) tension is low, redirecting blood flow to better-ventilated alveoli, and is believed to be modulated by nitric oxide (NO). The purpose of this study was to evaluate blood flow distribution in the anesthetized horse and to investigate the role of NO as a regulator of HPV in the anesthetized dorsally recumbent adult horse. Six adult horses anesthetized with pentobarbital were intubated via tracheostomy with a double-lumen tube, which separated gas flow to left and right lungs. Each lung was individually ventilated via a dual-lung ventilator, and 100% O 2 was delivered to both lungs. A hypoxic/hyperoxic state was then induced by ventilating the left lung with 100% nitrogen (N 2) while 100% O 2 was delivered to the right lung. Nitric oxide (NO) production was manipulated by administration of L-arginine (a NO precursor) and L- ii NAME (a NO synthase inhibitor). Each horse was instrumented for collection of pulmonary and arterial blood O 2 tensions. Pulmonary blood flow distribution was determined by the pattern of distribution of fluorescent microspheres, which were injected intravenously at strategic time points. Lungs were harvested, dried and sectioned prior to neutron activation and spectrographic analysis of the microspheres. Blood flow was influenced somewhat by gravity, however distribution was mainly heterogeneous in isogravitational planes, and highest in the central lung. Hypoxic pulmonary vasoconstriction was not active in this model, as evidenced by persistent systemic hypoxemia after ventilation of the left lung with 100% N 2. Manipulation of NO produced appropriate changes in pulmonary arterial pressure, but had minimal effect on blood flow distribution and systemic arterial oxygenation. Our study suggest that manipulation of NO is unlikely to be helpful in correction of severe hypoxemia due to V/Q mismatching seen during anesthesia in clinical equine patients. iii Dedicated to Peter and Irene iv ACKNOWLEDGMENTS I wish to thank my adviser, Bill Muir, for his inspiring quest for scientific truth, his ability to evaluate everything with clear and critical thought, and his constant support. I would like to thank Chad Andrews, Cheri Edwards, Shawn Rosensteel, Steve Schumaker, Mike Suhie and Ashley Weise for help with the experiments. In addition to assisting with data collection and tabulation, Jennifer Gadawski deserves special thanks for her organizational skills and sense of humor which made the experimental phase run as smoothly as possible. Tim Vojt also deserves special thanks for providing some of the drawings for this document, and for his help with technical problems I encountered when creating the figures in the results section. This research was supported by a grant from the Southern California Equine Foundation, Inc. v VITA October 30, 1968 Born – Tynemouth, United Kingdom 1992 BVSc, University of Pretoria 1997 - 2000 Veterinary Anesthesiology Resident, The Ohio State University 2000 - present Graduate Research Associate, The Ohio State University 2002 MS (Veterinary Clinical Science), The Ohio State University 2004 Diplomate of the American College of Veterinary Anesthesiologists PUBLICATIONS 1. Lerche P, Muir WW. Effect of medetomidine on breathing and inspiratory neuromuscular drive in conscious dogs. American Journal of Veterinary Research, 2004, 65: 720-724 2. Drost TW, McLoughlin MA, Mattoon JS, Lerche P, Samii VF, DiBartola SP, Chew DJ, Barthez PY. Determination of extrarenal plasma clearance and hepatic uptake of technetium-99m-mercaptoacetyltriglycine in cats. American Journal of Veterinary Research, 2003, 64: 1076-1080 3. Hunter SL, Culp LB, Muir WW, Lerche P, Birchard SJ, Smeak DD, McLoughlin. MA Sodium nitroprusside-induced deliberate hypotension to facilitate patent ductus arteriosus ligation in dogs. Veterinary Surgery 2003 32: 336-40 4. Yamashita K, Muir WW, Tsubakishita S, Abrahamsen E, Lerche P, Izumisawa Y, Kotani T. Infusion of guaifenesin, ketamine, and medetomidine in combination with inhalation of sevoflurane versus inhalation of sevoflurane alone for anesthesia of horses. Journal of the American Veterinary Medical Association, 2002 221: 1150- vi 1155 5. Yamashita K, Muir WW 3rd, Tsubakishita S, Abrahamsen E, Lerche P, Hubbell JA, Bednarski RM, Skarda RT, Izumisawa Y, Kotani T. Clinical comparison of xylazine and medetomidine for premedication of horses. Journal of the American Veterinary Medical Association, 2002 221: 1144-1149 6. Lerche P, Muir WW, Grubb TL. Mask induction of anaesthesia with isoflurane or sevoflurane in premedicated cats. Journal of Small Animal Practice, 2002; 43: 12-15 7. Muir WW, Lerche P, Robertson JT, Hubbell JA, Beard W, Miller T, Badgley B, Bothwell V. Comparison of four drug combinations for total intravenous anesthesia of horses undergoing surgical removal of an abdominal testis. Journal of the American Veterinary Medical Association, 2000; 217: 869-873 8. Lerche P, Nolan AM, Reid J. Comparative study of propofol or propofol and ketamine for the induction of anaesthesia in dogs. Veterinary Record, 2000; 146: 571-574 9. Flaherty D, Reid J, Welsh E, Monteiro AM, Lerche P, Nolan A. A pharmacodynamic study of propofol or propofol and ketamine infusions in ponies undergoing surgery. Research in Veterinary Science. 1997; 62: 179-184 FIELDS OF STUDY Major field: Veterinary Clinical Science vii TABLE OF CONTENTS Page Abstract...........................................................................................................................ii Dedication......................................................................................................................iv Acknowledgments...........................................................................................................v Vita ................................................................................................................................vi List of tables..................................................................................................................xii List of figures...............................................................................................................xiii Chapters: 1. Introduction...............................................................................................................1 1.1 Hypoxemia in anesthetized horses........................................................................1 1.2 Sequelae of hypoxemia ........................................................................................2 1.3 Causes of hypoxemia ...........................................................................................4 1.3.1 Hypoventilation...........................................................................................4 1.3.2 Decreased FiO 2 ...........................................................................................6 1.3.3 Diffusion impairment..................................................................................6 1.3.4 Shunt...........................................................................................................6 1.3.5 Ventilation-perfusion inequality ..................................................................7 1.4 Blood flow and ventilation distribution ...............................................................9 1.4.1 Distribution of ventilation ...........................................................................9 1.4.2 Distribution of blood flow ...........................................................................9 1.4.2.1 Passive mechanisms .........................................................................10 1.4.2.2 Active mechanisms...........................................................................11 1.5 Hypoxic pulmonary vasoconstriction .................................................................11 1.6 Nitric oxide........................................................................................................12 1.7 Investigation into the cause and resolution of hypoxemia in the anesthetized horse........................................................................................................................13 1.7.1 Body position............................................................................................14 1.7.2 Ventilation strategies.................................................................................15 viii 1.7.3 Drugs........................................................................................................15