Free
Clinical Science  |   October 1997
Effects of Rapid Increases of Desflurane and Sevoflurane to Concentrations of 1.5 MAC on Systemic Vascular Resistance and Catecholamine Response during Cardiopulmonary Bypass 
Author Notes
  • (Rodig, Keyl) Consultant in Anesthesiology.
  • (Kaluza) Perfusionist, Department of Cardiothoracic Surgery.
  • (Kees) Associate Professor of Pharmacology.
  • (Hobbhahn) Associate Professor of Anesthesiology.
  • Received from University Hospital, Department of Anesthesia, University of Regensburg, Regensburg, Germany. Submitted for publication January 10, 1997. Accepted for publication May 30, 1997.
  • Address reprint requests to Dr. Rodig: Department of Anesthesiology, University Hospital, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany.
Article Information
Clinical Science
Clinical Science   |   October 1997
Effects of Rapid Increases of Desflurane and Sevoflurane to Concentrations of 1.5 MAC on Systemic Vascular Resistance and Catecholamine Response during Cardiopulmonary Bypass 
Anesthesiology 10 1997, Vol.87, 801-807. doi:
Anesthesiology 10 1997, Vol.87, 801-807. doi:
Desflurane has been associated with transient cardiovascular stimulation when its concentration is increased rapidly to end-tidal concentrations exceeding approximately 1 MAC. [1–6 ] The mechanisms mediating the increases in sympathetic outflow are not yet fully understood. Because desflurane is a pungent agent, it has been suggested that airway irritation is involved in the marked activation of the neuroendocrine axis. [1,2,7 ] In contrast, sevoflurane, the least pungent of the volatile anesthetics, has not been found to cause neurocirculatory activation. [8 ] Strategies used to define the sites at which desflurane initiates its neurocirculatory activation revealed that activation of airway and systemic receptors may be involved. [9–12 ]
Application of volatile anesthetics into the oxygenator's gas supply line during cardiopulmonary bypass (CPB) avoids direct airway irritation by pungent agents.
Thus, we rapidly increased the exhaust gas concentration of desflurane and sevoflurane to 1.5 MAC during CPB and compared the effects on systemic vascular resistance (SVR), during the first 5 min, to assess early transient effects, and for another 10 min of steady state delivery of volatile anesthetics, and the catecholamine response, to further delineate the impact of airway irritation by desflurane.
Methods and Materials 
After obtaining approval of the local Ethics Committee and written informed consent, 48 patients (37 men) scheduled for elective coronary artery bypass graft surgery were studied. All patients were aged 65 yr or older (median, 68 yr; range, 65–74 yr). Patients were excluded if they had significant renal or hepatic impairment, peripheral vascular disease, or an ejection fraction of < 50%.
Patients were premedicated with oral clorazepate, 20–30 mg, on the evening before surgery and with clorazepate, 20 mg, approximately 1 h before surgery. All patients received their routine antianginal and antihypertensive medication up to and, except ACE inhibitors, including the morning of surgery.
Anesthesia was induced with intravenous sufentanil, 0.5 micro gram/kg, followed by etomidate until loss of consciousness. Neuromuscular block was obtained with pancuronium, 100 micro gram/kg. Before institution of CPB anesthesia was maintained with an infusion of propofol of 5 mg [center dot] kg sup -1 [center dot] h sup -1, supplemented with sufentanil bolus doses up to 2 micro gram/kg, and pancuronium, 50 micro gram/kg. The last sufentanil bolus was administered approximately 10 min before CPB.
A standard CPB technique was used in all patients. Before aortic cannulation, patients were anticoagulated with heparin (375 U/kg). A two-stage cannula was used for drainage of venous blood from the right atrium. The bypass circuit consisted of a capillary membrane oxygenator (Quadrox, Jostra Medizintechnik, Hirlingen, Germany) and a nonpulsatile pump (Stockert Instruments, Munich, Germany). The circuit was primed with a balanced crystalloid solution (1500 ml). A hardshell venous reservoir, open to air, was used. Nonpulsatile pump flow rates of 2.6 l [center dot] min sup -1 [center dot] m2+/- 10% were used and kept constant throughout the test sequence. Alpha-stat acid-base management was used during the entire bypass period. After application of the aortic cross-clamp and administration of cold crystalloid-based cardioplegic solution (Kardioplegische Perfusionslosung Fresenius, Bad Homburg, Germany), time was allowed for a stable level of perfusion pressure and mild hypothermia to develop (arterial and rectal temperature 32–33 [degree sign] Celsius). These variables remained constant for approximately 10 min before initiating the test sequence. Baseline values were recorded at the end of the stabilization period. Thereafter, the delivery of volatile anesthetics was started via a vaporizer, inserted into the oxygenator's gas supply line, during a constant gas flow of 3 l/min. Propofol was stopped in all patients at the beginning of CPB, and no opioids were given throughout the study period while surgery continued with the surgeons performing the coronary anastomoses.
The 48 patients were randomized according to the information on 48 closed envelopes to receive either desflurane, (24 patients, 12 patients including catecholamine measurements), or sevoflurane, at inspired concentrations that produced an exhaust gas concentration of 1.5 MAC (desflurane, 7.8 vol%; sevoflurane, 2.3 vol%[13 ]) within 2 min. These exhaust gas concentrations were sustained for another 13 min during stable hypothermia. Anesthetic gas concentrations were measured with a Datex multiple gas analysis monitor (Capnomac Ultima, Hoyer, Bremen, Germany) next to the gas inlet port and at the gas outlet port of the oxygenator. The sampling flow rate was 200 ml/min.
Systemic arterial pressures, measured via a femoral artery cannula, were continuously measured throughout the procedure. Recordings were made of mean arterial pressure (MAP) 1, 2, 3, 4, 5, 7, 9, 12, and 15 min after starting volatile anesthetic delivery. Systemic vascular resistance (SVR) was calculated from MAP (mmHg) and pump flow rate Q (l/min) as: SVR =(MAP/Q) 80 [dyn [center dot] s [center dot] cm sup -5]. Systemic vascular resistance index (SVRI) was equal to the SVR multiplied by the body surface area.
Hypotension during CPB requiring intervention was defined as MAP < 35 mmHg. When intervention was necessary in any patient, e.g., administration of exogenous catecholamines, all data from these patients were withdrawn from the study.
Arterial blood was sampled at baseline, 5, and 15 min after initiating administration of volatile anesthetics to measure catecholamine concentrations in 12 desflurane-treated patients and in 12 sevoflurane-treated patients. Blood samples were immediately placed in wet ice and separated and frozen at -70 [degree sign] Celsius until thawed for analysis. Plasma norepinephrine and epinephrine concentrations were determined by high performance liquid chromatography (HPLC) and electrochemical detection using a commercially available kit (Recipe, Munich, Germany). The intrato interassay variation at physiologic levels (300 pg/ml norepinephrine, 30 pg/ml epinephrine) was 4.2/9.2% for norepinephrine and 19/11% for epinephrine. The limit of quantification was 10 pg/ml for both catecholamines when 1 ml plasma was taken for analysis.
Hematocrit was determined at the beginning and at the end of the 15-min experimental period, during a period when no cardioplegic solution or any additional fluid was added to the bypass circuit.
Statistical Analysis 
All data are presented as median (range) unless otherwise stated.
Nonparametric tests were used for statistical analysis because the Kolmogorov-Smirnov test showed that the data were not normally distributed. The Friedmann two-way analysis of variance, followed by the Wilcoxon and Wilcox test for repeated measurements, was used for within-group comparisons of SVRI and catecholamine measurements. To compare the time course of Delta SVRI from baseline to 5 min and from 7 to 15 min values between groups, we calculated the slopes of a line, fitted to the corresponding Delta SVRI data of each patient, by linear regression analysis. [14 ] The slopes were compared by the Mann-Whitney U-test. Changes of catecholamine concentrations were analyzed by the Mann-Whitney U-test for intergroup comparisons, and the level of significance was corrected according to Bonferroni to compensate for the effect of multiple comparisons. The chi-square test was applied to categorical data. P < 0.05 was considered significant.
Results 
The groups were not significantly different for demographic data (sex, age, weight, body surface area), preoperative medication, and intraoperative medication before the study. Total doses of anesthetics before starting the test sequence did not differ between the groups (sufentanil, 2.5 micro gram/kg; propofol, 5 mg [center dot] kg sup -1 [center dot] h sup -1; pancuronium, 150 micro gram/kg). The target value of 1.5 MAC (exhaust gas) was achieved in all patients within 2 min after initiating administration of desflurane or sevoflurane.
There were no significant differences between the groups in baseline SVRI measurements. SVRI at baseline was 1,783 dyn [center dot] s [center dot] cm sup -5 [center dot] m2(1,273–2,016) in the desflurane group and 1,804 dyn [center dot] s [center dot] cm sup -5 [center dot] m2(1,254–2,275) in the sevoflurane group. Intragroup comparisons (Table 1) revealed that SVRI in the desflurane group initially remained unchanged to baseline level, thereafter declining to significantly lower values at 9, 12, and 15 min compared with values from 0 to 5 min. However, the addition of equi-MAC concentrations of sevoflurane to the fresh gas resulted in an immediate and significant reduction in SVRI (Table 1). A perfusion pressure of 35 mmHg, defined as the lowest acceptable level, was reached in one patient receiving sevoflurane at 9 min and in one patient at 12 min. Two patients receiving desflurane, one of them from the group including catecholamine measurements, reached the limit of 35 mmHg at 12 min. All data from these four patients who did not complete the protocol were withdrawn from the study. Figure 1presents the changes in SVRI from baseline values (Delta SVRI) in the 22 patients receiving desflurane and in the 22 patients receiving sevoflurane, during a constant pump-flow rate. The time-course of Delta SVRI from baseline to 5 min was found to differ significantly between desflurane- and sevoflurane-treated patients, whereas there was no statistically significant difference between the curves from 7 to 15 min.
Table 1. SVRI and MAP after Increases in Desflurane and Sevoflurane Concentrations to 1.5 MAC 
Image not available
Table 1. SVRI and MAP after Increases in Desflurane and Sevoflurane Concentrations to 1.5 MAC 
×
Figure 1. Time-course of changes of SVRI (median, range) from baseline (0 min) in 22 desflurane-treated ([round bullet, filled]) and 22 sevoflurane-treated ([circle, open]) patients. A significant difference in the time-course (slope analysis of curves) from 0 to 5 min was found. No difference between groups from 7 to 15 min was noted.
Figure 1. Time-course of changes of SVRI (median, range) from baseline (0 min) in 22 desflurane-treated ([round bullet, filled]) and 22 sevoflurane-treated ([circle, open]) patients. A significant difference in the time-course (slope analysis of curves) from 0 to 5 min was found. No difference between groups from 7 to 15 min was noted.
Figure 1. Time-course of changes of SVRI (median, range) from baseline (0 min) in 22 desflurane-treated ([round bullet, filled]) and 22 sevoflurane-treated ([circle, open]) patients. A significant difference in the time-course (slope analysis of curves) from 0 to 5 min was found. No difference between groups from 7 to 15 min was noted.
×
Plasma norepinephrine concentrations, 383 pg/ml (113–841) in 11 desflurane-treated patients and 580 pg/ml (215–927) in 12 sevoflurane-treated patients, and epinephrine concentrations, 67 pg/ml (10–293) in the desflurane-treated patients, respectively, 55 pg/ml (24–279) in the sevoflurane-treated patients, did not differ between groups at baseline, although there were substantial differences in individual baseline values of norepinephrine and epinephrine. Individual changes in catecholamine concentrations are presented in Figure 2to delineate the relation between the initial catecholamine concentration and subsequent changes in the catecholamine concentration initiated by desflurane or sevoflurane. Changes in plasma norepinephrine concentrations from baseline values were significantly different in the desflurane-treated patients at 5 and 15 min (Table 2) compared with the sevoflurane-treated patients, whereby concentrations in the desflurane group were higher compared with those of the sevoflurane group. Differences in changes in plasma epinephrine concentrations reached statistical significance between groups at 15 min. In patients receiving 1.5 MAC desflurane, there were no differences in norepinephrine and epinephrine concentrations with time. In sevoflurane-treated patients, norepinephrine concentrations at 15 min were significantly lower compared with baseline and 5 min values, and epinephrine concentrations at 15 min were lower compared with baseline. Exogenous catecholamines were not administered to any patient before CPB or during the test sequence.
Figure 2. Individual changes in plasma norepinephrine and epinephrine concentrations from baseline (0 min) in 11 desflurane-treated (left) and in 12 sevoflurane-treated patients (right), solid lines and filled symbols denote patients with an initial (from 0 to 5 min) increase in concentrations, whereas dotted lines and white symbols indicate no change or decrease in catecholamine concentrations.
Figure 2. Individual changes in plasma norepinephrine and epinephrine concentrations from baseline (0 min) in 11 desflurane-treated (left) and in 12 sevoflurane-treated patients (right), solid lines and filled symbols denote patients with an initial (from 0 to 5 min) increase in concentrations, whereas dotted lines and white symbols indicate no change or decrease in catecholamine concentrations.
Figure 2. Individual changes in plasma norepinephrine and epinephrine concentrations from baseline (0 min) in 11 desflurane-treated (left) and in 12 sevoflurane-treated patients (right), solid lines and filled symbols denote patients with an initial (from 0 to 5 min) increase in concentrations, whereas dotted lines and white symbols indicate no change or decrease in catecholamine concentrations.
×
Table 2. Changes in Catecholamine Concentrations from Baseline 
Image not available
Table 2. Changes in Catecholamine Concentrations from Baseline 
×
Hematocrit did not change significantly in any patient during the 15-min study.
Discussion 
It has been suggested that the pungent properties of desflurane may cause airway irritation, thus stimulating a sympathetic response. [1,2,7,15 ] Application of volatile anesthetics into the oxygenator's gas supply line during CPB avoids direct airway irritation as a possible trigger of sympathetic stimulation. The bronchial and pleural circulation originating from systemic arteries constituting 1–3% of cardiac output may only bring negligible amounts of volatile anesthetics into contact with the trachea or lungs. [16 ]
Exhaust gas concentrations measured at the gas outlet port of the oxygenator correlate reasonably well with simultaneously obtained arterial blood partial pressures of volatile anesthetics using bubble oxygenators. [17 ] In vitro studies of volatile anesthetics' pharmacokinetics using membrane oxygenators revealed differences as a result of membrane oxygenators' design and composition. Even though exact data of the QUADROX we used (polypropylene in hollow-fiber form) are not available, an acceptable correlation between exhaust gas concentrations and arterial blood partial pressures is assumed. [18 ]
For the first 5 min after initiating the delivery of desflurane and sevoflurane into the oxygenator' gas supply line during CPB, the time-course of Delta SVRI was significantly different in the desflurane group compared with the sevoflurane group, whereas there was no difference from 7 to 15 min. In the desflurane group, SVRI initially remained unchanged to baseline level, thereafter declining to lower levels at 9, 12, and 15 min, whereas sevoflurane produced an immediate and significant reduction in SVRI.
This different hemodynamic response between desflurane and sevoflurane was associated with a difference in plasma norepinephrine and epinephrine concentrations in the desflurane group compared with the sevoflurane group. With desflurane administration, plasma catecholamine concentrations remained unchanged to baseline level, whereas with sevoflurane administrations, catecholamine concentrations decreased with time. The difference in norepinephrine concentrations between the desflurane and sevoflurane groups reached statistical significance at 5 and 15 min, in epinephrine concentrations at 15 min.
The time-course of the differences in the hemodynamic response between desflurane and sevoflurane is similar to the rapidity of onset and the rapidity of decay of hemodynamic changes observed after rapid increases in desflurane concentrations in a healthy and young population. [1,2,4,5 ] In accordance with findings of Ebert et al., [8 ] the rapid increase of desflurane was related to a difference in the hemodynamic response compared with sevoflurane, the administration of sevoflurane resulting in an immediate reduction in SVRI according to its vasodilatory properties. [19 ]
Changes in plasma catecholamine concentrations associated with hemodynamic changes were observed by others [1,3,20,21 ]; cardiovascular stimulation being accompanied by increases in catecholamine concentration. The time-course of longer-lasting changes in catecholamine concentrations compared with peak cardiovascular changes is comparable with findings of Weiskopf [1 ] and Gormely. [9 ] The hormonal activation may be counteracted by direct, relaxing effects of desflurane. [6 ]
However, we neither observed cardiovascular stimulation, as would be indicated by significant increases in SVRI, nor significant increases in catecholamine concentrations in our patients aged more than 65 yr and who, in addition, had received opioids known to blunt the hemodynamic stimulation to desflurane, [20,22 ] during the conditions of desflurane application during hypothermic CPB.
CPB alone may affect SVRI and catecholamine concentrations depending on the degree of hypothermia, the composition of pump circuit priming fluids, the pulsatility of the perfusion, or the degree of hemodilution. [23,24 ] However, because all our patients were treated identically other than anesthetic agent selected, the observed differences between groups should be agent-related.
Because our data show significant differences in the hemodynamic and catecholamine response between desflurane and sevoflurane, when rapidly increased to concentrations of 1.5 MAC during mild hypothermic CPB and thus avoiding airway contact, these results strongly suggest a trigger besides airway irritation.
References 
References 
Weiskopf RB, Moore MA, Eger EI II, Noorani M, McKay L, Chortkoff B, Hart PS, Damask M: Rapid increase in desflurane concentration is associated with greater transient cardiovascular stimulation than with rapid increase in isoflurane concentration in humans. Anesthesiology 1994; 80:1035-45.
Ebert TJ, Muzi M: Sympathetic hyperactivity during desflurane anesthesia in healthy volunteers. Anesthesiology 1993; 79:444-53.
Daniel M, Eger EI II, Weiskopf RB, Noorani M: Propofol fails to attenuate the cardiovascular response to rapid increases in desflurane concentration. Anesthesiology 1996; 84:75-80.
Pacentine GG, Muzi M, Ebert TJ: Effects of fentanyl on sympathetic activation associated with the administration of desflurane. Anesthesiology 1995; 82:823-31.
Devcic A, Muzi M, Ebert TJ: The effects of clonidine on desflurane-mediated sympathoexcitation in humans. Anesth Analg 1995; 80:773-9.
Weiskopf RB: Cardiovascular effects of desflurane in experimental animals and volunteers. Anaesthesia 1995; 50:14-7.
Weiskopf RB, Eger EI II, Noorani M, Daniel M: Repetitive rapid increases in desflurane concentration blunt transient cardiovascular stimulation in humans. Anesthesiology 1994; 81:843-9.
Ebert TJ, Muzi M, Lopatka CW: Neurocirculatory responses to sevoflurane in humans. Anesthesiology 1995; 83:88-95.
Gormley WP, Murray JM, Trinick TR: Intravenous lidocaine does not attenuate the cardiovascular and catecholamine response to a rapid increase in desflurane concentration. Anesth Analg 1996; 82:358-61.
Bunting He, Kelly MC, Milligan KR: Effect of nebulized lignocaine on airway irrigation and haemodynamic changes during induction of anaesthesia with desflurane. Br J Anaesth 1995; 75:631-3.
Weiskopf RB, Eger EI II, Daniel M, Noorani M: Cardiovascular stimulation induced by rapid increases in desflurane concentration in humans results from activation of tracheopulmonary and systemic receptors. Anesthesiology 1995; 83:1173-8.
Muzi M, Ebert TJ, Hope WG, Robinson BJ, Bell LB: Site(s) of mediating sympathetic activation with desflurane. Anesthesiology 1996; 85: 737-47.
Gold M, Abello D, Herrington C: Minimum alveolar concentration of desflurane in patients older than 65 yr. Anesthesiology 1993; 79:710-4.
Matthews JNS, Altman DG, Campbell MJ, Royston P: Analysis of serial measurements in medical research. BMJ 1990; 300:230-5.
Moore MA, Weiskopf RB, Eger EI II, Noorani M, McKay L, Damask M: Rapid 1% increases of end-tidal desflurane concentrations to greater than 5% transiently increase heart rate and blood pressure in humans. Anesthesiology 1994; 81:94-8.
Benumof JL: Respiratory physiology and respiratory function during anesthesia, Anesthesia. Edited by Miller RD. New York, Churchill Livingstone, 1990, pp 505-49.
Nussmeier NA, Lambert ML, Moskowitz GJ, Cohen NH, Weiskopf RB, Fisher DM, Eger EI II: Washin and washout of isoflurane administered via bubble oxygenators during hypothermic cardiopulmonary bypass. Anesthesiology 1989; 71:519-25.
Hickey S, Gaylor JDS, Kenny GNC: In vitro uptake and elimination of isoflurane by different membrane oxygenators. J Cardiothorac Vasc Anesth 1996; 10:352-5.
Ebert TJ, Harkin CP, Muzi M: Cardiovascular responses to sevoflurane: a review. Anesth Analg 1995; 81:S11-22.
Weiskopf RB, Eger EI II, Noorani M, Daniel M: Fentanyl, esmolol, and clonidine blunt the transient cardiovascular stimulation induced by desflurane in humans. Anesthesiology 1994; 81:1350-5.
Ciofolo MJ, Jansson E, Johansson G, Morrison S, Reiz S: Sympathetic activation by desflurane is not mediated by airway or lung receptors. Br J Anaesth 1995; Suppl 1:A218.
Yonker-Sell AE, Muzi M, Hope WG, Ebert TJ: Alfentanil modifies the neurocirculatory responses to desflurane. Anesth Analg 1996; 82:162-6.
Kennedy DJ, Butterworth JF IV: Endocrine function during and after cardiopulmonary bypass. Recent observations. J Clin Endocrinol Metab 1994; 78:997-1002.
Downing SW, Edmunds LH: Release of vasoactive substances during cardiopulmonary bypass. Ann Thorac Surg 1992; 54:1236-43.
Figure 1. Time-course of changes of SVRI (median, range) from baseline (0 min) in 22 desflurane-treated ([round bullet, filled]) and 22 sevoflurane-treated ([circle, open]) patients. A significant difference in the time-course (slope analysis of curves) from 0 to 5 min was found. No difference between groups from 7 to 15 min was noted.
Figure 1. Time-course of changes of SVRI (median, range) from baseline (0 min) in 22 desflurane-treated ([round bullet, filled]) and 22 sevoflurane-treated ([circle, open]) patients. A significant difference in the time-course (slope analysis of curves) from 0 to 5 min was found. No difference between groups from 7 to 15 min was noted.
Figure 1. Time-course of changes of SVRI (median, range) from baseline (0 min) in 22 desflurane-treated ([round bullet, filled]) and 22 sevoflurane-treated ([circle, open]) patients. A significant difference in the time-course (slope analysis of curves) from 0 to 5 min was found. No difference between groups from 7 to 15 min was noted.
×
Figure 2. Individual changes in plasma norepinephrine and epinephrine concentrations from baseline (0 min) in 11 desflurane-treated (left) and in 12 sevoflurane-treated patients (right), solid lines and filled symbols denote patients with an initial (from 0 to 5 min) increase in concentrations, whereas dotted lines and white symbols indicate no change or decrease in catecholamine concentrations.
Figure 2. Individual changes in plasma norepinephrine and epinephrine concentrations from baseline (0 min) in 11 desflurane-treated (left) and in 12 sevoflurane-treated patients (right), solid lines and filled symbols denote patients with an initial (from 0 to 5 min) increase in concentrations, whereas dotted lines and white symbols indicate no change or decrease in catecholamine concentrations.
Figure 2. Individual changes in plasma norepinephrine and epinephrine concentrations from baseline (0 min) in 11 desflurane-treated (left) and in 12 sevoflurane-treated patients (right), solid lines and filled symbols denote patients with an initial (from 0 to 5 min) increase in concentrations, whereas dotted lines and white symbols indicate no change or decrease in catecholamine concentrations.
×
Table 1. SVRI and MAP after Increases in Desflurane and Sevoflurane Concentrations to 1.5 MAC 
Image not available
Table 1. SVRI and MAP after Increases in Desflurane and Sevoflurane Concentrations to 1.5 MAC 
×
Table 2. Changes in Catecholamine Concentrations from Baseline 
Image not available
Table 2. Changes in Catecholamine Concentrations from Baseline 
×