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Dexmedetomidine Decreases Perioperative Myocardial Lactate Release in Dogs

Willigers, Henriëtte M. MD*; Prinzen, Frits W. PhD; Roekaerts, Paul M. MD, PhD*; de Lange, Simon MB, BS, PhD, FRCA*; Durieux, Marcel E. MD, PhD*

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doi: 10.1213/01.ANE.0000048708.75957.FF
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Early postoperative myocardial ischemia is one of the most important risk factors for adverse cardiac outcome in surgical patients with coronary artery disease (1). Because this risk factor appears related to the stress response associated with surgery and emergence from anesthesia, methods to reduce this stress response have been studied. Examples include epidural analgesia, profound opioid analgesia, and the administration of β-adrenoceptor antagonists or α2-adrenergic agonists (2). The last modality in particular seems promising because, in contrast to β-adrenoceptor antagonists, α2-agonists reduce overall tonic sympathetic action, reduce anesthetic requirements, and induce analgesia and anxiolysis (3).

α2-Adrenergic agonists can attenuate the stress response associated with emergence from anesthesia (4–6). However, whether this translates to less postoperative myocardial ischemia is unknown. This is partly because only two studies have focused directly on this issue (7,8). Also, although these studies show that α2-agonists decrease the incidence of emergence-related ST depression and postoperative cardiac deaths in high-risk surgical patients, no effect on myocardial infarction has been demonstrated.

One of the main reasons for the paucity of information on the effect of α2-agonists on postoperative myocardial ischemia is the difficulty in selecting a practical and clinically relevant outcome measure. The outcome measure myocardial infarction has a small incidence, which requires studying a large number of patients. Selecting ST segment changes as an outcome measure may not always be clinically relevant because such changes also result from changes in temperature, serum electrolytes, position, and the administration of drugs (9). A more precise measure of myocardial ischemia, but one that is difficult to obtain in patients, is the presence of lactate release from the myocardial area at risk. Also, it has been shown that not the incidence, but the load (i.e., duration), of myocardial ischemia is most significantly associated with adverse cardiac outcome (10) and therefore may be a more appropriate outcome measure.

Therefore, our aim was to determine in a placebo-controlled study whether dexmedetomidine, the most specific α2- agonist available, can decrease cumulative myocardial lactate release in dogs with coronary stenosis that are emerging from surgery and anesthesia. To obtain more insight into potential mechanisms, we also measured the effects of dexmedetomidine on hemodynamic variables, neurohumoral indices of the stress response, and indices of myocardial oxygen supply and demand.


With the approval of the Animal Care and Use Committee at the University of Maastricht, we studied 18 adult mongrel dogs. After the induction of anesthesia with 20 mg/kg of sodium thiopental IV, the dogs were intubated and ventilated with halothane in oxygen/nitrous oxide. After thoracotomy, a screw-driven plastic occluder was placed nonconstrictively distal to the first diagonal branch of the left anterior descending coronary artery (LAD). This occluder allows the creation of a fixed stenosis from controllable narrowing of coronary arteries. Catheters were inserted into the left femoral artery, the left anterior coronary vein, and a distal pulmonary artery for arterial (A), coronary venous (CV), and mixed venous blood sampling. To measure regional myocardial blood flow, a catheter for injection of microspheres was implanted in the left atrial appendage. Pressure sensors (Sentron 180 S; Cordis, Roden, the Netherlands) were inserted through the right femoral artery into the ascending aorta and left ventricle. Ultrasonic transit-time flowprobes (Transonic Systems, Ithaca, NY) were placed around the aortic root and just proximal to the coronary occluder. Heart rate (HR) was monitored by using limb lead II of the electrocardiogram. To measure regional myocardial shortening, a pair of 1.5-mm-diameter piezoelectric crystals were inserted parallel to circumferential midwall fibers in the area perfused by the LAD and connected to a digital sonomicrometer (Sonometrics Corp., London, Ontario, Canada).

Throughout the experiment, all signals were continuously displayed on monitors, and the corresponding values were stored every minute. During each period of measurement, digitized signals (12-bit analog/digital interface; sample frequency, 200 Hz) and corresponding beat-to-beat values were stored for 5 min. During off-line processing, all data of a 2-min stable period (i.e., <5% HR variation) within this 5-min acquisition period were averaged.

All blood samples were collected on ice. Samples to be analyzed afterward were centrifuged within 15 min at 4°C to separate plasma and stored at −70°C.

At the start of the study protocol, anesthesia was standardized to 1% halothane in oxygen/nitrous oxide (33%:66%). After 20 min, a stenosis of the LAD, standardized as the tightest stenosis not resulting in myocardial lactate release during stable anesthesia, was applied (Fig. 1). We aimed to increase the probability of myocardial lactate release from emergence-related stress responses by creating comparable degrees of borderline ischemia, and we used lactate release as a primary outcome variable.

Figure 1
Figure 1:
Schematic representation of the study protocol. Black arrows represent periods of measurements of hemodynamic variables, hemoglobin content, arterial and coronary venous blood gases, poststenotic coronary flow, lactate release, and regional myocardial contractile function. Stress hormones (SH) and regional myocardial blood flow (MBF) were measured less frequently. The time axis shows the exact number of minutes from the start of spontaneous breathing (first emergence period measurement) and the approximate number of minutes before this event. Note that baseline stenosis measurements were performed before study drug administration. P = before coronary stenosis; St = coronary stenosis; S = stop anesthesia; R = first emergence period measurement at the start of spontaneous respiration; 2, 3, 4,… = emergence period measurements.

To create similar borderline ischemia in both groups, the coronary artery was narrowed step by step at 5-min intervals until the poststenotic myocardium released lactate, i.e., [(CV − A) lactate] > 0. Then the occluder was released step by step until lactate release just ceased. During this procedure, lactate concentrations were measured within 3 min by using an absorption photometric method (DR Lange cuvette test LKM 140, Berlin, Germany). After a stabilization period of 15 min, the following baseline variables were measured: 1) hemodynamic variables (HR, aortic pressure, end-diastolic and maximum first derivative of left ventricular pressure, and aortic flow); 2) stress hormones (arterial plasma concentrations of norepinephrine, epinephrine, and cortisol); and 3) indicators of myocardial oxygen balance (LAD flow, regional myocardial blood flow, fractional oxygen extraction, and poststenotic myocardial lactate release).

After these baseline stenosis measurements, the study drug was administered. Animals were randomly assigned to one of two groups: those receiving dexmedetomidine (initial loading dose 0.5 μg/kg followed by a continuous infusion of 0.6 μg · kg−1 · h−1; dexmed group, n = 9) or those receiving placebo (0.9% NaCl; control group, n = 9). We did not blind the administration of the study drug because the marked bradycardic effect of dexmedetomidine makes this virtually impossible. The target plasma concentration of dexmedetomidine was 0.5 ng/mL because this concentration does not have major vasoconstrictive effects (11) and reduces sympathetic tone effectively in dogs (12) and in humans (4). The corresponding infusion scheme (timing and dose) was obtained from the pharmacokinetic data of our pilot study.

Approximately 10 min after the study drug was started, the chest wall was closed, and care was taken to maintain the position of the occluder by observing coronary flow and myocardial shortening signals. The pneumothorax was evacuated by careful manual inflation of the lungs. To mimic perioperative blood loss and to decrease the number of animals needed in our study, blood was collected from the femoral artery and replaced simultaneously with a colloid solution (Hemacel®; Behringwerke AG, Marburg, Germany) until a hemoglobin (Hb) value of approximately 6.5 mmol/L was reached. After completion of surgery, 0.01 mg/kg of buprenorphine was injected IM for postoperative analgesia (13), the dogs were restrained, and measurements were repeated. Then the emergence period was started by changing the inspiratory gas to 100% oxygen. The first emergence period measurement was made at the time of the first spontaneous breathing. This was done to standardize the level of consciousness during the emergence period. Then, measurements were repeated every 10 min for 90 min. By protocol, no interventions were made if ventricular fibrillation (VF) occurred. At the end of the experiment, the dogs were killed by pentobarbital overdose, and their hearts were stored at −20°C for regional blood flow analysis.

Plasma lactate concentrations were determined spectrophotometrically (Cobas Bio System; Hoffman La Roche, Basel, Switzerland) afterward, and the presence of myocardial lactate release ([(CV − A) lactate] > 0) was identified. For each dog, the cumulative myocardial ischemic load of the emergence period, our primary outcome measure, was calculated as the percentage of measurements indicating myocardial lactate release. In dogs that died from VF, missing lactate measurements were added to the myocardial ischemic load provided that VF occurred during a period of lactate release. We consider this appropriate because VF is a more severe consequence of myocardial ischemia than is myocardial lactate release, and not coding these measurements would have underestimated myocardial ischemia in these dogs.

Hb content (mmol/L) and oxygen saturation (Sao2 [%]) of A, CV, and mixed venous samples were measured with a hemoximeter (OSM-2; Radiometer, Copenhagen, Denmark), and oxygen tension (Po2 [kPa]) was measured with a blood-gas analyzer (ABL 3; Radiometer). The oxygen content (mmol/L) was calculated as Hb × Sao2 + 0.0102 × Po2. From this, oxygen extraction and consumption were calculated by using standard formulas.

Myocardial circumferential segment lengths at beginning of ejection (Be sl) and end of ejection (Ee sl) were measured by using the aortic flow signal to delineate the ejection period. From these, the percentage of systolic shortening during the ejection period (Sse) was calculated as SSE (%) = 100 × (Be sl − Ee sl)/Be sl.

Regional myocardial blood flow was measured with fluorescent labeled microspheres (polystyrene; diameter, 15.5 μm ± 2%; Molecular Probes, Eugene, OR) of six different colors (blue-green, yellow-green, orange, red, crimson, and scarlet), as described in detail elsewhere (14). Briefly, for each measurement, approximately 4 × 106 microspheres of a single color were injected into the left atrium; simultaneously, a reference arterial blood sample was withdrawn. Afterward, several adjacent myocardial samples were taken from the poststenotic myocardial wall and from the remote nonischemic myocardial wall and divided into subendocardial and subepicardial samples. Microspheres were isolated, their fluorescence was determined, and regional myocardial blood flow was calculated. Of the poststenotic myocardial wall, the area with the least flow immediately after application of the stenosis was used for analysis.

Catecholamines were measured fluorometrically (15). Serum cortisol concentration was determined by using solid-phase chemiluminescent enzyme immunoassay (Immulite® cortisol kit; DPC, Los Angeles, CA). Plasma concentrations of dexmedetomidine were determined by gas chromatography-mass spectrometry (16) at Farmos Research, Turku, Finland.

The pressure work index (PWI; μmol · min−1 · g−1) was calculated as a measure of myocardial oxygen demand (17):MATH where SV = stroke volume (mL); SBP = systolic blood pressure (mm Hg); DBP = diastolic blood pressure (mm Hg); HR = heart rate; BW = body weight (kg); C1 = 1.63 × 104; and C2 = 1.30 × 104.

From the 18 dogs, 1 dog from each group was not included in the statistical analysis, in the control group because of VF before the administration of the study drug and in the dexmed group because of severe postoperative hemorrhage. For some variables, data from at most one experiment were missing because of technical problems; these missing points were handled by appropriate statistical techniques. Data are presented as mean ± sem, unless stated otherwise.

Emergence-period values of each experiment were summarized as median values. This was done because the use of a summary measure is considered the most appropriate approach for analyzing serial measurements (18). Differences between groups were evaluated by the Mann-Whitney U-test, within-group changes were evaluated by Wilcoxon’s signed rank test with Bonferroni’s correction, and differences between ratios were evaluated by Fisher’s exact test. A P value <0.05 was considered statistically significant. Additionally, individual time points were analyzed with two-way repeated-measures ANOVA followed by Tukey’s test for multiple comparisons.


During emergence, the cumulative myocardial ischemic load was 46% less in the dexmed group than in the control group (95% confidence interval [CI], 20%–80%;P = 0.02;Fig. 2). Simultaneously, dexmedetomidine increased total coronary blood flow distal to the stenosis (Fig. 3), especially in the endocardial layers, as indicated by a 35% larger endo-/epicardial blood flow ratio (Table 1). The other determinants of myocardial oxygen supply—Hb concentration and partial arterial oxygen pressure—were similar in both groups (Table 1). Regarding demand, dexmedetomidine decreased HR during the emergence period by approximately 23%, but it did not affect aortic flow, aortic pressure, or PWI (Table 2). In neither group was myocardial ischemia preceded by a change in HR, blood pressure, or coronary flow (data not shown). The differences in incidence between groups of 1) myocardial lactate release (95% CI, −19% to 65%) and 2) VF (95% CI, −5% to 62%) were not statistically significant (Fig. 2B).

Figure 2
Figure 2:
Effect of dexmedetomidine on poststenotic myocardial lactate release in dogs emerging from anesthesia. A, Time course of individual coronary venous (CV) to arterial (A) lactate differences in the control group (left) and the dexmedetomidine (dexmed) group (right). In one dog of the control group, no lactate data were obtained because of technical problems. B, Data from Panel A are represented as either the presence (•) or absence (○ of episodes of myocardial lactate release. C, Mean values ± sem of the cumulative myocardial ischemic load during the emergence period [(episodes of lactate release or ventricular fibrillation/total emergence period measurements] × 100%). p = before coronary stenosis; St = coronary stenosis; S = stop anesthesia; R = first emergence period measurement at the start of spontaneous respiration; 2, 3, 4,… = emergence period measurements. #P = 0.02, dexmed versus control group.
Figure 3
Figure 3:
Changes in time in hemodynamics, plasma norepinephrine concentration, and poststenotic myocardial oxygenation in the dexmedetomidine (dexmed) group (•) and control group (○. Values are plotted as mean percentages of baseline stenosis measurements. Error bars indicate sem. For plasma norepinephrine concentrations, median values are plotted. The arrow indicates the start of administration of the study drug. P = before coronary stenosis; St = coronary stenosis; S = stop anesthesia; R = first emergence period measurement at the start of spontaneous respiration; 2, 3, 4,… = emergence period measurements; PWI = pressure work index. Absolute values of these data are given in Tables 1 and 2. * P < 0.05, control group versus dexmed group (two-way repeated-measures analysis of variance on absolute values followed by Tukey’s test for multiple comparisons).
Table 1
Table 1:
Changes in Myocardial Oxygen Supply Indices
Table 2
Table 2:
Changes in Hemodynamic Variables and Stress Hormones

With regard to the emergence-related stress response, plasma catecholamines, HR, and oxygen consumption of the body were less in the dexmed group than in the control group (Table 2, Fig. 3). Of these, dexmedetomidine prevented only an increase in plasma catecholamines compared with the preceding intraoperative measurements. The time to regain spontaneous breathing after stopping the anesthetics, as a measure of emergence, tended to be longer in the dexmed group, but this was not statistically significant (dexmed group, 30 ± 6 min; control group, 16 ± 2 min; 95% CI for the difference between groups, −3 to 29 min;P > 0.2).

Before emergence, the prevalence of myocardial lactate release was 57% less in the dexmed group than in the control group (95% CI, 20%–94%;P = 0.03; stop values, Fig. 2B). Simultaneously, dexmedetomidine decreased plasma concentrations of norepinephrine by 66%, decreased myocardial oxygen demand (PWI) by 29% (Table 2), and increased the endo-/epicardial blood flow ratio by 45% (Table 1).

Intraoperative procedures were the same in both groups. First, application of the stenosis resulted in a similar decrease in myocardial oxygenation. This is because 1) myocardial lactate release was absent in both groups (control group, −0.1 ± 0.1 mmol/L; dexmed group, −0.2 ± 0.0 mmol/L [CV − A] [lactate];P = 0.16;Fig. 2A, stenosis values), 2) endocardial flow decreased similarly (dexmed group, 59% ± 6%; control group, 66% ± 8%;P > 0.5;Table 1), and 3) baseline stenosis values were similar for all variables except end-diastolic pressure (stenosis values:Tables 1 and 2, Fig. 2A). Second, the duration of surgery and anesthesia was the same in both groups because the time between the “stenosis” and “stop anesthesia” measurements was 81 ± 8 min in the dexmed group and 76 ± 9 min in the control group (95% CI, −19 to 20 min;P > 0.5). Finally, intraoperative hemodilution resulted in a similar Hb (Table 1). Plasma concentrations of dexmedetomidine were stable and approximated the target of 0.5 ng/mL (Fig. 4), and no animal in either group required additional buprenorphine.

Figure 4
Figure 4:
Stability of plasma concentrations of dexmedetomidine (mean ± sem;n = 8 dogs) in relation to a target plasma concentration of 0.5 ng/mL. p = before coronary stenosis; Sten = coronary stenosis; S = stop anesthesia (approximately 35 min after starting dexmedetomidine); R = first emergence period measurement at the start of spontaneous respiration; 2, 3, 4,… = emergence period measurements.


In this study, the α2- agonist dexmedetomidine decreased myocardial ischemic load in dogs with a coronary stenosis that were emerging from anesthesia. This antiischemic effect of dexmedetomidine was associated with a decreased sympathetic tone and improved myocardial oxygen balance. The unique feature of our study was that we used invasive measurements of myocardial oxygenation of the area of risk that are not obtainable from human studies. Our data, therefore, may help to explain clinical findings that perioperative infusion of an α2-agonist has the potential to limit postoperative myocardial ischemia (7).

A decrease in myocardial ischemic load is a clinically relevant outcome measure because it has been shown that several periods of myocardial ischemia have a cumulative effect and can cause subendocardial necrosis in dogs (19). In humans, a prolonged duration of ST segment depression leads to myocardial damage, as measured by cardiac troponin I levels (20), and is associated with adverse cardiac outcome (10). Whether dexmedetomidine can decrease the incidence of myocardial ischemia during emergence remains unknown from this study because it was not powered for this outcome measure (e.g., to detect differences in the incidence of myocardial ischemia with a power of 0.80 and an α of 0.05, 62 dogs in each group would have been necessary). However, the importance of decreasing the incidence of myocardial ischemia, in addition to its load, remains unknown.

The decrease in emergence-related myocardial ischemic load from dexmedetomidine may be explained from its sympatholytic effects, which improve the myocardial oxygen supply/demand ratio. In accordance with previous studies in humans (6) and in dogs (21), dexmedetomidine had sympatholytic effects during the emergence period, as indicated by a decrease in plasma catecholamines and HR. These effects coincided with a redistribution of supply to the vulnerable endocardium, as indicated by an increased endo-/epicardial blood flow ratio. Although relatively large doses of α2-adrenergic agonists may produce coronary vasoconstriction (11), the redistribution of blood flow toward the endocardium indicates that the sympatholytic and HR-decreasing effects of dexmedetomidine most likely prevailed at the dose used.

Coronary artery thrombosis may decrease myocardial blood flow and, thus, supply. However, this was unlikely in this study, because dogs are not prone to coronary atherosclerosis, and we did not observe any macroscopic intracoronary thrombi at dissection afterward.

Other determinants of myocardial oxygen supply—plasma Hb values and Po2—were not different between groups and therefore are not likely to have confounded the observed differences in myocardial lactate release. Hb values were 6–7 mmol/L after hemodilution. These values are generally accepted for almost all surgical patients (22) and, as such, do not lead to myocardial ischemia. However, if the vasodilating capacity of the coronary artery is limited, moderate hemodilution may increase the risk of myocardial ischemia (23). This effect was considered ethically advantageous because it reduced the number of animals required.

Of the hemodynamic factors potentially involved in the genesis of emergence-related myocardial ischemia, dexmedetomidine decreased HR. A reduced HR is of pivotal importance in decreasing myocardial ischemia because it improves supply from a prolonged diastolic perfusion time and is the most important determinant of myocardial oxygen demand (24). Thus, the decrease in myocardial ischemic load from dexmedetomidine in this study most likely results from its sympatholytic effects, mitigating emergence-related tachycardia and improving myocardial oxygen balance.

The beneficial effect of dexmedetomidine started intraoperatively because it decreased the prevalence of myocardial ischemia before emergence. This coincided with a decrease in demand, as indicated by the PWI, and with an improved endo-/epicardial blood flow ratio. The finding that dexmedetomidine decreased myocardial oxygen requirements during the intraoperative period is in accordance with our previous studies in halothane-anesthetized dogs (11,25). We started the infusion of dexmedetomidine intraoperatively to obtain stable plasma concentrations of dexmedetomidine at the start of the emergence period. This approach also may have clinical relevance because it has been shown recently in vascular surgery patients that most ischemic events occur between 50 minutes before and 60 minutes after the end of surgery (20).

A critical aspect of our study is the methodology to create a stable coronary stenosis, because small changes in diameter may cause large changes in coronary flow. However, immediately after application of the stenosis, the relative decrease in poststenotic endocardial flow was the same in both groups. Also, major kinking of the plastic screw occluder is unlikely because no sudden decreases of the coronary flow or myocardial shortening signals were observed. Most importantly, it is unlikely that potential variations in diameter of the stenosis explain the differences in myocardial ischemic load between groups because the probability of these variations is the same in both groups.

In conclusion, a stable plasma concentration of dexmedetomidine of 0.5 ng/mL in dogs with an artificial coronary stenosis decreases the myocardial ischemic load during the first two hours of emergence from halothane anesthesia. This effect of dexmedetomidine can be explained by its sympatholytic and HR-decreasing effects improving myocardial oxygen balance. Although extrapolation of our findings to the clinical setting should be performed with care, our study suggests that perioperative infusion of α2-adrenergic receptor agonists may offer a pharmacologic means of decreasing the ischemic load on the myocardium during emergence.

The authors want to thank Ruud Kruger, Theo van der Nagel, Anita Rousseau, and Jean Willigers for their technical assistance and A. Kester for his statistical advice.


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