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Sevoflurane Requirement to Maintain Bispectral Index–Guided Steady-StateLevel of Anesthesia During the Rewarming Phase of Cardiopulmonary Bypass

With Moderate Hypothermia

Divya Amol Chandran Mahaldar, DM,* Shrinivas Gadhinglajkar, MD,† and Rupa Sreedhar, MD†

Objectives: The authors aimed to quantify any increase

and the extent of the increase in sevoflurane requirements

for maintaining hypnosis during hypothermic cardiopulmo-

nary bypass (CPB) with the bispectral index (BIS) maintained

between 40 and 50.

Design: An observational prospective study.

Setting: A single-center tertiary referral center at a univer-

sity hospital.

Participants: Fifty patients undergoing elective coronary

artery bypass graft surgery with CPB.

Interventions: End-tidal oxygenator expiratory gas con-

centrations were used to quantify sevoflurane requirements

while maintaining a BIS level between 40 and 50 during the

rewarming phase.

Results: Sevoflurane requirements progressively in-

creased as temperature increased. The difference in sevoflu-

phase of CPB with moderate hypothermia.

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Journal of Cardiothoracic and Vascular Anesthesia, Vol 27, No 1 (February

analysis of variance for repeated measures, which was sta-

tistically significant. When relating temperature and sevo-

flurane requirement, the Pearson correlation coefficient was

0.67. Linear regression analysis using temperature as the

independent variable and expiratory sevoflurane as the de-

pendent variable showed a temperature �-coefficient of 0.11

and a constant of �2.34. Other parameters like fresh gas

flows and pump flows were correlated to find out if they

affected end-tidal sevoflurane levels on CPB. They were not

significant in multivariate analysis.

Conclusions: The sevoflurane requirement increases dur-

ing the rewarming phase of hypothermic CPB. The percent

increase in the requirement for sevoflurane is uniform and

follows a particular pattern, which may be predicted.

© 2012 Elsevier Inc. All rights reserved.

KEY WORDS: cardipulmonary bypass, bispectral index,

rane requirement at 35°C and 29°C was compared using depth of anesthesia, sevoflurane, rewarming

ANESTHESIA DURING CARDIOPULMONARY BYPASS(CPB) is challenging with regards to the potential for

atient awareness. CPB is associated with unphysiologic condi-ions including hemodilution, hypotension, hypothermia, and non-ulsatile blood flow. CPB alters pharmacokinetics and pharmaco-ynamics of drugs that principally affect the drug absorption,istribution, metabolism, and elimination.1-3 The oxygenator andubing also may bind large amounts of drugs administered duringnesthesia.1 Hypothermic CPB especially is associated with aecreased level of consciousness and a decreased metabolic rate.2

The net result may be the administration of inappropriately high orlow doses of hypnotics and anesthetics.

During the rewarming phase of CPB, there may be a change inthe requirement of anesthetic agents because of an altered cerebralmetabolic rate and changes in the gas characteristics. A studypublished by Liu et al involving monitoring of the isofluraneconcentration on CPB suggests that the requirement for isofluraneincreases during the rewarming phase of CPB.4 However, similartudies on sevoflurane are lacking. Isoflurane and sevofluraneiffer in their physical characteristics like blood-gas solubility,otency, the oil-gas coefficient, and the wash-in and washoutroperties. Hence, sevoflurane requirements during the re-arming phase may not be identical with those of isoflurane.he results of this study will help with sevoflurane dosinguring the rewarming phase of hypothermic CPB.The present authors titrated the sevoflurane concentration toaintain a steady-state level of hypnosis during hypothermicPB. The bispectral index (BIS) was used as the hypnosisonitor, and the BIS value was maintained between 40 and 50.xpiratory gas from the CPB machine oxygenator, havingquilibrated with the patient’s blood in the oxygenator, couldeflect the blood sevoflurane concentrations. This is analogouso measuring end-tidal anesthetic gas concentrations in a ven-ilated patient.5 The objective of this study was to measure the

changes in sevoflurane requirements during the rewarming

METHODS

Approval was obtained from the institutional ethics committee. Thepatients were given an informational brochure regarding anesthesia and thesurgery, and written informed consent was obtained from the patientsbefore the study. Fifty adult patients undergoing elective coronary arterybypass graft (CABG) surgery requiring CPB were included in the study.The exclusion criteria included pre-existing neurologic disease, chronictreatment with sedative drugs, chronic alcoholism, a left ventricularejection fraction �50%, significant renal disease (ie, serum creatinine�2 mg/dL or blood urea nitrogen �20 mg/dL), hepatic disease (ie,SGPT �150 IU and total bilirubin �3 mg/dL), age �70 years, andpatients at risk of malignant hyperthermia.

The patients were premedicated with oral diazepam, 10 mg, the nightbefore and the day of surgery. Antihypertensive medication was con-tinued on the day of surgery except angiotensin-converting enzymeinhibitors. All oral hypoglycemic medications were omitted on themorning of surgery. Anesthesia was induced with fentanyl, 5 �g/kg,nd midazolam, 0.05 mg/kg, and 0.5 to 1.0 mg/kg of propofol wasdministered to maintain a BIS value between 40 and 50. Muscleelaxation was achieved with pancuronium, 0.2 mg/kg. After trachealntubation, the lungs were ventilated using intermittent positive-pres-ure ventilation, maintaining an end-tidal carbon dioxide level between5 and 45 mmHg. Intraoperative monitoring consisted of 5-lead elec-rocardiography (with ST-segment analysis), invasive arterial bloodressure, central venous pressure, pulse oximetry, capnography, naso-haryngeal and rectal temperature, and urine output. Anesthesia wasaintained with inhaled sevoflurane throughout surgery, which was

itrated against the BIS value. Morphine infusion was commenced at

From the *VIVUS-SMRC Heart Centre, Goa, India; and †Depart-ment of Anesthesia, Sree Chitra Tirunal Institute for Medical Sciencesand Technology, Trivandrum, Kerala, India.

Address reprint requests to Divya Amol Chandran Mahaldar, DM,VIVUS-SMRC Heart Centre, Goa, India. E-mail: dramoldivya@gmail.com

© 2012 Elsevier Inc. All rights reserved.1053-0770/2701-0001$36.00/0

http://dx.doi.org/10.1053/j.jvca.2012.05.017

59), 2013: pp 59-62

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60 CHANDRAN MAHALDAR, GADHINGLAJKAR, AND SREEDHAR

the rate of 20 �g/kg/h after induction and was continued into thepostoperative period for analgesia.

The SARNS 9000 (Terumo Corporation, Tokyo, Japan) CPB ma-chine and the Affinity Adult Oxygenator (Medtronics, Minneapolis,MN) were used during the conduct of CPB. Patients were on full CPBflows, and the lungs were not ventilated during the study period.Sevoflurane was delivered into the oxygenator by routing the fresh gasflow through a Tec 7 sevoflurane vaporizer (Datex Ohmeda, Madison,WI) mounted on the CPB machine. Expiratory gas was sampled fromthe oxygenator’s sole expiratory port. Patients’ temperatures wereregulated using the heat exchanger and warm/cold water-circulatingmattress. BIS monitoring (BIS XP forehead electrode; Aspect MedicalSystems, Inc, Newtown, MA) was commenced before inducing anes-thesia, and this was continued throughout anesthesia and surgery.Sevoflurane concentrations were measured using the agent analyzer ofthe S/5 anesthesia monitor (GE Healthcare, Hertfordshire, UK). DuringCPB, this agent analyzer was connected using a separate gas samplingtube to the expiratory gas port of the oxygenator. Gas-tight connectionswere secured to prevent atmospheric gas contaminating the sampledgases. The fresh gas flow was adjusted to maintain the normal acid-basebalance using alpha-stat strategy, which was guided by half hourlymeasurements of arterial blood gases. The anesthesiologist adjusted thevaporizer settings to maintain a moderate depth of anesthesia, with theBIS index between 40 and 50.

Per institutional protocol, the oxygenator temperature is lowered to29°C and then rewarmed to 35°C during CABG surgery. Rewarmingwas performed at the rate of 3 to 5 minutes per 1°C. The total durationof rewarming from 29°C to 35°C was approximately 20 to 30 minutes.During the rewarming phase, the gradient between the nasopharyngealand rectal temperatures was kept to �2°C to aid in gradual andcomplete rewarming. The sevoflurane concentrations were measured ateach degree Celsius rise in nasopharyngeal temperature from 29°C to35°C. The variations in the BIS value were limited to a minimumextent during this period.

The mean perfusion pressures were maintained in the range of 60 to 80mmHg during CPB using vasoconstrictors (ie, phenylephrine and norepi-nephrine) or vasodilators (sodium nitroprusside) whenever required. Sys-temic arterial pressures, measured via a radial artery cannula, were mon-itored continuously throughout the procedure. Hypotension during CPBrequiring intervention was defined as a mean arterial pressure �50mmHg and hypertension as a mean arterial pressure �90 mmHg. At theend of surgery, all patients were transferred to the cardiothoracicintensive care unit. Analgesia, sedation, weaning from artificial venti-lation, and extubation followed the institutional protocol.

All data are presented as the mean � standard deviation. ThePearson correlation coefficient was used to assess whether there wasany increase in the expiratory sevoflurane requirement with the rise inthe oxygenator temperature. Linear regression was used to quantify thisassociation. An analysis of variance with repeated measures was usedto compare the means of expiratory sevoflurane at 29°C and 35°C. TheMauchly test of sphericity, when applied, indicated that the assumptionof sphericity had been violated. The Greeenhouse-Geiser correctionwas used to correct the degrees of freedom for F distribution. There wasa significant difference between expiratory sevoflurane at 29°C and35°C (p � 0.001). Pair-wise comparison using the Bonferroni methodshowed a significant difference between expiratory sevoflurane at eachdegree rise in temperature when compared with the baseline expiratorysevoflurane at 29°C (p � 0.001).

Fresh gas flows and pump flows were identified as possible con-founding factors. These independent factors were compared againstrising temperatures to assess statistical significance. Multiple regres-sion analysis was applied to predict the significance of factors affecting

changes in anesthesia requirement. Fifty patients were recruited to have

95% power to detect a difference in the expiratory sevoflurane con-centrations at these 2 temperatures with an �-error of 5%.

RESULTS

Forty-four male and six female patients were included in thisstudy. The mean age (standard deviation) was 58.5 (�7.3)ears, and the mean body surface area of patients in the studyroup was 1.68 (�0.15) m2. The expiratory sevoflurane con-

centrations required to maintain a BIS level between 40 and 50over a temperature range of 29° to 35°C during the rewarmingphase of CPB are shown in Table 1.

There was a progressive increase in the sevoflurane require-ments as temperature increased. The sevoflurane requirements at35°C were compared with that at 29°C using analysis of variancewith repeated measures. The difference was both clinically per-ceptible (0.45%) and statistically significant (p � 0.001). Whenrelating temperature and sevoflurane requirements, the Pearsoncorrelation coefficient was 0.67, suggesting a good positive asso-ciation between the 2 variables. Linear regression using tempera-ture as the independent variable and expiratory sevoflurane as thedependent variable showed a temperature �-coefficient of 0.11nd a constant of �2.34. Hence, sevoflurane levels can be pre-icted with reasonable accuracy by using the following equationhen the temperature is known:

nd-tidal sevoflurane concentration (%)

� 0.11 � temperature (°C) � 2.34

Fresh gas flows and pump flows also were correlated usinglinear regression to find out if they affected end-tidal sevoflu-rane levels on CPB. Temperature and pump flows achievedstatistical significance. When temperature and pump flows wereevaluated using multiple regression analysis, only temperaturehad a good correlation with statistical significance. None of thestudy patients had difficulty in weaning from CPB.

DISCUSSION

Volatile anesthetic agents form an integral part of anesthesiafor cardiac surgery. Intraoperative awareness remains one ofthe major concerns during cardiac surgery. By virtue of theiramnestic properties, volatile anesthetic agents markedly de-crease the incidence of awareness while allowing easy titrat-

Table 1. Expiratory Sevoflurane Concentration at Temperatures

Between 29° and 35°C to Maintain the BIS Between 40 and 50

Temperature (°C)Expiratory Sevoflurane

Mean % (� SD)BIS

Mean (� SD)

29 0.81 (0.15) 41.9 (3.14)30 0.96 (0.15) 42.06 (4.06)31 1.07 (0.22) 42.52 (3.13)32 1.19 (0.27) 43.44 (4.11)33 1.31 (0.29) 44.34 (3.85)34 1.37 (0.28) 45.54 (4.45)35 1.48 (0.28) 50.10 (5.61)

Abbreviation: SD, standard deviation.

ability of anesthetic depth.6,7

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61SEVOFLURANE REQUIREMENT AND BIS

This study showed that sevoflurane requirements for hypno-sis are increased during the rewarming phase of hypothermicCPB when the hypnosis is guided by BIS monitoring. Theincreased sevoflurane requirement was statistically significantin the multivariate analysis with a strong positive correlation.These findings agree with a previous study published by Liu etal4 evaluating isoflurane requirement during the rewarminghase of hypothermic CPB. Because the R2 value, which is a

measure of goodness of fit, was 0.67, it implies that there isminimal discrepancy between observed values and the valuesexpected under the statistical model in question. This implies thatthe percent increase in the requirement for sevoflurane is uniformand follows a particular pattern, which may be predicted using thepreviously described formula. This pattern may be valuable toadjust the concentration of inhaled sevoflurane during the rewarm-ing phase of CPB based on the patient temperature.

A study on the usefulness of volatile agents during CPBconcluded that oxygenator exhaust partial pressures of anes-thetic agents correlated with simultaneously obtained bloodpartial pressures, suggesting that monitoring exhaust gas maybe useful clinically.8 In a study by Nussmeier et al,5 increasingthe gas inflow to the oxygenator from 3 to 12 L/min hastenedthe wash-in and washout slightly. The fresh gas flow require-ment in the present patients varied very little (ie, from 1.6 to1.99 L/min). The increase in the sevoflurane concentrationcorrelated weakly with increasing marginal fresh gas flows anddid not show statistical significance in this study. Hence, freshgas flow could not have had much effect on sevoflurane con-centrations. Nussmeier et al also reported that increasing thepump blood flow from 3 to 5 L/min had no effect on thewash-in and washout of the inhalation agent. The presentstudy’s results were comparable with those of Nussmeier et al.Although pump flow was significant in linear regression withsignificant p values (p � 0.001), in the multivariate analysis itfailed to show any statistical significance.

Although BIS monitoring has been advocated for guidinganesthetic requirements during CPB,9,10 BIS algorithms arebased primarily on normothermic patients. It is unclear if BIShas the same relationship to hypnosis during hypothermic con-ditions. Severe hypothermia itself can cause slowing of theelectroencephalogram and loss of consciousness.11 Dewandret al12 studied BIS in patients undergoing CABG surgery under

mild hypothermic (30°C) CPB. They observed that the BISvalue was not affected by surgical stimulation or by CPB andmild hypothermia. They concluded that BIS was a reliablemonitor to assess the hypnotic effects of anesthetics duringnormothermic or mild hypothermic CPB. Because the oxygen-ator temperature was maintained between 29°C and 35°C in thepresent study, the authors presume that BIS accurately mea-sured the hypnotic effects of sevoflurane on CPB. The meanarterial pressure was maintained between 60 and 80 mm Hg

throughout CPB. This is in accordance with the various studies

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hat showed satisfactory outcomes when the pressures wereaintained in that range.The BIS value at 35°C in the patients in this study wasaintained at about 50.10 (�5.61) when sevoflurane was ad-inistered continuously. Hence, discontinuation of the anes-

hetic agent would predispose the patients to the risk of aware-ess during the warming phase of CPB. An adequate depth ofnesthesia should be ensured at the time of weaning the patientrom CPB because short-acting agents facilitating fast-trackecovery increasingly are used in modern cardiac anesthesia.

Wodey et al13 found that heart rate and cardiac index werenot significantly different under sevoflurane anesthesia whencompared with those during an awake condition. The shorten-ing fraction and rate-corrected velocity of circumferential fibershortening have been found to decrease at 1.5 minimum alve-olar concentration but not at 1 minimum alveolar concentrationof sevoflurane.13 The present study’s findings suggest that theevels of sevoflurane required to maintain an adequate depth ofnesthesia during the rewarming stage of CPB are in the rangehat may not result in myocardial depression.

LIMITATIONS

A limitation of the present study was that sevoflurane re-quirements were assessed only during the rewarming phase,which may not be identical to those during the cooling phase.Also, the sevoflurane requirement would be difficult to estimatebecause a considerable drift would be expected in the oxygen-ator temperature even before active cooling commences afterthe establishment of CPB. Although the authors performedrewarming at a slow pace to ensure its homogeneity, it was notalways possible to prevent overshooting the nasopharyngealtemperatures. This study was conducted on patients undergoingCABG surgery who were subjected to mild hypothermia.Hence, the observations cannot be extrapolated to patients whoare rewarmed from deep hypothermia. The expiratory gas sevo-flurane concentration is assumed to be equal to the bloodsevoflurane concentration. The authors followed a standardanesthesia method as far as possible; however, the unpredict-able pharmacokinetic and pharmacodynamic properties of an-esthetic drugs in the extracorporeal circulation and variabilityin patient responses to them could have introduced confound-ing factors in this study. Although it was found that end-tidalsevoflurane requirements may be predicted during the rewarm-ing phase of CPB, considering the small sample size of thepresent study, larger studies are required to support this obser-vation. Also, these results may not be identical with thoseinvolving different anesthetic drug regimens. In summary,sevoflurane requirement increases during the rewarming phaseof hypothermic CPB. The percent increase in the requirementfor sevoflurane is uniform and follows a particular pattern,

which may be predicted.

REFE

1. Tempe DK, Siddiquie RA: Awareness during cardiac surgery.Cardiothorac Vasc Anesth 113:214-219, 1999

2. Hall RI: Cardiopulmonary bypass and the systemic inflammatoryesponse: Effects on drug action. J Cardiothorac Vasc Anesth 16:83-98,

CES

3. Phillips AA, Mclean RF, Devitt JH, et al: Recall of intraoperativevents after general anaesthesia and cardiopulmonary bypass. Can Jnaesth 40:922-926, 1993

4. Liu EHC, Dhara SS: Monitoring oxygenator expiratory isoflurane

oncentrations and the bispectral index to guide isoflurane require-

62 CHANDRAN MAHALDAR, GADHINGLAJKAR, AND SREEDHAR

ments during cardiopulmonary bypass. J Cardiothorac Vasc Anesth19:485-487, 2005

5. Nussmeier NA, Moskowitz GJ, Weiskopf RB, et al: In vitroanesthetic washin and washout via bubble oxygenators: Influence ofanesthetic solubility and rates of carrier gas inflow and pump bloodflow. Anesth Analg 67:982-987, 1988

6. Joshi GP, McIlroy D: Inhalational techniques in ambulatory an-esthesia. Semin Cardiothorac Vasc Anesth 9:5-16, 2005

7. Dowd NP, Cheng DC, Karski JM, et al: Intraoperative awarenessin fast-track cardiac anesthesia. Anesthesiology 89:1068-1073, 1998

8. Hickey S, Gaylor JD, Kenny GN, et al: In vivo uptake andelimination of isoflurane by different membrane oxygenators during

cardiopulmonary bypass. Anesthesiology 97:133-138, 2002

9. Sebel PS: Central nervous system monitoring during open heartsurgery: an update. J Cardiothorac Vasc Anesth 12:3-8, 1998

10. Heier T, Steen PA: Awareness in anesthesia: Incidences, con-sequences and prevention. Acta Anaesthesiol Scand 40:1073-1086,1996

11. Dahaba AA: Different conditions that could result in the bispec-tral index indicating an incorrect hypnotic state. Anesth Analg 101:765-773, 2005

12. Dewandre PY, Hans P, Bonhomme V, et al: Effects of mildhypothermic cardiopulmonary bypass on EEG bispectral index. ActaAnaestheiol Belg 51:187-190, 2000

13. Wodey E, Pladys P, Copin C, et al: Comparative hemodynamicdepression of sevoflurane versus halothane in infants: An echocardio-

graphic study. Anesthesiology 87:795-800, 1997