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Anesth Analg 1999;88:985-991
© 1999 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Cardiovascular Autonomic Dysfunction and Hemodynamic Response to Anesthetic Induction in Patients with Coronary Artery Disease and Diabetes Mellitus

Cornelius Keyl, MD*, Peter Lemberger, MD*, Klaus-Dieter Palitzsch, MD{dagger}, Karin Hochmuth, MD*, Andreas Liebold, MD{ddagger}, and Jonny Hobbhahn, MD*

Departments of *Anesthesiology, {dagger}Internal Medicine, and {ddagger}Heart Surgery, University Medical Center, Regensburg, Germany

Address correspondence and reprint requests to Dr. Cornelius Keyl, Department of Anesthesiology, University Medical Center, 93042 Regensburg, Germany. Address e-mail to Keyl{at}rkanaw1.ngate.uni-regensburg.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Autonomic neuropathy is a major complication of diabetes mellitus and is reported to be associated with increased perioperative hemodynamic instability. We investigated the relationship between autonomic dysfunction and hemodynamic response to anesthetic induction in diabetic and nondiabetic patients with coronary artery disease. We studied 60 patients scheduled for coronary artery surgery, 30 suffering from diabetes mellitus. Preoperative evaluation included traditional cardiovascular autonomic function tests (coefficient of variation of 150 beat-to-beat intervals in heart rate at rest, heart rate response to deep breathing, and heart rate and arterial blood pressure response to standing), spectral analysis of blood pressure and heart rate variability (HRV), and the computation of spontaneous baroreflex sensitivity. After premedication with clorazepate, anesthesia was induced with sufentanil (0.5 µg/kg), etomidate (0.1–0.2 mg/kg), and vecuronium (0.1 mg/kg). Heart rate and blood pressure before anesthetic induction and before and after tracheal intubation were compared between groups. Autonomic function tests, spectral analysis of HRV, and spontaneous baroreflex sensitivity revealed significant differences between patient groups. Most diabetic patients (n = 23) had one or more abnormal test results, in contrast to most nondiabetic patients, who did not show signs of autonomic neuropathy (n = 23). There was no relationship between cardiovascular autonomic function and hemodynamic behavior during anesthetic induction. The blood pressure response to anesthetic induction was not different between patient groups, even when comparing the subgroups with and without abnormal autonomic function tests. These findings indicate that increased hemodynamic instability during anesthetic induction is not obligatory in patients with diabetes mellitus and autonomic dysfunction.

Implications: This study indicates that increased hemodynamic instability during anesthetic induction is not obligatory in patients with coronary artery disease and autonomic dysfunction.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Diabetes mellitus is the most common endocrinopathy, affecting >6% of the population in developed countries (1). Therefore, problems caused by impaired organ function due to diabetes mellitus are common in the perioperative period. A major long-term complication of diabetes mellitus is cardiovascular autonomic neuropathy, with a prevalence rate ranging from 16% to >30%, with no differences between patients with insulin-dependent and noninsulin–dependent diabetes mellitus (2,3). Cardiovascular autonomic neuropathy is associated with increased morbidity and mortality (4,5), and several authors observed hemodynamic instability in patients with autonomic dysfunction during anesthetic induction and maintenance (6–10). Impaired regulation of blood pressure and heart rate may cause imbalances in myocardial oxygen demand and supply and may increase risk in patients with coronary artery disease (CAD). Therefore, the relationship between cardiovascular autonomic neuropathy and perioperative hemodynamic regulation is of interest in patients with CAD.

In the present study, we compared cardiovascular autonomic function and hemodynamic responses to anesthetic induction between diabetic and nondiabetic patients scheduled for coronary artery surgery. Preoperatively, cardiovascular autonomic function was assessed in both groups by using traditional autonomic function tests. Additionally, spectral analysis of heart rate variability (HRV) and systolic blood pressure variability was performed. Spectral analysis of HRV can be used as a tool to assess early cardiovascular autonomic dysfunction (11). Furthermore, heart rate oscillations may be linked to blood pressure oscillations and are probably mediated by baroreceptor control mechanisms (12,13). Cardiovascular baroreflex control is an important physiological mechanism to maintain blood pressure at a steady-state level, and the impairment of baroreflex sensitivity is considered an early sign of autonomic dysfunction in patients with diabetes mellitus, which may not be detected by traditional function tests (14). Therefore, we assessed baroreceptor activity from systolic blood pressure and heart rate power spectra via transfer function analysis and used this variable as an additional measure of cardiovascular autonomic function. In the present study, anesthetic induction was accomplished with drugs selected because of their minimal cardiocirculatory side effects, to avoid provoking hemodynamic instability as a side effect of the induction drugs. Therefore, we used an opioid (fentanyl) in combination with a muscle relaxant without cardiovascular side effects (vecuronium) and an induction drug (etomidate) that has been shown to maintain hemodynamic stability better than drugs such as propofol or thiopental (15).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval by our institutional ethical board and with written informed consent, 60 patients scheduled for coronary artery surgery were studied, 30 of whom suffered from type II diabetes mellitus for >5 yr. All patients had a normal myocardial function (angiographic left ventricular ejection fraction >60%). Any previous myocardial infarction had occurred at least 2 mo before. Details of patient demography are reported in Table 1.


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  		Table 1. Demographic characteristics
 
On the afternoon of the preoperative day, the patients underwent cardiovascular autonomic function tests using continuous monitoring of electrocardiogram (ECG) (Sirecust 302D; Siemens, Erlangen, Germany) and noninvasive blood pressure (Finapress; Ohmeda, Louisville, CO). Additionally, respiration was monitored using a nasal-oral thermistor (Jaeger GmbH, Höchberg, Germany).

All signals were relayed to a 12-bit analog to digital converter and sampled at 1000 Hz on a personal computer using a program based on commercially available software (Lab-VIEW; National Instruments, Austin, TX) and designed by our group. R waves and systolic blood pressure were automatically detected, and the beat-to-beat intervals (expressed as RR intervals) were calculated. Additionally, the signals were inspected visually and checked for artifacts and heterotopic beats.

Several standard cardiovascular autonomic tests (16,17) were conducted. The coefficient of variation of 150 RR intervals (artifact free) at rest was determined, with ECG and blood pressure registered for 5 min after a resting period of at least 20 min.

Heart rate response to deep breathing was evaluated after the patients were instructed to breathe deeply at a frequency of 6 breaths/min. The ratio of the longest RR interval during expiration and the shortest RR interval during inspiration was calculated for each breathing cycle. The maximal quotient was used for the analysis. Heart rate response to standing was assessed as the ratio of the longest RR interval of beats 20–40 to the shortest RR interval of beats 5–25. This modification of the standard 30/15 test was suggested by Ziegler et al. (17), who found it to be of superior diagnostic value compared with the original Ewing test, which measures the ratio of the longest RR interval around the 30th beat and the shortest RR interval around the 15th beat. Postural change in blood pressure was quantified as the maximal difference between systolic blood pressure measured with the patient in the supine position and after standing upright. Blood pressure was continuously recorded. Resting blood pressure was defined as the average of five beats in the supine position immediately before standing. After standing, the lowest value of systolic blood pressure during a 5-min period was used for analysis.

The results of the autonomic function tests were interpreted using the age-related normal ranges published by Ziegler et al. (17). The postural decrease in systolic blood pressure is not age-dependent and was interpreted as pathological when exceeding 30 mm Hg (17). Power spectral analysis of RR intervals and systolic blood pressure were conducted over 5-min epochs. Only episodes with <5% ectopic beats or artifacts were accepted for analysis. After evaluation of stationarity of data [reverse arrangement test due to Bendat and Piersol (18)], the data were resampled at 4 Hz using a moving 500-ms rectangular window (19). Nonsinus beats were recognized due to interval criteria and replaced by means of preceding values. Each 5-min interval was divided into four segments overlapping 50%. After linear trend removing, DC offset subtraction, and application of a Hanning window, an autospectral density function was estimated by computing a discrete Fourier analysis for the segments and averaging the results (18). The area under the curve was calculated for the following frequency bands: total frequency (<0.5 Hz), low frequency (LF; 0.05–0.15 Hz), and high frequency (HF; 0.15–0.5 Hz).

Transfer function analysis was used to demonstrate a significant relationship between respiration and HF HRV and establish that there were no respiratory-dependent oscillations in heart rate in the LF component. Furthermore, transfer analysis was computed to analyze the relationship between oscillations in systolic arterial blood pressure (SBP) and RR intervals with SBP as the input and RR intervals as the output signal. A coherence function was calculated as a measure of the linear relationship between input and output. A squared coherence >0.5 was interpreted as an indicator of stable phase shift, signifying a significant relationship between input and output, and could be observed in the LF band around 0.1 Hz and at the respiratory frequency. The gain of the transfer function, which represents the ratio between changes in blood pressure and changes in RR intervals, was calculated for the frequencies with high coherence and averaged for the LF and HF bands.

On the day of surgery, the patients were premedicated with 20–30 mg of clorazepate. Heart rate was monitored during anesthetic induction by two-channel ECG (leads II and V5). Blood pressure was continuously monitored via an arterial catheter in the femoral artery. After an infusion of 500 mL of isotonic crystalloid solution, anesthesia was induced with sufentanil (0.5 µg/kg over approximately 60 s), etomidate (0.1–0.2 mg/kg until loss of consciousness, over approximately 60 s), and vecuronium (0.1 mg/kg). Tracheal intubation was performed 3 min after the injection of the muscle relaxant. Heart rate and blood pressure were continuously recorded, averaging the values of each five beats. The values registered immediately before anesthetic induction, the minimal value before tracheal intubation, and the maximal value registered 5 min after intubation were taken for further analysis. A decrease in systolic blood pressure <90 mm Hg was treated with phenylephrine 0.1–0.2 mg IV. After insertion of a central venous catheter, the central venous pressure was measured.

Data were checked for normal distribution using the Lillifors modification of the Kolmogorov-Smirnov test. For normally distributed, data are presented as means ± SD; otherwise, data are shown as medians (range). Differences between groups of patients were analyzed using the Mann-Whitney U-test or Student's t-test when appropriate. The {chi}2 test was used to analyze relationships between the characteristics of the patients and the groups, and between autonomic function test results and the incidence of vasopressor treatment during anesthetic induction. Multiple linear regression analysis with stepwise selection of independent variables was used to identify relationships among the test results, HRV, baroreflex sensitivity, and hemodynamic regulation during anesthetic induction. Discriminant analysis was performed to evaluate the ability of cardiovascular test results to distinguish between patients with and without hemodynamic instability during anesthetic induction. The {alpha} error level was selected at 0.05. Under the condition that a difference in blood pressure of at least 10 mm Hg between groups was of interest during anesthetic induction, and assuming an effect size of 0.7, the ß error level was determined to be approximately 0.2.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The results of the traditional autonomic function tests are presented in Table 2. All tests were significantly different between patient groups, with the exception of the postural blood pressure change. In the group without diabetes mellitus, 23 subjects had normal test results, 6 patients had one abnormal test result, and 1 patient had two abnormal test results. In the group with diabetes mellitus, seven patients had normal autonomic function tests, seven patients had one abnormal test result, seven patients had two abnormal tests, and five patients three abnormal tests. All autonomic function tests were abnormal in four patients with diabetes mellitus.


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  		Table 2. Results of Autonomic Function Tests
 
Results of spectral analysis of RR intervals and SBP are presented in Table 3. SBP variability was similar between patients with and without diabetes. HRV was significantly decreased in all calculated frequency bands in patients with diabetes mellitus. The ratio of LF to HF power was not different between patient groups. In all patients, squared coherence—indicating the linear relationship between blood pressure and RR interval variability—exceeded 0.5 in the frequency around 0.1 Hz and in the respiration-linked component. The transfer gain of the RR interval-SBP relationship was significantly less in these components in patients with diabetes mellitus compared with nondiabetic patients.


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  		Table 3. RR Interval Variability, Systolic Blood Pressure Variability, and Gain of Transfer Analysis in Patients With and Without Diabetes Mellitus
 
Hemodynamic values during anesthetic induction are presented in Table 4. Heart rate was significantly higher in patients with diabetes compared with nondiabetic patients before anesthesia induction and before tracheal intubation. Blood pressure values did not differ between groups. Central venous pressure was comparable between the groups of patients. Nine patients without diabetes and seven patients with diabetes showed a decrease in SBP <90 mm Hg and were treated with a vasoconstrictor (phenylephrine 0.1–0.2 mg IV). Cardiovascular autonomic function, HRV, and baroreflex sensitivity was not different between patients with and without decreases in SBP <90 mm Hg. Multiple linear regression analysis did not identify any relationship among autonomic test results, HRV, spontaneous baroreflex sensitivity, and behavior of blood pressure during anesthetic induction. Discriminant analysis did not identify variables that were able to distinguish between patients with and without a decrease in SBP <90 mm Hg during anesthetic induction. Both groups of patients showed similar changes in blood pressure and heart rate after tracheal intubation.


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  		Table 4. Heart Rate and Blood Pressure
 
The comparison of hemodynamic response to anesthetic induction between diabetic patients with one or more abnormal test results (n = 23) and nondiabetic patients without any abnormal test result (n = 23) did not reveal significant differences, with the exception of heart rate, which was increased in diabetic patients before tracheal intubation.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In the present study, autonomic function tests, spectral analysis of HRV, and spontaneous baroreflex sensitivity revealed significant differences between diabetic and nondiabetic patients with CAD. Most diabetic patients had one or more abnormal test result, whereas most nondiabetic patients did not show signs of autonomic neuropathy. However, in contrast to previous investigations, we could not find any relationship between cardiovascular autonomic function and hemodynamic behavior during anesthetic induction.

The diagnosis of autonomic neuropathy is generally based on nonvasive cardiovascular function tests, as described by Ewing et al. (16), which were modified by other investigators who published age-related normal values (17). In all studies investigating cardiovascular regulation during anesthesia, autonomic function tests were performed and interpreted in different ways (6–10). Therefore, a comparison of subjects' autonomic function between the different studies is possible only in a very limited way.

In contrast to previous studies that evaluated autonomic dysfunction in patients with diabetes mellitus via traditional autonomic function tests (6,7,9,10), we also computed HRV and blood pressure variability and assessed spontaneous baroreflex sensitivity. This methodology was chosen because analysis of HRV is a very sensitive tool to assess autonomic nerve function (11,20) and is influenced by blood pressure variability via the baroreflex arch (12,21). Baroreflex sensitivity is also impaired in patients with autonomic dysfunction undetected by conventional tests (14).

Autonomic polyneuropathy may affect parasympathetic as well as sympathetic nerve functions. Most of our diabetic and nondiabetic patients were treated with ß-adrenergic blockers. Nevertheless, we observed a higher heart rate in patients with diabetes mellitus preoperatively and after anesthetic induction than that in control patients. This is generally interpreted as a sign of isolated vagal neuropathia. The impairment of the parasympathetic branch of the autonomic nervous system is thought to occur as an early phenomenon in diabetic neuropathia, followed by a late alteration of sympathetic function (22).

However, there are several contradictory findings that do not support this hypothesis. Most autonomic function tests, such as heart rate variation at rest and during deep breathing, mainly indicate vagal function. Sympathetic function is supposed to be evaluated by tests such as blood pressure and heart rate response while standing, which are considered relatively insensitive for assessing early alterations in sympathetic function (3,11). Therefore, it is not surprising that the use of more sophisticated methods demonstrated signs of both early vagal and sympathetic neuropathy in patients with diabetes mellitus (23,24). These results are supported by recent studies using spectral analysis of HRV, which indicated early impairment of the parasympathetic, as well as the sympathetic nerve system (11,20). This interpretation is based on the phenomenon that HF oscillations in heart rate (commonly around the respiratory frequency) are mainly mediated by vagal activity, whereas oscillations in the LF component (around 0.1 Hz) reflect changes in sympathetic, as well as parasympathetic, activity (25). Several authors proposed that the ratio of LF to HF power may indicate changes in the balance between sympathetic and parasympathetic activity (26,27). Consistent with this hypothesis, our diabetic patients showed a significantly decreased LF and HF power, compared with the nondiabetic control group, without changes in the ratio of LF to HF power, thus indicating parasympathetic as well as sympathetic dysfunction. This observation is in agreement with previous results (20), but it does not explain the higher heart rate that we observed in diabetic patients. Thus, using HRV as a simple measure of sympathovagal balance may be difficult. Furthermore, our findings must be considered in view of the fact that the autonomic function may have been additionally influenced by other factors. Cardiovascular diseases such as hypertension and CAD may affect autonomic regulation (28,29). Nevertheless, autonomic function tests were normal in most nondiabetic patients. Two thirds of our patients were receiving ß-adrenoreceptor blocking drugs, which may shift the LF to HF ratio toward lower values and may normalize baroreceptor activity (26,29,30). Additionally, autonomic regulation may be influenced by angiotensin-converting enzyme inhibitors and calcium channel blockers (25,31). It is obvious that autonomic function tests cannot differentiate between the variety of factors, such as cardiovascular diseases, diabetic neuropathia, and effects of medication on the autonomic nervous system. Although our patient groups were comparable with respect to underlying cardiovascular diseases and medication, cardiovascular-acting drugs may influence autonomic function in patients with and without diabetes mellitus in a different manner.

Another consideration is the influence of blood pressure fluctuations on HRV. The origin of neither the HF nor the LF component of power spectrum of HRV is totally clear. Respiratory sinus arrhythmia may contribute to arterial pressure oscillations (32). However, findings indicate an influence of arterial baroreceptors on respiratory sinus arrhythmia, as well as on 0.1-Hz oscillations in heart rate in humans (12,13,21,33). In view of these possible relationships, it seems advisable to consider blood pressure variability when analyzing HRV. We did not observe differences in SBP variability between the groups of patients, thus excluding the possibility that differences in HRV might be caused by different blood pressure fluctuations.

Several methods have been described to assess spontaneous baroreflex sensitivity. We used a method based on cross-spectral analysis between SBP variability and HRV (34). Under the condition that baroreflex contributes to HRV, at least in the 0.1-Hz region (12), transfer analysis is considered as a reliable tool for estimating spontaneous baroreflex sensitivity (34). The gain of the transfer function in the LF component has been found to represent baroreflex sensitivity, which is mediated by parasympathetic and sympathetic nerve action (34). Like spectral analysis of HRV, this approach seems to be more sensitive for assessing autonomic dysfunction than the traditional autonomic function tests (14). Spontaneous baroreflex sensitivity was markedly reduced in diabetic patients, comparable to the results of other studies using pharmacological methods for baroreflex evaluation (35). The data of the nondiabetic patients are also similar to previously published data (29).

Surprisingly, neither the results of traditional function tests, HRV, nor baroreflex sensitivity were related to hemodynamic responses during anesthetic induction. This finding is in contrast to previous studies (6–10) and may be caused by several circumstances.

Three investigators found significant decreases in arterial blood pressure in patients with autonomic dysfunction during anesthetic induction (6–8). Two authors observed a marked increase in arterial blood pressure (10) and heart rate (9) after tracheal intubation in patients with diabetes mellitus, but not in a nondiabetic control group.

Investigators previously studied patients scheduled for ophthalmic surgery or a heterogenous group of day-surgery patients (6–10). We studied a relatively homogenous group of patients with CAD, all suffering from stable angina pectoris. Patients with and without diabetes mellitus were similar with regard to cardiovascular medications. These medications were not discontinued preoperatively, with the exception of angiotensin-converting enzyme inhibitors. The patients in previous studies had no clinical signs of cardiovascular diseases preoperatively or were not treated with ß-adrenergic blockers (6,9,10), or antihypertensive medication was discontinued on the day of operation (7).

Besides the differences in selection of patients and drug management, differences in anesthesia management may be responsible for different study results. In our study, premedication consisted of a benzodiazepine. In contrast to other authors (6), we did not use anticholinergic substances, which act on cardiac autonomic tone. Additionally, we hydrated patients before anesthetic induction. Anesthesia was induced with etomidate, which has minimal cardiovascular depressant effects, as well as minimal effects on autonomic function (15,36). The studies that reported a greater blood pressure decrease in diabetic patients than in control subjects used either thiopental (6–8) or propofol (9) for anesthetic induction. The vasodilating and myocardial depressant properties, as well as different effects on autonomic function of thiopentone and propofol, may "unmask" autonomic dysfunction to a greater degree than etomidate.

In our study, vasopressors were required in 23% of diabetic patients and 30% of nondiabetic patients. This is a smaller percentage than that reported by Knüttgen et al. (7) (77%) and similar to that reported by Burgos et al. (6). The results of Latson et al. (8) are not comparable because of a different study design. We used a larger opioid dose than other authors, which may have intensified the decrease in blood pressure before tracheal intubation but may also have prevented cardiovascular reactions due to intubation, which occurred in other studies (6,9,10). Other authors who reported similar hemodynamic responses after the injection of the induction drug in diabetic and nondiabetic patients noted marked increases in hemodynamic variables after intubation in patients with diabetes mellitus (9,10), a phenomenon that should be avoided, especially in patients with cardiovascular diseases. Thus, the combination of an induction drug with minimal hemodynamic effects and an opioid seems to be favorable for anesthetic induction in patients with autonomic dysfunction.

In conclusion, we found abnormal autonomic function tests, reduced HRV, and spontaneous baroreflex sensitivity in most patients with CAD and diabetes mellitus compared with nondiabetic patients, who mostly had normal test results. We could not detect any relationship between cardiovascular autonomic function and hemodynamic behavior during anesthetic induction. The hemodynamic response to anesthesia induction was therefore not different between patients with and without diabetes mellitus, even when comparing the subgroups with and without abnormal autonomic test results. Thus, our study indicates that increased hemodynamic instability during anesthesia induction is not obligatory in patients with CAD and autonomic dysfunction.


   References
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 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication January 23, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press