HYPERCAPNIC HYPERVENTILATION SPEEDS EMERGENCE FROM INHALED ANESTHESIA. Nishant A Gopalakrishnan

Transcription

1 HYPERCAPNIC HYPERVENTILATION SPEEDS EMERGENCE FROM INHALED ANESTHESIA By Nishant A Gopalakrishnan A dissertation submitted to the faculty of The University of Utah in partial fulfillment of the requirements of Doctor of Philosophy Department of Bioengineering The University of Utah December 2006

2 Copyright Nishant A Gopalakrishnan 2006 All Rights Reserved

3 THE UNIVERSITY OF UTAH GRADUATE SCHOOL SUPERVISORY COMMITTEE APPROVAL of a dissertation submitted by This dissertation has been read by each member of the following supervisory committee and by majority vote has been found to be satisfactory. Chair:

4 THE UNIVERSITY OF UTAH GRADUATE SCHOOL FINAL READING APPROVAL To the Graduate Council of the University of Utah: I have read the dissertation of in its final form and have found that (1) its format, citations, and bibliographic style are consistent and acceptable; (2) its illustrative materials including figures, tables, and charts are in place; and (3) the final manuscript is satisfactory to the supervisory committee and is ready for submission to The Graduate School. Date Chair: Supervisory Committee Approved for the Major Department Chair/Dean Approved for the Graduate Council David S. Chapman Dean of The Graduate School

5 ABSTRACT Anesthetic clearance from the lungs and the circle breathing system can be maximized using hyperventilation and high fresh gas flow. However, the concomitant clearance of CO 2 also lowers arterial partial pressure of CO 2 thereby decreasing cerebral blood flow and hence the clearance of anesthetic from the brain. Emergence time from inhaled anesthesia can be significantly reduced by maintaining hypercapnia (feedback controlled infusion of CO 2 or rebreathing) during hyperventilation. We anesthetized seven pigs with 2 MAC PIG (minimum alveolar concentration) of isoflurane and four each with 2 MAC PIG of sevoflurane or 1 MAC PIG of desflurane. After two hours of anesthesia, the animals were hyperventilated and the time to movement of multiple limbs was measured under hypocapnic (EtCO 2 =22 mmhg) and hypercapnic (EtCO 2 =55 mmhg) conditions. Emergence time from isoflurane and sevoflurane anesthesia was shortened by an average of 65% with rebreathing or with the CO 2 controller (p<0.05). The emergence times obtained from rebreathing were not statistically different from those obtained from precisely tuned feedback controller. We evaluated the differences in emergence time in fifty two surgical patients undergoing 1 MAC of isoflurane, sevoflurane or desflurane anesthesia under mild hypocapnia (EtCO 2 =29 mmhg) and mild hypercapnia (EtCO 2 =55 mmhg). The minute ventilation in half the patients was doubled during emergence and hypercapnia was maintained by insertion of additional airway dead space to keep the EtCO 2 close to 55

6 mmhg during hyperventilation. A charcoal canister adsorbed volatile anesthetic agent from the rebreathed dead space. Fresh gas flow was raised to 10 L/min during emergence in all the patients. The time between turning off the vaporizer and the time when the patients opened their eyes in response to command was faster when hypercapnic hyperventilation was maintained using the rebreathing adsorber (p<0.05). The time to tracheal extubation was shortened by 57%. We used a multi compartmental mathematical model to estimate cerebral awakening concentration of anesthetic agent (when patients responded to a command to open eyes) and emergence times from anesthesia. The normalized cerebral awakening concentration to age adjusted MAC for desflurane, sevoflurane and isoflurane were ± 0.044, ± and ± respectively. The root mean square error of the performance error (calculated as a percent of the predicted value) was between 10% and 24%. The model estimated that there will be at least a 56% reduction in emergence time with hypercapnic hyperventilation. The emergence time after isoflurane, sevoflurane and desflurane anesthesia was shortened significantly by using hypercapnic hyperventilation. The rebreathing device described in the study should be considered following a surgical procedure where a high concentration of the anesthetic agent is maintained right up to the end of the procedure or when surgery ends abruptly without warning. v

7 TABLE OF CONTENTS ABSTRACT iv LIST OF TABLES viii LIST OF FIGURES ix ACNOWLEDGEMENTS xi 1. INTRODUCTION Inhaled Anesthetic Agents Anesthesia Delivery System MAC and MAC awake Pharmacology of Inhaled Anesthetics Recovery from Anesthesia Importance of a Rapid Recovery References ANIMAL STUDIES Abstract Introduction Methods Results Discussion Conclusions References CLINICAL EVALUATION OF REBREATHING DEVICE Abstract Introduction Methods Results Discussion Conclusions References

8 4. MODEL TO PREDICT EMERGENCE FROM INHALED ANESTHESIA Abstract Introduction Methods Results Discussion Conclusions References SUMMARY AND CONCLUSIONS Project Overview Conclusions Limitations of the Study Future Work References APPENDIX: EQUATIONS USED IN THE MATHEMATICAL MODEL vii

9 LIST OF TABLES Table Page 1.1. Tissue/blood partition coefficients Average cost of 1 MAC hour of anesthesia Average time to spontaneous breathing, EtCO 2 during emergence, pre-emergence minute ventilation and emergence minute ventilation Patient demographics Duration of surgery and total dose of opioids EtCO 2 at extubation, pre-emergence and emergence BIS and minute ventilation Time to open eyes, mouth and extubation Volume and blood flow for each compartment Partition coefficients used in the model Performance measures of the model during each trial Estimated emergence times after 0.5, 2 and 8 hours of anesthesia Estimated total inhaled and exhaled agent after 0.5,2 and 8 hours of anesthesia

10 LIST OF FIGURES Figure Page 1.1. Circle breathing circuit Block diagram of feedback controller Rebreathing device with rebreathing hose, activated charcoal and one-way valves Simulated EtCO 2 for a various rebreathing hose volumes Normalized BIS during emergence from isoflurane and desflurane Average time to movement of multiple limbs after isoflurane, sevoflurane and desflurane anesthesia Average time to normalized BIS to rise to 0.95 after isoflurane, sevoflurane and desflurane anesthesia Average time to movement of multiple limbs after 1 MAC of desflurane anesthesia Typical controller tuning curves for the proportional constant Typical controller tuning curves for the integral constant Response of the controller for a step change in ventilation and set point Inspired agent concentration for the rebreathing device with and without valves Rebreathing device Normalized BIS during emergence from isoflurane, sevoflurane and desflurane anesthesia Average time to tracheal extubation after isoflurane, sevoflurane and desflurane anesthesia

11 3.4. Average time to normalized BIS to rise to 0.95 after isoflurane, sevoflurane and desflurane anesthesia Schematic of the compartments in the model Predicted and measured emergence times from 1 MAC of desflurane Predicted and measured emergence times from 1 MAC of sevoflurane Predicted and measured emergence times from 1 MAC of isoflurane Estimated emergence times from 1 MAC of desflurane for different combinations of EtCO 2 and minute ventilation Estimated emergence times from 1 MAC of sevoflurane for different combinations of EtCO 2 and minute ventilation Estimated emergence times from 1 MAC of isoflurane for different combinations of EtCO 2 and minute ventilation x

12 ACKNOWLEDGMENTS First and foremost, I would like to thank Dr Westenskow for his generous support and for providing me with an opportunity to work with him on this project. I will always look back on my five years in the Anesthesia Bioengineering Laboratory with great fondness. I appreciate the time and guidance provided by the members of my supervisory committee: Dwayne Westenskow, Joseph Orr, Douglas Christensen, Kenneth Horch and Derek Sakata. I am also indebted to Robert G. Loeb at the University of Arizona, who reviewed this dissertation and provided many useful comments. I would like to thank Dr Sakata for his guidance and assistance with the clinical studies and Scott Mc James for his assistance with the animal studies. I would also like to thank Joseph Orr for his able guidance throughout the project. I am grateful to Anecare Laboratories for their support and interest in this project, to the Society of Technology in Anesthesia and the Anesthesiology Department at the University of Utah for the financial support they have provided. I would like to thank my parents and my wife for the support and encouragement they have provided over the years.

13 CHAPTER 1 INTRODUCTION 1.1 Inhaled anesthetic agents Inhaled anesthetic agents are available as volatile liquids which are vaporized and mixed with oxygen or air and delivered to the patient s lungs. The agent is absorbed from the alveoli into the systemic circulation and is distributed around the body and to the brain and spinal cord which are the sites of action of the drug. Elimination of agent occurs mainly through the lungs and a small amount may be eliminated by the kidneys and liver. Inhalational anesthetic agents offer the greatest control over the anesthetic state offering the ability to quickly increase or decrease and monitor anesthetic levels, along with the advantages of providing anesthesia at a low cost. Inhalational agents by themselves are able to provide amnesia, muscle relaxation and a limited amount of analgesia. The first use of inhalational agents for providing anesthesia dates back to the 1850 s with the administration of nitrous oxide and later with the introduction of diethyl ether and chloroform. Ether had a slow onset and recovery and also caused a significant amount of post operative nausea and vomiting. Later non flammable fluorinated hydrocarbons methoxyflourane, halothane, isoflurane, enflurane, sevoflurane and

14 2 desflurane were developed. The newer anesthetic agents offered the advantages of less solubility and resistance to degradation in the body. The volatile agents commonly used in clinical practice in the United States today include isoflurane, sevoflurane and desflurane. 1.2 Anesthesia delivery system The primary method of volatile anesthetic delivery in the United States is the circle rebreathing system (Figure 1.1). The circle system allows rebreathing of previously exhaled anesthetic gas, thereby conserving anesthetic vapor as well as retaining heat and humidity. Soda lime is used to absorb CO 2 so that it is not rebreathed by the patient. In the circle system, fresh gas containing anesthetic vapor flows through the inspiratory valve and the inspiratory limb to the patient. The expired gas flows through the endotracheal tube, Y piece, expiratory limb and through the expiratory valve. The gas at this point either exits the circuit through the pop off valve to the gas scavenging system or passes through the CO 2 absorber. The gas that passes through the absorber mixes with the fresh gas that flows from the anesthesia machine. During anesthesia maintainenance, low fresh gas flow (1 to 3 L/min) is used so as to minimize anesthetic loss from the circuit. 1.3 MAC and MAC awake The alveolar concentration of anesthetic agent is determined by the difference between the amount of anesthetic introduced into the lungs by minute ventilation and the amount removed from the lungs by the circulating blood. The minimum alveolar

15 Figure 1.1. Circle breathing circuit 3

16 4 concentration (MAC) of anesthetic agent at which 50% of the subjects do not respond to a surgical incision is used to compare the potency of different anesthetic agents. When vapor is used as the primary anesthetic, anesthesiologists maintain a concentration 10 to 30 percent greater than MAC to ensure immobilization of nearly all patients. MAC decreases with age and the MAC requirements are also reduced by the use of opioids. MAC awake is the average alveolar agent concentration that permits voluntary response to command. MAC awake for commonly used inhaled agents isoflurane, sevoflurane and desflurane is approximately one third of the MAC.(1-2) The alveolar concentration of agent approximates blood concentration, which is used at a surrogate for cerebral concentration. The cerebral anesthetic concentration is believed to be a better indicator of the depth of anesthesia, especially during rapid washout of anesthetic during hyperventilation accompanied by changes in the partial pressure of CO Pharmacology of inhalational anesthetics The rate of uptake, distribution, speed of recovery and relative changes in the alveolar concentration with changes in minute ventilation are determined by the solubility of the agent in blood and tissues. A more soluble agent will have a larger inspired to alveolar concentration difference during induction of anesthesia due to larger amount of agent being absorbed by the tissues from the blood stream. Relatively insoluble agents show a more rapid equilibration of alveolar concentration with the inspired concentration and are less affected by changes in cardiac output and ventilation.

17 5 The solubility of an anesthetic agent in an equilibrium state is expressed in terms of a partition coefficient that describes the ratio of the concentration of the agent in the two phases and hence the affinity of the agent for the two phases. Table 1.1 lists the partition coefficients for the commonly used inhaled agents. Amongst the agents, desflurane and sevoflurane have lower blood and tissue partition coefficients and thus give better control of anesthetic depth during induction of anesthesia as well as during anesthesia maintenance. Desflurane has a faster recovery profile when compared to sevoflurane and sevoflurane has a faster recovery profile when compared to isoflurane.(3-5) With the more soluble anesthetic agents like isoflurane, a decrease in anesthetic dosage towards the end of the case would be required to achieve shorter emergence times comparable with the less soluble agents. 1.5 Recovery from anesthesia The cerebral concentration of anesthetic agent is determined by the concentration of agent circulating in the arterial blood stream and the amount of cerebral perfusion. The cerebral blood flow is intrinsically controlled by cerebrovascular resistance and not affected much by arterial pressure. For return of consciousness following inhaled anesthesia, the cerebral concentration of agent must drop below the threshold for emergence. In clinical practice, this is achieved by turning off the vaporizer and either ventilating the patient with the same minute ventilation as during anesthesia maintenance or ventilating the patient with a slightly increased minute ventilation. Fresh gas flow is usually raised to 10 L/min for rapid removal of agent from the circle system and to prevent re-inhalation of anesthetic agent. Neuromuscular blockades are reversed before emergence for return of ventilatory

18 6 Table 1.1 Tissue/Blood partition coefficients(6-7) (Except for Blood/Gas partition coefficients) Tissue Desflurane Sevoflurane Isoflurane Blood/gas Brain Heart Liver Kidney Muscle Adipose Lung Connective

19 7 muscle strength. The alveolar agent concentration during emergence depends on the difference between the amount of agent delivered to the alveoli by the circulating blood and the amount of agent removed from the lungs by minute ventilation. The alveolar agent concentration during the initial stages of washout of anesthetic is mainly from the well perfused tissues like brain, liver, heart and kidney that receive the largest fraction of the cardiac output. Subsequently less perfused tissues like muscle and fat also start contributing a significant fraction of the alveolar concentration. The fraction of anesthetic cleared from the blood (F) as it passes through the lungs is given by Equation 1.1, 1 F = ( 100% )* 1+ λ * Q V A (1.1) where Q is the cardiac output, λ is the blood gas partition coefficient and V A is the alveolar ventilation. After a longer duration of anesthesia, more anesthetic will be stored in fat and tissues and will increase the time to a given decrement in agent concentration. This could considerably delay emergence for the more soluble agents like isoflurane if the ventilation is not increased to clear the agent from the blood stream. Increases in cardiac output during emergence could possibly increase the release of anesthetic stored in tissues and thereby delay emergence from anesthesia. Thus more ventilation is necessary to remove a more soluble agent when compared to a less soluble agent.

20 8 Hyperventilation could be used to accelerate clearance of anesthetic from the lungs. However, during hyperventilation the rate of CO 2 elimination exceeds its rate of production and as a result, the arterial partial pressure of CO 2 (PaCO 2 ) decreases. PaCO 2 has to be sufficiently high during emergence to stimulate the ventilatory center to initiate ventilatory efforts by the patient. PaCO 2 also has a significant effect on cerebral blood flow. A decrease in PaCO 2 causes vasoconstriction in cerebral vasculature and decreases cerebral blood flow. Hypercapnia on the other hand increases cerebral blood flow by 6% per mmhg increase in PaCO 2.(8) Cerebral arterial smooth muscle dilates with a decrease in the extracellular ph as CO 2 is rapidly hydrated to form carbonic acid. The local acidic environment enhances the vasodilatory effects of adenosine and increases potassium ion conductance in smooth muscle, resulting in vasodilatation.(9) PaCO 2 during emergence could be increased by hypoventilation. However, hypoventilation results in a slower clearance of anesthetic from the lungs due to a decrease in the alveolar-blood anesthetic gradient, thus resulting in a slower emergence. Clinicians thus have to make a compromise between increasing PaCO 2 and hence the cerebral clearance of anesthetic by hypoventilation and increasing alveolar clearance of agent by hyperventilation. Some older anesthesia machines, which are not in current use had a manual valve to bypass the CO 2 absorber and enable rebreathing of CO 2 (Ohio 18 Absorber, Ohio Medical Products, Madison WI) (A100 Absorber, Penlon Limited, Abingdon, UK).(10) The amount of CO 2 rebreathed and the level of hypercapnia was controlled by adjusting the fresh gas flow to the breathing circuit. The CO 2 absorber bypass is of limited utility because high fresh gas flow is needed to clear exhaled anesthetic from the breathing

21 9 circuit, which reduces the amount of CO 2 rebreathing and limits the rate at which CO 2 increases.(11-12) Advocates of low flow anesthesia also used activated charcoal to rapidly decrease the inspired agent concentration in the circle system without the use of high fresh gas flows.(13-15) They were able to reduce the inspired agent concentration to zero within a minute and were able to attain a faster decline in the end tidal isoflurane concentrations towards MAC awake values with the use of activated charcoal. The bypass option is not available on new anesthesia machines because of the risk of inadvertently leaving the bypass active at the start of a procedure.(10) Carbon dioxide could be added to the inspired gas in sufficient concentration so as to prevent a decrease in PaCO 2 during hyperventilation. In the past, many anesthesia machines were equipped with a tank containing 100% CO 2. The flow of CO 2 was adjusted during emergence to maintain normal or slightly elevated PaCO 2 during hyperventilation. In 1989, 60% of the anesthesiologists in the United Kingdom routinely administered CO 2 to their patients.(16) They were however concerned with the risks of hypoxia and inadvertent hypercapnia and 80% of them thought that limiting the flow of CO 2 to less than 1 L/min would improve safety. The practice is very seldom used in the United States today because of the risk of inadvertent hypercapnia.(17-18) 1.6 Importance of a rapid recovery A more rapid recovery and a higher PaCO 2 during emergence from anesthesia might lead to an early return of the patient s capacity to sustain his own airway, protect against aspiration and maintain oxygenation. Rapid recovery also promotes return of normal cardiovascular function.(19) An early recovery might also lead to an early

22 10 discharge from the post anesthesia care unit if hyperventilation is able to reduce the residual anesthetic in the body to a level that could allow the return of normal psychomotor function. A larger amount of agent removed during hyperventilation might also lead to a lesser amount of agent being left in the body that could undergo degradation to toxic byproducts. The ventilatory depressant effects of neuromuscular blocking agents are enhanced by the presence of inhaled anesthetic agents. A rapid removal of agent from the body might reduce issues with ventilatory failure due to inadequate reversal of neuromuscular blocks. Anesthetic concentrations in the 0.1 MAC range instead of decreasing the perception of pain has a hyperalgesic effect.(20-21) A rapid emergence might lead to a rapid progression through these low concentrations that are typically encountered during slow washout of anesthetic and thus possibly decrease post operative pain. Although greater cost saving could be achieved by improving efficiency in the operating room rather than minimizing anesthetic cost, anesthetic drugs continue to be a major part of the pharmacy budget and appropriate use of the agent is recommended to minimize costs. The cost of inhalation anesthesia is determined by the acquisitions cost of the agent, amount of vapor produced per ml of anesthetic, fresh gas flow used, equipment needed for delivering and monitoring the agent, emergence time from anesthesia and post operative adverse effects (Table 1.2). A rapid emergence from anesthesia might be possible even with the slower agents which are less expensive using hypercapnic hyperventilation. The use of hypercapnia during hyperventilation to speed up emergence from anesthesia looks promising provided the safety concerns regarding high CO 2 could be

23 11 adequately addressed. This dissertation is organized as follows. Chapter 2 introduces two methods of raising PaCO 2 during hyperventilation. A very simple device using rebreathing of CO 2 and a more complex and accurate device using feedback controlled infusion of CO 2 is described The remainder of Chapter 2 describes the evaluation of the rebreathing device and the CO 2 controller in speeding emergence from isoflurane, sevoflurane and desflurane anesthesia in 15 pigs. Chapter 3 describes the clinical evaluation of the rebreathing device in a study involving 52 patients undergoing anesthesia with 1 MAC of isoflurane, sevoflurane or desflurane. The differences in emergence times with hypercapnic hyperventilation (EtCO 2 =55 mmhg).and mild hypocapnia during hyperventilation (EtCO 2 =29 mmhg) were compared. Chapter 4 describes a mathematical model of inhaled anesthetic uptake, distribution and elimination that we modified to simulate working of the rebreathing device as well as changes in cerebral perfusion with different agents and changes in EtCO 2.The data from the clinical study was used to estimate the cerebral awakening concentration of agent at which the patients opened their eyes in response to command and estimate the predictive accuracy of the model using the estimated concentrations. Chapter 4 also describes simulations which help us better understand the relative contribution of hypercapnia and hyperventilation in speeding emergence from 1MAC of isoflurane, sevoflurane or desflurane anesthesia. A summary of the project and concluding remarks are given in Chapter 5.

24 12 Table 1.2 Average Cost of agents for 1MAC hour of anesthesia(22) Anesthetic Cost/ml Average Cost/1 MAC Hour at given FGF Rate $0.47 at 0.5 L/min Isoflurane $0.26 $0.94 at 1 L/min $1.88 at 2 L/min $5.39 at 0.5 L/min Desflurane $0.62 $10.78 at 1 L/min $21.55 at 2 L/min $8.34 at 1 L/min Sevoflurane $1.27 $16.68 at 2 L/min $25.02 at 3 L/min

25 References 1. Katoh T, Suguro Y, Ikeda T et al. Influence of age on awakening concentrations of sevoflurane and isoflurane. Anesth Analg 1993;76: Chortkoff BS, Eger EI, 2nd, Crankshaw DP et al. Concentrations of desflurane and propofol that suppress response to command in humans. Anesth Analg 1995;81: Smith I, Ding Y, White PF. Comparison of induction, maintenance, and recovery characteristics of sevoflurane-n2o and propofol-sevoflurane-n2o with propofolisoflurane-n2o anesthesia. Anesth Analg 1992;74: Frink EJ, Jr., Malan TP, Atlas M et al. Clinical comparison of sevoflurane and isoflurane in healthy patients. Anesth Analg 1992;74: Nathanson MH, Fredman B, Smith I, White PF. Sevoflurane versus desflurane for outpatient anesthesia: a comparison of maintenance and recovery profiles. Anesth Analg 1995;81: Eger EI, 2nd, Saidman LJ. Illustrations of inhaled anesthetic uptake, including intertissue diffusion to and from fat. Anesth Analg 2005;100: Lerou JG, Dirksen R, Beneken Kolmer HH, Booij LH. A system model for closed-circuit inhalation anesthesia. I. Computer study. Anesthesiology 1991;75: Ito H, Kanno I, Ibaraki M et al. Changes in human cerebral blood flow and cerebral blood volume during hypercapnia and hypocapnia measured by positron emission tomography. J Cereb Blood Flow Metab 2003;23: Brian JE, Jr. Carbon dioxide and the cerebral circulation. Anesthesiology 1998;88: Dorsch J, Dorsch, SE. Understanding Anesthesia Eequipment. Second ed. Baltimore, MD: Williams & Wilkins, Bergman JJ, Eisele JH. The efficiency of partial soda-lime bypass circuits. Anesthesiology 1972;36:94-5.

26 Ivanov SD, Nunn JF. Methods of elevation of PCO2 after anaesthesia with passive hyperventilation. Br J Anaesth 1968;40: Romano E, Pegoraro M, Vacri A et al. [Charcoal and isoflurane alveolar washout in low-flow circuit]. Minerva Anestesiol 1993;59: Romano E, Pegoraro M, Vacri A et al. Low-flow anaesthesia systems, charcoal and isoflurane kinetics. Anaesthesia 1992;47: Ernst EA. Use of charcoal to rapidly decrease depth of anesthesia while maintaining a closed circuit. Anesthesiology 1982;57: Razis PA. Carbon dioxide--a survey of its use in anaesthesia in the UK. Anaesthesia 1989;44: Shipton EA, Roelofse JA, van der Merwe CA. Accidental severe hypercapnia during anaesthesia. Case reports and a review of some physiological effects. S Afr Med J 1983;64: Prys-Roberts C, Smith WD, Nunn JF. Accidental severe hypercapnia during anaesthesia. A case report and review of some physiological effects. Br J Anaesth 1967;39: Widmark C, Olaison J, Reftel B et al. Spectral analysis of heart rate variability during desflurane and isoflurane anaesthesia in patients undergoing arthroscopy. Acta Anaesthesiol Scand 1998;42: Sonner J, Li J, Eger EI, 2nd. Desflurane and nitrous oxide, but not nonimmobilizers, affect nociceptive responses. Anesth Analg 1998;86: Zhang Y, Eger EI, 2nd, Dutton RC, Sonner JM. Inhaled anesthetics have hyperalgesic effects at 0.1 minimum alveolar anesthetic concentration. Anesth Analg 2000;91: Sakai EM, Connolly LA, Klauck JA. Inhalation anesthesiology and volatile liquid anesthetics: focus on isoflurane, desflurane, and sevoflurane. Pharmacotherapy 2005;25:

27 CHAPTER 2 ANIMAL STUDIES 2.1 Abstract Anesthetic clearance from the lungs and the circle breathing system can be maximized by using hyperventilation and high fresh gas flows. However, the concomitant clearance of CO 2 also lowers PaCO 2 thereby decreasing cerebral blood flow and hence the clearance of anesthetic from the brain. This study shows that in addition to hyperventilation, hypercapnia (CO 2 infusion or rebreathing) is a significant factor in decreasing emergence time from inhaled anesthesia. We anesthetized 7 pigs with 2 MAC PIG of isoflurane (3.1%) and 4 each with 2 MAC PIG of sevoflurane (3.94%) or 1 MAC PIG of desflurane (10.0%). After two hours of anesthesia, the animals were hyperventilated and the time to movement of multiple limbs was measured under hypocapnia (EtCO 2 =22 mmhg) and hypercapnia (EtCO 2 =55 mmhg). The time between turning off the vaporizer and to movement of multiple limbs was faster with hypercapnia during hyperventilation. Emergence time from isoflurane and sevoflurane anesthesia was shortened by an average of 65% with rebreathing or with feedback controlled infusion of CO 2 (p<0.05). Hypercapnia in conjunction with hyperventilation may be used clinically to decrease emergence time from inhaled anesthesia. This time savings could potentially reduce drug and

28 16 personnel costs. Anesthesiologists will also feel less pressure to titrate anesthetic towards the end of the case to shorten emergence time, possibly decreasing the incidence of intra operative awareness. In addition, higher PaCO 2 during emergence may enhance respiratory drive and airway protection following extubation. 2.2 Introduction Rapid removal of anesthetic during emergence allows for a rapid egress from stage II of anesthesia. In addition, a rapid return of consciousness is desirable to allow patients to quickly leave the operating suite, thereby reducing personnel costs.(1) Rapid removal of anesthetic is also desirable in clinical procedures that require the patient to be awakened during the surgery.(2) Recovery time after inhaled anesthesia depends on alveolar ventilation, solubility of the agent in blood and tissues and anesthesia duration.(3-4) However, when hyperventilation is used during emergence to quickly lower the alveolar and arterial concentration of the agent, the rate of CO 2 removal from the lungs exceeds its rate of production and hypocapnia ensues. Hypocapnia decreases cerebral blood flow, which decreases the rate of clearance of anesthetic from the brain. Veseley et al maintained normocapnia during hyperventilation and showed the role of increased minute ventilation in decreasing emergence time.(5) We maintained hypercapnia during hyperventilation to show the role of increased cerebral blood flow in decreasing emergence time. Normocapnia or hypercapnia can be maintained during hyperventilation by introducing CO 2 into the inspired gas mixture. A survey of anesthesiologists in the United Kingdom in 1989 showed that 60% of them infused CO 2 during emergence. They were

29 17 however concerned with the risks of hypoxia and inadvertent hypercapnia and 80% of them thought that limiting the flow of CO 2 to less than 1 L/min would improve safety.(6-8) Perhaps a safer approach would be to add dead space to the breathing circuit to induce hypercapnia.(9) Rebreathing of CO 2 recovers the CO 2 that would otherwise be eliminated during hyperventilation. Our study measures the decrease in emergence time in pigs after isoflurane, sevoflurane or desflurane anesthesia when hypercapnia was maintained during hyperventilation using rebreathing of CO 2 or feedback controlled infusion of CO Methods We tested two methods of raising PaCO 2 during hyperventilation. EtCO 2 can be more accurately maintained during hyperventilation using feedback controlled infusion of CO 2. However, a relatively simple and inexpensive method is to use rebreathing of CO 2. The feedback controller introduced CO 2 into the breathing circuit at the optimum rate and provided an ideal control condition against which to compare rebreathing Feedback controller Figure 2.1 shows the block diagram of the feedback controller we implemented and tuned to actively induce and maintain hypercapnia during hyperventilation. The controller consists of a CO 2 SMO Plus monitor (Respironics Inc, USA) to measure EtCO 2, inspired tidal volumes and respiratory rate. The computer ran a proportional-integral (PI) control algorithm which compared the measured EtCO 2 from the previous breath to the desired target EtCO 2

30 18 and determined the amount of CO 2 to be added to the inspired gas in the subsequent breath. The PI controller used the equation CO [ ] () t CO( t 1) K [ EtCO ( t) EtCO ( t )] + K T SetCO EtCO () t = (2.1) p i 2 2 where CO () t and ( t 1) EtCO 2 () t and ( t ) is the target end tidal CO 2, the sampling period. CO are the controller outputs for the current and previous breath, EtCO2 1 are the end tidal CO 2 for the current and previous breath, SetCO 2 K p and Ki are the proportional and integral constants and T is A timer circuit was used to regulate the amount of CO 2 added to the inspired gas depending on the value sent to it by the PI controller. The inlet pressure to the valve was maintained at 20 psi. The integral and proportional constants were tuned as functions of minute volume and respiratory rate using a mechanical test lung (TTL Test Lung, Michigan Instruments, MI, USA) connected to an anesthesia ventilator (Modulus CD, Ohmeda, Madison, WI). CO 2 was introduced into the mechanical test lung at constant flow rate using a mass flow controller to simulate metabolic CO 2 production. The constants were functions of respiratory rate and tidal volume so that the controller would have the same response time irrespective of the patient s minute ventilation. The controller was tuned to produce a stable response and achieve its target level within 30 seconds. CO 2 was introduced into the inspired gas mixture during the start of inspiration to prevent artifacts in the capnogram that would have been seen if the patient should exhale spontaneously during the inspiratory period. When exhalation occurred during inspiration the CO 2 waveform was segmented into six sections to calculate EtCO 2 accurately. The section with the minimum standard deviation of

31 19 Patient CO 2 SMO (Novametrix Medical Systems Inc) Computer (Proportional Integral Controller) Valve Timer Circuit CO 2 tank Figure 2.1. Block diagram of feedback controller.

32 20 CO 2 after the dead-space gas had been exhaled was used to calculate EtCO Rebreathing device We used the device shown in Figure 2.2 to passively increase PaCO 2 during hyperventilation. The device consists of a rebreathing hose, a canister filled with anesthetic adsorbent and two valves to maintain unidirectional flow of gas through the adsorbent. The rebreathing hose is a 22mm ID corrugated breathing hose having 150 ml of dead space when collapsed and 665 ml when fully extended. The canister 7.5 cm diameter and 0.95 cm thick holds 18 gm of medical grade activated charcoal to adsorb anesthetic agent from the inspired gas as it is rebreathed Volume of rebreathing hose The volume of rebreathing hose should be sufficient to raise the PaCO 2 of a patient to 55mmHg during emergence. We estimated the volume of rebreathing that would be required using a mathematical simulation implemented in Matlab. Rebreathing of CO 2 was simulated for a 70 kg and a 140 kg patient. A constant metabolic CO 2 production based on body weight was assumed. The model also assumed that 85% of the volume of CO 2 left in the rebreathing hose from the previous breath is inhaled in the subsequent breath. The change in CO 2 in the body is given by the difference between the total CO 2 increase in the body (due to metabolic CO 2 production and inspiration of CO 2 from the hose) and the amount excreted by the lungs. The resting ventilation was set to maintain an EtCO 2 of 33 mmhg was 5.04 L/min at a respiratory rate of 8 breaths/min for the 70 kg patient and 10 L/min at 8 breaths/min for the 140 kg patient. The simulated patients were hyperventilated by doubling the minute

33 Figure 2.2. Rebreathing device with rebreathing hose, activated charcoal and one-way valves. 21

34 22 ventilation. We expect the emergence times with the device to be less than 10 minutes and hence the EtCO 2 ten minutes since start of hyperventilation was recorded for different rebreathing hose volumes. Figure 2.3 shows the EtCO 2 ten minutes since the start of hyperventilation for varying rebreathing hose volumes. From the simulations it appears that a rebreathing hoses volume greater than 0.5 L would be required for a typical 70 kg patient Amount of activated charcoal The amount of activated charcoal in the rebreathing device should be sufficient to adsorb anesthetic agent exhaled by the patient during emergence so that none is re-inhaled by the patient. Desflurane requires a larger volume % of agent for a MAC of anesthesia when compared to sevoflurane or isoflurane due to its lower potency. For estimating the amount of activated charcoal required, we implemented a model of inhaled anesthetic uptake, distribution and elimination described by Lerou, et al.(10) We simulated anesthesia maintainenance at 1 MAC of desflurane (6.44 % for humans) for a 140 kg, 1.83 m adult male for 8 hours of anesthesia. During anesthesia maintainenance, the minute volume was set to 10 L/min to maintain an EtCO 2 of 33 mmhg. Emergence times for desflurane after 8 hours of anesthesia are expected to be much less than 15 min with hypercapnic hyperventilation. We simulated emergence from anesthesia by setting the vaporizer to zero and doubling the minute ventilation. We recorded the total amount of agent exhaled by the subject during the 15 min period. The total amount of agent exhaled by the subject was estimated to be 1064 standard cubic centimeter (scc). Assuming an 85% rebreathing efficiency, the total amount of desflurane to be adsorbed would be 904 scc. The equilibrium capacity of activated charcoal

35 23 EtCO2 (mmhg) Kg 140 kg Rebreathing hose volume (L) Figure 2.3. EtCO 2 10 min since start of hyperventilation for a simulated 70 kg and 140 kg patient for with varying of rebreathing hose volumes.

36 24 for desflurane at 24 C is approximately 75 scc/g. Thus 12 g of charcoal would be adequate to adsorb all the agent expired by the patient so that none of it is reinhaled. It is safer to use charcoal in excess of 12 gm as a safety measure. We tested the adsorption efficiency of the device for agent isoflurane with a canister 7.5 cm diameter and 0.95 cm thick holding 18 gm of activated charcoal. The device was connected between an anesthesia ventilator (NarkoMed 2B, North American Drager, Telford, PA) and a mechanical test lung (TTL, Michigan Instruments Inc, Grand Rapids, MI). The minute ventilation as set to 10L/min and the vaporizer was set to give an inspired agent concentration of 2%. The concentration of agent that flows into the device and the concentration of agent that exits the device were recorded using two anesthetic gas analyzers (CapnoMAC Ultima, Datex-Ohmeda, Helsinki, Finland).The adsorption efficiency was calculated as the ratio of the difference between the input and exit agent concentration to the input agent concentration through the device. The device showed an adsorption efficiency of 80% until 1200 ml of isoflurane had been adsorbed. We believe that the adsorption performance of the device with 18gm of activated charcoal would be adequate for the worst possible scenario that might be encountered in clinical practice Study protocol After Institutional Animal Care and Use Committee approval we studied 15 pigs of either sex weighing 34 to 44 kg. We induced anesthesia with telazol (tiletamine hydrochloride, zolazepam hydrochloride) (10mg/kg). The animal s trachea was intubated without the use of muscle relaxants. Anesthesia was maintained in 7 pigs with 2 MAC PIG of

37 25 isoflurane (3.1%). In 4 pigs anesthesia was maintained with 2 MAC PIG of sevoflurane (3.94%) and another 4 were anesthetized with 1 MAC PIG of desflurane (10.0%). The volatile anesthetic agent concentration was monitored continuously using an anesthetic gas analyzer (CapnoMAC Ultima, Datex-Ohmeda, Helsinki, Finland). We placed ECG leads, pulse oximetry probe, invasive blood pressure sensor with arterial line, rectal temperature probe and BIS electrodes to monitor vital signs. Sedation level was monitored using Bispectral Index (BIS, Aspect Medical Systems, Nutton, Massachusetts). The mean arterial blood pressure was maintained above 50 mmhg by titrating the infusion of Lactated Ringers solution. The respiratory rate was set at 10 breaths/min. The tidal volume was adjusted to maintain EtCO 2 at 33 mmhg with a circle absorber rebreathing circuit (Modulus CD, Ohmeda, Madison, WI). Anesthesia was maintained for 2 hours for each animal studied.etco 2, inspired and expired agent concentrations and BIS were recorded electronically using a personal computer running custom software written in Borland C++ Builder (Inprise Corporation, USA). Emergence time was measured after 2 hours of anesthesia. Emergence began when the vaporizer was turned off. The fresh gas flow was raised to 10 L/min and the respiratory rate was set to 20 breaths per minute, resulting in an approximate doubling of minute ventilation during emergence. Once awake, each animal was reanesthetized with the anesthetic agent by turning on the vaporizer. Each animal was emerged from anesthesia three times under the following conditions. EtCO 2 increased slowly from 33 to 55 mmhg by CO 2 rebreathing. EtCO 2 increased rapidly from 33 to 55 mmhg by the CO 2 controller.

38 26 EtCO 2 falls to hypocapnic level (~22mmHg) during hyperventilation without adding CO 2. In additions to the three emergence conditions listed above the animal was also emerged from desflurane anesthesia at an EtCO2=30 mmhg by maintaining the same ventilation settings as during anesthesia maintenance and turning up the fresh gas flow during emergence. We recorded the time between when the vaporizer was turned off until the return of spontaneous breathing and movement of two or more limbs. Spontaneous breathing during mechanical ventilation was ascertained by movement of the chest wall and out of sync spontaneous breaths observed in the capnogram. Once the movement of multiple limbs occurred, the animals were reanesthetized with anesthetic vapor by turning on the vaporizer and increasing fresh gas flow to 10 L/min. Once the BIS, blood pressure, and heart rate returned to the values recorded prior to turning off the vaporizer, anesthesia was maintained for an additional 30 min before the next emergence occurred. To minimize the possibility of a prior emergence influencing our results, the order of emergence was randomly selected. The BIS data recorded electronically for each emergence was normalized using the following equation: Normalized BIS ( BIS pre emergence BIS) ( imum BIS preemergence BIS) = max (2.2) where pre-emergence BIS is the average BIS two minutes prior to turning off the vaporizer and maximum BIS is the maximum BIS value observed during emergence and subsequent

39 27 induction. The time for the normalized BIS to reach 0.95 from the time the vaporizer was turned off was calculated for each emergence Statistical analysis Analysis was performed using SigmaStat version 2.03 (SPSS Inc).The effect of the anesthetic agent and method of emergence on the time to movement of multiple limbs, time to spontaneous breathing and time for the normalized BIS to rise to 0.95 were compared using 2 way repeated measures ANOVA. Post hoc Bonferroni tests were performed when the interaction effects were found to be significant. 2.4 Results Table 2.1 lists the time from when the vaporizer was turned off to the return of spontaneous breathing. Figure 2.4 shows the normalized BIS during emergence from agent s isoflurane and sevoflurane. Figures 2.5 and 2.6 shows the average time to movement of multiple limbs and the average time for the normalized BIS to rise to 0.95, respectively. The time to movement of multiple limbs, time to spontaneous breathing and time to normalized BIS to rise to 0.95 were significantly shorter when hypercapnia was maintained during emergence from isoflurane and sevoflurane (p<0.05). Emergence times were not statistically different when rebreathing was used from those obtained when the CO 2 controller was used. Normalization of BIS values assumes that the pre-emergence BIS and maximum BIS are similar for each emergence within each animal. The maximum standard deviation of preemergence BIS (within each animal) in the animals receiving isoflurane, sevoflurane and

40 28 Table 2.1 Average time to spontaneous breathing (mean ± SD), average EtCO 2 at time of movement of multiple limbs, average minute ventilation during anesthesia maintenance as recorded immediately before turning off the vaporizer(maintenance) and average minute ventilation at the time of movement of multiple limbs(emergence) (mean ± SD). Isoflurane (n=7) Sevoflurane (n=4) Desflurane (n=4) Time to spontaneous breathing Hypocapnia 19.1 ± ± ± 4.8 Rebreathing device (min) CO 2 controller 3.8 ± ± ± ± ± ± 0.5 EtCO 2 at emergence (mmhg) Hypocapnia 22.1 ± ± ± 2.9 Rebreathing device CO 2 controller 54.7 ± ± ± ± ± ± 1.3 Minute ventilation during maintenance Hypocapnia 6.1 ± ± 0.8 * Rebreathing device (L/min) CO 2 controller 6.1 ± ± 0.7 * 5.6 ± ± ± 0.6 Minute ventilation during emergence (L/min) Hypocapnia 12.5 ± ± 1.7 * Rebreathing device CO 2 controller 12.6 ± ± 1.3 * 12.2 ± ± ± 1.2 * Minute ventilations were not logged.

41 Figure 2.4. Normalized BIS during emergence from 2 MAC PIG of isoflurane and sevoflurane anesthesia for the 3 emergence scenarios. 29

42 Time to movement of multiple limbs (min±sd) ISO SEVO DES ISO SEVO DES ISO SEVO DES Hypocapnia Rebreathing Device CO2 Controller Figure 2.5. Average time from turning off the vaporizer to time to movement of multiple limbs after 2 MAC PIG of isoflurane, 2 MAC PIG of sevoflurane and 1 MAC PIG of desflurane anesthesia (mean + SD).

43 31 25 Time to Normalized BIS to rise t o0.95 (min±sd) ISO SEVO DES ISO SEVO DES ISO SEVO DES Hypocapnia Rebreathing Device CO2 Controller Figure 2.6. Average time from turning off the vaporizer to time to normalized BIS to rise to 0.95 during emergence after 2 MAC PIG of isoflurane, 2 MAC PIG of sevoflurane and 1 MAC PIG of desflurane anesthesia (mean + SD).

44 32 desflurane anesthesia were 4.7, 5.6 and 5.0 respectively. The maximum standard deviation of the peak BIS value (within each animal) during emergence from isoflurane, sevoflurane and desflurane anesthesia was 3.4, 4.2 and 2.3, respectively. With desflurane, the results were not statistically significant. The time to movement of multiple limbs was shortest when hypercapnia in conjunction with hyperventilation was used during emergence. Maintaining normocapnic CO 2 by keeping the same minute ventilation as during maintenance gave a lower emergence time when compared to hypercapnic hyperventilation (Figure 2.7). Figures 2.8 and 2.9 show the proportional and integral constants used in the controller for various respiratory rates and minute ventilations. After isoflurane anesthesia, the feedback controller increased the EtCO 2 from 33 mmhg to a target of 55 mmhg in ± 6 seconds (95% of target value) (Figure 2.10). In steady state, the average EtCO 2 was ± 0.63 mmhg. Figure 2.11 shows the performance of the rebreathing adsorber device with regard to adsorption of anesthetic with and without the valves for a pig emerging from 2 MAC of sevoflurane anesthesia. Without the valves, the inspired agent showed an increase to 0.15% and the device started functioning like an anesthetic conserving device providing a fixed inspired agent concentration. With the added valves, the performance of the device was significantly improved and the inspired agent concentrations remained below 0.02% during the emergence.

45 Time to movement of multiple limbs (min±sd Hypocapnia (21 mmhg) Normocapnia (31 mmhg)* Hypercapnia (55 mmhg) Figure 2.7. Average time from turning off the vaporizer to time to movement of multiple limbs during emergence from 1 MAC PIG of desflurane. * Maintainenance ventilation was used during emergence.

46 Proportional constant (Kp) Minute Ventilation (L/min) Figure 2.8. Typical controller tuning curves for the proportional constant (K p ) for different respiratory rates.