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Deep Sedation with Dexmedetomidine in a Porcine Model Does Not Compromise the Viability of Free Microvascular Flap as Depicted by Microdialysis and Tissue Oxygen Tension

Nunes, Silvia MD, PhD*; Berg, Leena MD, PhD; Raittinen, L.-P; Ahonen, Heikki RN§; Laranne, Jussi MD, PhD; Lindgren, Leena MD, PhD; Parviainen, Iikka MD, PhD§; Ruokonen, Esko MD, PhD§; Tenhunen, Jyrki MD, PhD*

doi: 10.1213/01.ane.0000277488.47328.f5
Anesthetic Pharmacology: Research Report
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BACKGROUND: Deep sedation is often necessary after major reconstructive plastic surgery in the face and neck regions to prevent sudden spontaneous movements capable of inflicting mechanical injury to the transplanted musculocutaneous flap(s). An adequate positioning may help to optimize oxygenation and perfusion of the transplanted tissues. We hypothesized that dexmedetomidine, a central α2-agonist and otherwise potentially ideal postoperative sedative drug, may induce vasoconstriction in denervated flaps, and thus increase the risk of tissue deterioration.

METHODS: Two symmetrical myocutaneous flaps were raised on each side of the upper abdomen in 12 anesthetized pigs. The sympathetic nerve fibers were stripped from the arteries in one of the flaps (denervated flap), while nerve fibers were kept untouched in the other (innervated flap). After simulation of ischemia and reperfusion periods, the animals were randomized to deep postoperative sedation with either propofol (n = 6) or dexmedetomidine (n = 6). Flap tissue metabolism was monitored by microdialysis and tissue-oxygen partial pressure. Glucose, lactate, and pyruvate concentrations were analyzed from the dialysate every 30 min for 4 h.

RESULTS: Mean arterial blood pressure was higher in the dexmedetomidine group (P = 0.036). Flap tissue metabolism remained stable throughout the experiment as measured by lactate–pyruvate and lactate–glucose ratios (median ranges 14.3–24.5 for lactate–pyruvate and 0.3–0.6 for lactate–glucose) and by tissue-oxygen partial pressure, and no differences were found between groups.

CONCLUSIONS: Our data suggest that dexmedetomidine, even if used for deep sedation, does not have deleterious effects on local perfusion or tissue metabolism in denervated musculocutaneous flaps.

IMPLICATIONS: Dexmedetomidine is a potential sedative drug after major facial reconstructive surgery, but may induce vasoconstriction in denervated flaps and thus increase the risk of tissue damage. Our data suggest that, even if used for deep sedation, dexmedetomidine does not have deleterious effects on tissue perfusion in denervated musculocutaneous flaps.

From the Critical Care Medicine Research Group, *Department of Intensive Care, Tampere University Hospital, Tampere, Finland; †Department of Surgery, Kuopio University Hospital, Kuopio, Finland; ‡Department of Otorhinolaryngology, Tampere University Hospital, Tampere, Finland; §Department of Intensive Care, Kuopio University Hospital, Kuopio, Finland; and ∥Department of Anesthesiology, Tampere University Hospital, Tampere, Finland.

Accepted for publication May 17, 2007.

Address correspondence and reprint requests to Jyrki Tenhunen, Department of Intensive Care, Tampere University Hospital, PO Box 2000, 33521 Tampere, Finland. Address e-mail to jyrki.tenhunen@pshp.fi.

Major reconstructive plastic surgery in the face and neck regions is often followed by a period of postoperative deep sedation (Richmond Agitation-Sedation Scale (RASS) −4 or −5) (1) to avoid possible mechanical strain to the transplanted tissues caused by spontaneous movements. An adequate positioning may help to optimize oxygenation and perfusion pressures in the transplanted musculocutaneous flap(s). Sedation is usually achieved by propofol infusion, which may per se decrease systemic blood pressures (SAPs) and lead to decreased flap perfusion pressures, increasing the risk of hypoperfusion and flap necrosis.

Dexmedetomidine is a highly specific α2-adrenoreceptor agonist developed as a sedation drug and accepted for sedation in the intensive care unit up to 24 h. The α2-receptors are involved in regulating the autonomic and cardiovascular systems. α2-Receptors are located on blood vessels, where they mediate vasoconstriction, and on sympathetic terminals, where they inhibit noradrenaline release (2,3). α2-receptors are also located within the central nervous system (specifically in the locus coeruleus), and their activation leads to sedation, a 60%–80% reduction of tonic levels of sympathetic outflow and catecholamines (2–7), and an augmentation of cardiac vagal activity (8). In addition, α2-receptors within the spinal cord modulate pain pathways, thereby providing some degree of analgesia (9–11).

In awake subjects, dexmedetomidine has been shown to decrease systolic blood pressure and induce vasodilation in neurally intact vascular beds. Conversely, in denervated vascular beds or in the presence of decreased sympathetic nervous system activity (during anesthesia), dexmedetomidine has been shown to produce vasoconstriction (12).

We hypothesized that if dexmedetomidine is used as a single sedation drug after major plastic surgery, higher SAPs, when compared with propofol, could lead to better perfusion pressures in the transplanted musculocutaneous flaps. However, the denervation of these flaps could blunt the centrally induced vasodilator effect of dexmedetomidine and produce flap vasoconstriction with an associated increased risk of necrosis. This effect could be expected to be even more pronounced in the presence of high doses of dexmedetomidine (4), as needed to achieve deep levels of sedation.

To study our hypothesis, we simulated the transplant of innervated and denervated musculocutaneous flaps in 12 domestic pigs and monitored flap oxygenation and metabolism by tissue oxygen partial pressure (ptiO2) and microdialysis during deep sedation with dexmedetomidine.

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METHODS

Animals and Anesthesia

The study protocol was approved by the Ethics Committee for animal experiments of the University of Kuopio. Twelve female domestic pigs (25–35 kg) were deprived of food with free access to water 24 h before the experiments. The animals were premedicated with IM midazolam 0.2 mg/kg of body weight and ketamine 10 mg/kg. Cannulation of an ear vein followed, and 2 mg/kg propofol was administered IV before tracheostomy. Anesthesia was maintained with propofol (15–20 mg · kg−1 · h−1—titrated to bispectral index 40–60) and fentanyl (30 μg · kg−1 · h−1 until the end of surgery, 5 μg · kg−1 · h−1 thereafter). Vecuronium bolus injections of 4 mg were given when necessary to maintain muscle relaxation (train-of-four ≤4/4) until the end of the stabilization period. To simulate the postoperative period, neuromuscular blockage was discontinued thereafter. Without muscle relaxation, bispectral index measurements were considered unreliable due to strong myoelectric interference. Sedation was therefore titrated to absence of cornea reflex and spontaneous movement as to mimic deep sedation (RASS −4 or −5) (1). The animals were ventilated with a volume-controlled mode (Servo 900, Siemens, Elema AB, Solna Sweden) with 5 cm H2O of positive end-expiratory pressure. Fio2 (0.3–0.6) was adjusted to keep Pao2 levels between 13.3 kPa (100 mm Hg) and 20 kPa (150 mm Hg). Tidal volume was kept at 10 mL/kg and the minute ventilation adjusted to maintain Paco2 levels between 4.5 and 5.5 kPa (34–41 mm Hg).

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Animal Preparation

A fluid-filled catheter was inserted into the left femoral artery (single-lumen central venous catheter, Arrow, Arrow International Inc, Reading, PA), and a pulmonary artery catheter (7.5F flow-directed, Arrow) was introduced via the right internal jugular vein. Kefuroxim 750 mg IV was administered before instrumentation as antibiotic prophylaxis. During the perioperative period, the animals received 5 mL · kg−1 · h−1 infusion of saline. Low mean SAP (<60 mm Hg) was treated with Ringer's acetate solution or hydroxyethyl starch (5–10 mL/kg) to achieve stable hemodynamics. Additional fluid was administered when necessary to keep pulmonary artery occlusion pressure between 5 and 8 mm Hg. The body temperature of the animals was kept above 38°C using an operating table heater and warmed fluids when necessary. After the experiment, the animals were killed with a high dose of IV magnesium sulfate.

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Experimental Protocol

Two symmetrical rectus abdominis myocutaneous flaps (size, 7 × 10 cm2) were raised on each side of the upper abdomen served by superior epigastric vessels. The adventitia with its sympathetic nerve fibers was carefully stripped from the arteries in one of the flaps (denervated flap), while innervation was kept untouched in the remaining flap (innervated flap). Flaps were fixed in their original positions with skin sutures. Sixty minutes of hemodynamic stabilization was allowed after surgery (Fig. 1). Sixty minutes of global flap ischemia followed. This was achieved by occluding the pedicular vessels with Ackland V2 or V3 clamps, simulating the time needed for vessel anastomosis in clinical microsurgery. After unclamping of the pedicles, 60 min of reperfusion was allowed (Fig. 1). After this period, the initial propofol infusion was halved, and the animals were randomized to receive either propofol [10 mg/mL] (n = 6) or dexmedetomidine [10 μg/mL] (n = 6) in a double-blind manner (Fig. 1). Fentanyl infusion was kept at a constant rate of 5 μg · kg−1 · h−1 until the end of the experiment. The study drug (propofol or dexmedetomidine) was started at 1 mL · kg−1 · h−1 30 min after halving the initial infusion rate of open propofol. After another 30 min, the open propofol infusion was stopped, and the study drug infusion was increased to 2 mL · kg−1 · h−1 (Fig. 1). The study drug was then titrated until the end of the experiment (range 2–5 mL · kg−1 · h−1) to absence of cornea reflex and spontaneous movement. Fentanyl 50–100 μg IV bolus was given as rescue sedation when needed. Black opaque syringes and lines were used for study drug infusion, and special care was taken to cover the transparent segment of the central venous line to avoid unblinding. An independent person was responsible for connecting and changing the syringes and lines when necessary.

Figure 1

Figure 1

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Hemodynamic Monitoring

Femoral arterial pressure, pulmonary arterial pressure, and central venous pressure were recorded with quartz pressure transducers and displayed continuously on a multimodular monitor (S/5 Compact Critical Care Monitor, Datex-Ohmeda™, Helsinki, Finland). Data were collected and subsequently filtered into 2-minute medians and stored through a dedicated information management system (Clinisoft, Datex-Ohmeda™, Helsinki, Finland). All pressure transducers were calibrated simultaneously and zeroed to the level of the heart. Cardiac output (CO) (L/min) was measured by a thermodilution technique (mean value of three measurements, CO module, Datex-Ohmeda™, Helsinki, Finland). Heart rate was measured from the electrocardiogram, which was also continuously monitored. Depth of anesthesia was monitored during instrumentation and the stabilization period by a bispectral index monitor using three scalp needle electrodes.

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Microdialysis

Commercially available microdialysis catheters were used (CMA 20 Microdialysis Catheter, CMA/ Microdialysis AB, Stockholm, Sweden) (13–15). The catheter consists of a dialysis tube (20,000 molecular weight cut-off) glued to the end of a double-lumen catheter. The inlet tube of the catheter was connected to an infusion pump (CMA 100 Microinjection Pump, CMA/Microdialysis AB, Stockholm, Sweden), and was continuously perfused with a sterile isotonic lactated Ringer's solution at a flow rate of 1 μL/min. The solution flowed in the outer cannula inside the dialysis membrane to the distal end of the catheter. Equilibration with extracellular substances occurred through a permeable membrane at the tip of the microdialysis catheter. Six microdialysis catheters were inserted in each animal. Two catheters were inserted just under the dermal layer of the skin (one in each rectus abdominis myocutaneous flap [denervated dermis and innervated dermis]) and two catheters were inserted into the muscle (one in each flap [denervated muscle and innervated muscle]). The two remaining catheters were inserted under the intact dermis of the right groin region (control dermis) and into the right femoral muscle (control muscle). The equilibrated solution (i.e., the dialysate) was collected in microvials and analyzed for glucose, lactate, and pyruvate concentrations every 30 min from baseline (BL) (n = 9) (Fig. 1) by a microdialysis analyzer (CMA 600 Microdialysis Analyzer, CMA/Microdialysis AB). Lactate/pyruvate (L/P) and lactate/glucose (L/G) ratios were calculated for each data point.

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ptiO2

The Licox® probe is one of the standard clinical probes for the observation of brain tissue oxygenation (16–18). The same probe has also been successfully used for the monitoring of tissue-oxygen in free-flap surgery (19,20). Standard CC1.2 microcatheter ptiO2 probes (Integra, Hampshire, UK) were used for the measurements. Three Licox probes were used IM; one in the denervated rectus abdominis myocutaneous flap (Licox denervated), one in the innervated flap (Licox innervated), and one in the right femoral muscle (Licox control). ptiO2 was intermittently monitored from each probe in periods of 5 min from the end of reperfusion until the end of the experiment. Continuous ptiO2 values were graphically displayed on a linked laptop, and data were automatically registered every 20 s.

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Data Analysis and Statistics

Values from each variable were sampled at nine points in every animal (Fig. 1), and these values were used for further calculations. A normal distribution of the obtained data could not be assumed because of the small sample size. Data were therefore presented as median (25th–75th percentiles), and nonparametric statistical tests were used. BL was established at 60 min after reperfusion. This data point represents both the end of the simulation of the tissue flap transplant and the BL condition before randomization to one of the postoperative sedation formulas (Fig. 1). BL data were compared with those of later time points during postoperative sedation using the Friedman two-way analysis of variance. The study drug (propofol/ dexmedetomidine) was started (SD0) 30 min after BL and data points followed at 30 min intervals (SD30, SD60, SD90, SD120, SD150, SD180, and SD210) (Fig. 1). When the Friedman test was found significant, the Wilcoxon's signed rank test was used to compare the values at stabilization with each of the subsequent values. Two-tailed tests were used. The Kruskal– Wallis test was used for comparison between the propofol and dexmedetomidine groups. SPSS software (SPSS™ 13.0 for Windows, SPSS Inc., USA) was used for all statistical analyses. The exact P value without correction for multiple comparisons was provided to the reader, since we believed it more important to decrease the risk for type II errors than for type I errors. A P value of <0.05 was considered significant.

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RESULTS

Deep Postoperative Sedation

Animals from both groups received sedation at the minimum allowed rate (2 mL · kg−1 · h−1) throughout the experiment.

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Systemic Hemodynamics

CO was lower and systemic vascular resistance (SVR) higher in the dexmedetomidine group already at BL (P = 0.025). CO remained lower in this group but statistically significant differences were achieved only at 60 and 180 min after start of the study drug as CO decreased in the propofol group. SVR increased further in the dexmedetomidine group after start of the study drug (Wilcoxon P = 0.028–0.043), thus maintaining clear differences when compared with the propofol group. Mean arterial blood pressure increased significantly after start of dexmedetomidine (Wilcoxon P = 0.028), leading to marked differences between the groups (P = 0.004–0.006) (Table 1). Central venous pressure and pulmonary artery occlusion pressure were comparable in the two groups.

Table 1

Table 1

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Tissue Metabolism

Flap tissue metabolism remained stable throughout the experiment as measured by L/P and L/G ratios and ptiO2. No differences were found between groups for either denervated and innervated flaps or controls (Figs. 2–5 and Table 2) except for the L/G ratio at BL in the dermal layer of the microvascular flap (P = 0.028) (Fig. 5). ptiO2 increased in both groups after start of the study drug in the control muscle, (Wilcoxon P = 0.028–0.043). The same tendency could also be observed in the denervated and innervated muscle flaps but without reaching significance (Table 2).

Figure 2

Figure 2

Figure 3

Figure 3

Figure 4

Figure 4

Figure 5

Figure 5

Table 2

Table 2

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DISCUSSION

In the present study, we evaluated the effect of deep dexmedetomidine sedation on the viability of musculocutaneous flaps, as assessed by microdialysate metabolites from both muscle and dermis and ptiO2 from muscle. We found that dexmedetomidine increases the SAPs apparently by increasing the SVR. However, increased vascular resistances did not seem to have a negative impact on local perfusion and/or viability of the denervated and innervated flaps as L/P and L/G ratios did not differ between the groups. In addition, flap tissue oxygenation was stable in both groups.

Earlier studies with microdialysis have shown that glucose and lactate concentrations change in a characteristic way when ischemia is present (21–23). Moreover, Setälä et al. (24) have shown in a similar animal model that microdialysis is a sensitive method in the early diagnosis of ischemia in musculocutaneous flaps. These authors have also found that the mathematical ratios L/P and L/G are more sensitive for the differentiation between arterial and venous ischemia than lactate, pyruvate, or glucose values analyzed alone. The use of ptiO2 for perioperative identification of flap ischemia has shown good sensitivity, although specificity may present a problem in the clinical setting (19,20,25). In our trial, L/P, L/G, and ptiO2 remained stable throughout the study period in all flaps and in both sedation groups. This suggests an absence of dexmedetomidine-induced tissue ischemia in the denervated flaps, even when reasonably high doses of dexmedetomidine were used.

An apparent limitation of the present experiment is that we had no objective measure of the sympathetic inflow to each of the flaps. In other words, we cannot guarantee that there were no single fibers left after careful stripping of the adventitia of the supplying artery in one of the flaps. Nor can we state that for certainty there was no damage to the sympathetic nerve fibers in the other flap. However, this does not change the results that clearly show the stable metabolism even with high dose dexmedetomidine in microvascular flaps with either presumably intact innervation or where the best attempt of stripping of the adventitia was performed.

No data are available on the doses of IV dexmedetomidine required for postoperative sedation in pigs. Our protocol was thus based on pilot data showing that 20 μg · kg−1 · h−1 was the minimum infusion rate capable of keeping the animals sedated and motionless as required by our laboratory setting (neuromuscular blockage was stopped after stabilization to simulate postoperative clinical conditions). It is reasonable to assume that this adequately simulates the deep sedation (RASS −4 or −5) (1) often needed immediately after microvascular surgery.

In our study, the animals receiving dexmedetomidine developed high mean SAP due to an increase in SVR. We believe that there is a multifactorial explanation for this observation. Some degree of rebound effect after cessation of propofol infusion may play a role, but is not likely to fully explain the obtained data. The level of sedation kept during our experiment can be expected to create some degree of blunting of the sympathetic responses. The use of dexmedetomidine in these circumstances has been shown to induce an increase in SVR in humans (12). In addition, the use of a maintained high dose infusion of dexmedetomidine [comparable to bolus doses used in other animal trials (26,27)] in animals with an already blunted sympathetic response may have led to a stronger activation of the peripheric α2B-adrenoceptors, leading to maintained peripheric vasoconstriction with a consequent increase in SVR and SAPs. A similar hemodynamic profile has been observed in humans receiving high doses of dexemedetomidine (4). Presumably by chance, the BL SVR was higher and CO was lower in the dexmedetomidine group. This might have had a negative impact, if any, on the tissue perfusion in these animals. This further suggests the safety of high doses of dexmedetomidine in this setting.

The high infusion rate of dexmedetomidine used in the present investigation and the lack of data concerning species differences on the effects of dexmedetomidine presents clear limitations to the interpretation of our data. Moreover, the limited number of animals studied may have induced some variation in our results. However, our experimental setting mimics the postoperative clinical setting in the way that patients are often deeply sedated after surgery, and thus some degree of dexmedetomidine-induced vasoconstriction could be expected in the clinical postoperative period. We observed a strong systemic vasoconstriction in our model, which did not affect the viability of any of the musculocutaneous flaps. If the same would occur in humans, one could expect a safe use of dexmedetomidine in the postoperative period of major reconstructive plastic surgery in the face and neck regions. Clinical trials are needed to confirm our results.

In conclusion, dexmedetomidine, a potentially ideal postoperative sedative drug, does not compromise tissue viability in an experimental model of microvascular flap surgery, even if used in high doses to induce deep postoperative sedation.

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