AN ABSTRACT OF THE THESIS OF Chiara De Caro Carella for the degree of Master of Science in Veterinary Science pre- sented on June 9, 2016 Title: Effect of Intravenous Tiletamine-zolazepam for Induction of General Anesthesia Prior to and during Maintenance with Isoflurane on Cardiorespiratory Parameters and Acid-base Status in Healthy Dogs: A Comparison with Alfaxalone, Ketamine-diaze- pam, and Propofol. Abstract approved: _____________________________________________________ Ronald E. Mandsager Abstract: The effects of alfaxalone (A-HPCD), propofol (P), ketamine-diazepam (KD) and tilet- amine-zolazepam (TZ) administered IV in dogs on cardiovascular and respiratory sys- tems, acid-base balance and electrolytes have been reported in the literature, but a study that compares IV TZ to the other induction protocols (IP) is needed. Six dogs enrolled in a randomized-crossover study were anesthetized with sevoflurane and instrumented. After at least 30 minutes post-recovery, baseline values for cardiovascular and respir- atory parameters were determined, cardiac output (CO) measured via thermodilution, and arterial (Art) and mixed venous (MV) blood samples collected. Anesthesia was induced with A-HPCD (4 mg/kg), P (6 mg/kg), KD (7 and 0.3 mg/kg, respectively), or TZ (5 mg/kg) administered IV in quarter increments to effect, and maintained with isoflurane (Et 1.14 ± 0.32%) for 60 minutes. Immediately post-induction (PI) and at Iso 10, 20, 40, and 60 minutes all measurements were repeated and blood sampled. Derived hemodynamic parameters were calculated. Cardiorespiratory and acid-base parameters compared with RM-ANOVA and a post-hoc t-test were considered significant when p < 0.05. The parameter most affected by protocol was heart rate (HR), with TZ produc- ing the highest HR PI and at 40 and 60 minutes. Oxygen delivery (DO ) was best main- 2 tained by TZ in the first 20 min, while A-HPCD maintained the highest DO at 60 2 minutes. No significant differences for CO, cardiac index, mean arterial pressure, and systemic vascular resistance were found among IP. Although still within normal limits, mean MV pH, Art and MV potassium were similarly increased with TZ and KD com- pared to P and A-HPCD. Although statistical significance was found for EtCO , pH, 2 lactate, and serum potassium, values stayed in the normal clinical range. TZ produced comparable respiratory changes to KD. Intravenous induction of general anesthesia with TZ maintained on isoflurane is a safe alternative to A-HPCD, KD, and P in healthy dogs and it is recommended for short anesthetic procedures. ©Copyright by Chiara De Caro Carella June 9, 2016 All Rights Reserved Effect of Intravenous Tiletamine-zolazepam for Induction of General Anesthesia Prior to and during Maintenance with Isoflurane on Cardiorespiratory Parameters and Acid-base Status in Healthy Dogs: A Comparison with Alfaxalone, Ketamine-diaze- pam, and Propofol by Chiara De Caro Carella A THESIS Submitted to Oregon State University in partial fulfillment of the requirements for the degree of Master of Science Presented June 9, 2016 Commencement June 2017 Master of Science thesis of Chiara De Caro Carella presented on June 9, 2016 APPROVED: Major Professor, representing Veterinary Science Dean of the College of Veterinary Medicine Dean of the Graduate School I understand that my thesis will become part of the permanent collection of Oregon State University libraries. My signature below authorizes release of my thesis to any reader upon request. Chiara De Caro Carella, Author ACKNOWLEDGEMENTS I would like to express my most sincere appreciation to Dr Thomas Riebold for his exceptional mentorship throughout my residency and this project. I would like to thank my graduate committee members, Dr Ron Mandsager (ODM), Dr Michael Huber, Dr Jennifer Warnock, and Dr Jana Gordon for their pre- cious support throughout my time at the Teaching Hospital. I would also truthfully thank Dr David Sisson, Dr Kate Scollan and Dr LeBlanc for their priceless help with the design and the realization of this research, April Si- mons, Jennifer Houston, and Shauna Smith for their effort and support with and during this project, Robyn Panico and Amy Berry for their infinite help with the instrument troubleshooting, and Dr Diggs for her extramural help and support. I wish to thank the amazing dogs involved in this extenuating project. You have impressed me every day for your professionalism. Finally, I wish to acknowledge the generous financial support provided by Zo- etis to make this research project possible. Thank you all. TABLE OF CONTENTS Page 1. Introduction……………………………………………………………………..…2 2. Objectives and Hypothesis………………………………………………………...6 3. Literature Review………………………………………………………………….8 3.1. General Anesthesia…………………………………………………8 3.2. Anesthetic Risk……………………………………………………..9 3.3. Respiratory Physiology for Anesthesia…………………………...10 3.4. Cardiovascular Physiology for Anesthesia………………………..17 3.5. Acid-Base Balance and Electrolytes and Anesthesia……………..27 3.6. Anesthetic Agents…………………………………………………34 3.6.1. Tiletamine-Zolazepam……………………………..…34 3.6.2. Alfaxalone-HPCD…………………………………….38 3.6.3. Ketamine-Diazepam……………………………….....42 3.6.4. Propofol…………………………………………..….46 3.6.5. Isoflurane…………………………….…………...….48 3.6.6. Recovery from General Anesthesia……………..…...49 4. Materials and Methods……………………………………………………...……62 4.1. Ethical Approval…………………………………………..……..62 4.2. Study Design……………………………………………...……...62 4.3. Animals…………………………………………………...……...62 4.4. Techniques………………………………………………..……...63 4.4.1. Arterial Blood Pressure Measurements……….....…..63 4.4.2. Cardiac Output Measurement………………………..65 4.5 Phase I: Instrumentation………………...…………………....….69 4.6 Phase II: Recovery from phase I……………………………...….71 4.7 Phase III: Measurements…………………………………...…….72 4.8 Phase IV: Recovery from Phase III………………………...……77 4.9 Post-hoc Calculated Parameters…………………………..……..78 4.10 Recovery Scores……………………………………………..…..78 Page 4.11 Statistical Analysis…………………………………………...…..79 5. Results………………………………………………………………….…..…….88 5.1. Cardiovascular Effects………………………………….…..……89 5.2. Respiratory Effects…………………………………….…..……..92 5.3. Effects on Acid-base and Electrolytes……………………..…….93 5.4. Recovery………………………………………………..………..94 6. Discussion………………………………………………………………...….....111 7. Conclusion……………………………………………………………..……….124 8. References……………………………………………………………...……….125 9. Appendix…………………………………………………………………...…...151 9.1. Abbreviations…………………………………………...……...151 LIST OF FIGURES Figure Page Figure 1. Oxyhemoglobin dissociation curve………………………………………..53 Figure 2. Determinants of oxygen delivery………………………………………….54 Figure 3. Frank Starling's curve showing physiologic relationship between stroke vol- ume and preload (solid line) in normal cardiac function. ………………….……......55 Figure 4. Relationship of oxygen saturation to oxygen content……………………..56 Figure 5. Gamblegram of the electrolyte distribution in normal canine plasma…….58 Figure 6. Relationship between oxygen delivery (DO ) and consumption (VO )…..59 2 2 Figure 7.Characteristic pressure waveforms of right atrium, right ventricle, pulmonary artery, and wedged pulmonary artery encountered while advancing a pulmonary arte- rial catheter into the pulmonary artery…………………………………………......…83 Figure 8. Cardiac output dilution curve by thermodilution technique. In orange the area under the curve (AUC)………………………………………………………….84 Figure 9. Cardiac output dilution curves. (a) represents a normal cardiac output, (b) a high cardiac output (small area under the curve), and (c) a low cardiac output (large area under the curve)…………………………………………………………………85 Figure 10. Fluroroscopy image of a pulmonary arterial catheter (PAC) in place before and during cardiac output measurements…………………………………………….87 Figure 11. Sample cardiac output measurement performed during the study. Values with variation > 10% in absolute value were discarded and three accepted measure- ments averaged………………………………………………………..……………...88 Figure 12. Keys for plot interpretation……………………………………………..103 Figure 13. Plots showing trends of heart rate (HR), cardiac output (CO), oxygen de- livery (DO ), and oxygen consumption (VO ) from baseline (-10) to 60 minutes post- 2 2 induction with four different induction regimens………………………..…………104 Figure 14. Plots showing trends of systolic arterial blood pressure (SABP), diastolic arterial blood pressure (DABP), mean arterial blood pressure (MABP), and total arte- rial Hb (Hb ) from baseline (-10) to 60 minutes post-induction with four different in- a duction regimens……………………………………………………………………105 Figure 15. Plots showing trends of systemic vascular resistance (SVR), and pulmo- nary vascular resistance (PVR) from baseline (-10) to 60 minutes post-induction with four different induction regimens…………………………………………..………106 Figure 16. Plots showing trends of oxygen saturation of arterial blood (SaO ), partial 2 pressure of oxygen (PaO ) and carbon dioxide (PaCO ) in arterial blood, and end- 2 2 tidal partial pressure of carbon dioxide (EtCO ) from baseline (-10) to 60 minutes 2 post-induction with four different induction regimens…………..…………………107 Figure 17. Plots showing trends of serum potassium of arterial (K+ arterial) and mixed-venous (K+ mixed) blood, and arterial and mixed venous concentrations of lac- tate from baseline (-10) to 60 minutes post-induction with four different induction regimens…………………………………………………………………………….108 Figure 18. Plot showing the relationship between average recovery scores and recov- ery time for six dogs anesthetized in 24 episodes with four different induction regi- mens. Lowest recovery scores are concentrated in a recovery time ranging between 10 and 16 minutes…………………………………..………………………………109 Figure 19. Stripchart showing distribution of recovery times according to drug admin- istered for induction of anesthesia in 6 dogs maintained under anesthesia with isoflu- rane at MAC values………………………………….……………………………..110