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Effect of the alpha2-adrenergic agonist dexmedetomidine on nutrient blood flow to various organs in anaesthetised dogs
a2
Effect of the alpha2-adrenergic agonist dexmedetomidine on nutrient blood flow to various organs in anaesthetised dogs. F.W. Prinzen PhD, C.J. Lawrence MD, C.J. van Leeuwen, S. de Lange MD, PhD Department Netherlands
of Anaesthesioloav.
Universitv
Hosoital
INTRODUCTION Dexmedetomidine (DM, Orion Corp. Farmos, Finland) and other alpha&agonists are known to increase systemic vascular resistance in anaesthetised dogs (1,2). Because alphaPreceptors are inhomogeneously distributed throughout the circulation, some organs might be affected more than others. Of particular interest is the cerebral circulation: sagittal sinus outflow decreased after administration of DM (3,4). We investigated the effect of various doses DM on the blood flow to various organs with use of the radioactive microsphere technique, which measures nutrient blood flow (5). METHODS Approval for the study was obtained from the local animal ethical committee. All dogs were induced with thiopental and ventilated with 67% N20 in 02. Anaesthesia was maintained by IV administration of chloralose + urethane (c+u group, n=6), or by ventilation with 0.5% Halothane and IV fentanyl (H+F group, n=8). They were instrumented to measure ECG, heart rate, blood pressure and cardiac output (thermodilulion). Blood flow in the brain, skin, kidney, spleen, gut and liver were determined with the radioactive microsphere method (5). For each measurement approximately 3.000.000 beads (diameter 15 micrometer, labeled with Ce141. Snlra, Flu103or Nbgs) were injected into the left atrium. After the experiment arterial reference samples and representative tissue samples from the various organs were counted, and regional blood flow (ml/min/g) was calculated (5). The microsphere content of the lungs was determined as well to assess the fraction of blood shunted through A-V anastomoses (5). Protocol: DM in doses of 0.1, 0.3, 1.0, 3.0 and 10 mcg/kg was administered IV over 2 min at 20 min intervals. Measurements were made at baseline (BL) and 15 min after administration (microspheres only at BL and at doses of 0.1, 1.0 and 10 mcgIkg). Data was evaluated for statistical significance with ANOVA and Fisher’s LSD tests. Pd.05 was considered significant. RESULTS (mean and SEM) Differences between the groups: At no time interval was cardiac output different between the two groups. At 1,3 and 10 mcg/kg DM, blood pressure tended to increase in the H+F, but tended to decrease in the c+U group. Significant differences in organ blood flow between the groups were observed only for the brain (higher in H+F) and for the liver (higher in c+u), predominantly at BL. Because of the limited differences between the groups, the data were pooled for further analysis. Effects of DM (see fig): Cardiac output significantly decreased at DM doses of 1 and 10 mcgikg. Cerebral blood flow decreased 1 out of 6 in the c+u group, but .in 5 out of 8 experiments in the H+F qroup. The changes in cerebral blood flow did not reach the level of statistical significante. Significant decreases in flow were observed for the kidney (-30%), gut (-40%) and liver (-45%). Organs with the largest relative decrease in blood flow were the skin (-80%) and spleen (-65%). Also the shunt flow decreased to a large extent, especially at 10 mcg/kg (-80%).
of Maastricht,
P 0. Box 5800, 6202 AZ Maastricht,
The
DISCUSSION The results from the present study demonstrate the inhomogeneous response of the vasculature to alpha2-adrenergic stimulation. At the 10 mcglkg dose of DM, a 53% decrease in cardiac output coincided with no significant decrease of cerebral blood flow, but a 65% decrease in splenic and a 80% decrease in cutaneous blood flow. The finding, that cerebral blood flow decreased only in a few animals (especially those with the high BL values) differs from the considerable decrease in sagittal sinus outflow measurement (3,4) These different findings might be explained by the fact, that by the latter technique also shunt flow.is taken into account. This idea is supported by the absence of changes in cerebral oxygen consumption in these studies (3,4) and our finding, that DM decreases total shunt flow. The decrease in cutaneous blood flow, and (part of ) the decrease in shunt flow, might be related to the role of alpha2-adrenoceptors in the regulation of cutaneous blood flow and thermoregulation (6). The decreased perfusion of the splanchnic organs is not completely understood, but might be related both directly to vasoconstriction and indirectly to autonomic neural and hormonal alterations (7). 1 Flacke JW et al Coronary and systemic hemodynamrc effects and oxygen extraction after dexmedetomidine, a potent and selective alpha2-adrenergic agonist. Pharmacologist 118: 31, 1989 2. Rutfolo et al. Receptor interactions of imidazolines. Influence of Ionization constant on the diffusion of clonidine and a series of structurally related imidazolines into and out of the central nervous 81: 367-375, 1982 system Eur J Pharmacol 3. Karlsson SR et al. Effect of dexmedetomidine. a selective and potent alpha2-agonist, on cerebral blood flow and oxygen consumption during halothane anesthesia in dogs. Anesth Analg 71: 125-129. 1990 4 Zornow MH et al. Dexrnedetomidine. an alpha2-adrenergic agonist. decreases cerebral blood flow in the isoflurane-anesthetized dog. Anesth Anafg 70: 624-630, 1990 5 Heymann MA et al. Blood flow measurements with radioactive nuclide labeled particles. Prog Cardiovasc 01s 20: 55-79, 1977 6 Flavahan NA. The role of vascular alpha2-adrenoceptors as cutaneous thermosensors. NIPS 6.251-255, 1991 7 Maze M and Tranquilli W. Alpha2 adrenoceptor agonists: definrng the role in clinical anesthesia. Anestheslofogv 74: 581-605, 1991 -cardrac
--+--
output Wmin)
cerebral blood
(‘0
flow
1mllminla~ _,
e
blood
flow
(ml/min/g)
a --.oleen
1
I----0
EL
6
6
4
4
2
2
0
0.1
1 10 DM (mc@kg)
EL
0.1 1 10 DM (mcgkg)
Effect of the alpha2-adrenergic agonist dexmedetomidine on nutrient blood flow to various organs in anaesthetised dogs. F.W. Prinzen PhD, C.J. Lawrence MD, C.J. van Leeuwen, S. de Lange MD, PhD Department Netherlands
of Anaesthesioloav.
Universitv
Hosoital
INTRODUCTION Dexmedetomidine (DM, Orion Corp. Farmos, Finland) and other alpha&agonists are known to increase systemic vascular resistance in anaesthetised dogs (1,2). Because alphaPreceptors are inhomogeneously distributed throughout the circulation, some organs might be affected more than others. Of particular interest is the cerebral circulation: sagittal sinus outflow decreased after administration of DM (3,4). We investigated the effect of various doses DM on the blood flow to various organs with use of the radioactive microsphere technique, which measures nutrient blood flow (5). METHODS Approval for the study was obtained from the local animal ethical committee. All dogs were induced with thiopental and ventilated with 67% N20 in 02. Anaesthesia was maintained by IV administration of chloralose + urethane (c+u group, n=6), or by ventilation with 0.5% Halothane and IV fentanyl (H+F group, n=8). They were instrumented to measure ECG, heart rate, blood pressure and cardiac output (thermodilulion). Blood flow in the brain, skin, kidney, spleen, gut and liver were determined with the radioactive microsphere method (5). For each measurement approximately 3.000.000 beads (diameter 15 micrometer, labeled with Ce141. Snlra, Flu103or Nbgs) were injected into the left atrium. After the experiment arterial reference samples and representative tissue samples from the various organs were counted, and regional blood flow (ml/min/g) was calculated (5). The microsphere content of the lungs was determined as well to assess the fraction of blood shunted through A-V anastomoses (5). Protocol: DM in doses of 0.1, 0.3, 1.0, 3.0 and 10 mcg/kg was administered IV over 2 min at 20 min intervals. Measurements were made at baseline (BL) and 15 min after administration (microspheres only at BL and at doses of 0.1, 1.0 and 10 mcgIkg). Data was evaluated for statistical significance with ANOVA and Fisher’s LSD tests. Pd.05 was considered significant. RESULTS (mean and SEM) Differences between the groups: At no time interval was cardiac output different between the two groups. At 1,3 and 10 mcg/kg DM, blood pressure tended to increase in the H+F, but tended to decrease in the c+U group. Significant differences in organ blood flow between the groups were observed only for the brain (higher in H+F) and for the liver (higher in c+u), predominantly at BL. Because of the limited differences between the groups, the data were pooled for further analysis. Effects of DM (see fig): Cardiac output significantly decreased at DM doses of 1 and 10 mcgikg. Cerebral blood flow decreased 1 out of 6 in the c+u group, but .in 5 out of 8 experiments in the H+F qroup. The changes in cerebral blood flow did not reach the level of statistical significante. Significant decreases in flow were observed for the kidney (-30%), gut (-40%) and liver (-45%). Organs with the largest relative decrease in blood flow were the skin (-80%) and spleen (-65%). Also the shunt flow decreased to a large extent, especially at 10 mcg/kg (-80%).
of Maastricht,
P 0. Box 5800, 6202 AZ Maastricht,
The
DISCUSSION The results from the present study demonstrate the inhomogeneous response of the vasculature to alpha2-adrenergic stimulation. At the 10 mcglkg dose of DM, a 53% decrease in cardiac output coincided with no significant decrease of cerebral blood flow, but a 65% decrease in splenic and a 80% decrease in cutaneous blood flow. The finding, that cerebral blood flow decreased only in a few animals (especially those with the high BL values) differs from the considerable decrease in sagittal sinus outflow measurement (3,4) These different findings might be explained by the fact, that by the latter technique also shunt flow.is taken into account. This idea is supported by the absence of changes in cerebral oxygen consumption in these studies (3,4) and our finding, that DM decreases total shunt flow. The decrease in cutaneous blood flow, and (part of ) the decrease in shunt flow, might be related to the role of alpha2-adrenoceptors in the regulation of cutaneous blood flow and thermoregulation (6). The decreased perfusion of the splanchnic organs is not completely understood, but might be related both directly to vasoconstriction and indirectly to autonomic neural and hormonal alterations (7). 1 Flacke JW et al Coronary and systemic hemodynamrc effects and oxygen extraction after dexmedetomidine, a potent and selective alpha2-adrenergic agonist. Pharmacologist 118: 31, 1989 2. Rutfolo et al. Receptor interactions of imidazolines. Influence of Ionization constant on the diffusion of clonidine and a series of structurally related imidazolines into and out of the central nervous 81: 367-375, 1982 system Eur J Pharmacol 3. Karlsson SR et al. Effect of dexmedetomidine. a selective and potent alpha2-agonist, on cerebral blood flow and oxygen consumption during halothane anesthesia in dogs. Anesth Analg 71: 125-129. 1990 4 Zornow MH et al. Dexrnedetomidine. an alpha2-adrenergic agonist. decreases cerebral blood flow in the isoflurane-anesthetized dog. Anesth Anafg 70: 624-630, 1990 5 Heymann MA et al. Blood flow measurements with radioactive nuclide labeled particles. Prog Cardiovasc 01s 20: 55-79, 1977 6 Flavahan NA. The role of vascular alpha2-adrenoceptors as cutaneous thermosensors. NIPS 6.251-255, 1991 7 Maze M and Tranquilli W. Alpha2 adrenoceptor agonists: definrng the role in clinical anesthesia. Anestheslofogv 74: 581-605, 1991 -cardrac
--+--
output Wmin)
cerebral blood
(‘0
flow
1mllminla~ _,
e
blood
flow
(ml/min/g)
a --.oleen
1
I----0
EL
6
6
4
4
2
2
0
0.1
1 10 DM (mc@kg)
EL
0.1 1 10 DM (mcgkg)