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Cerebral cortex regional blood flow and tissue oxygen tension during the trigeminal depressor response in rabbits
Journal of the Autonomic Nervous System 66 Ž1997. 111–118
Cerebral cortex regional blood flow and tissue oxygen tension during the trigeminal depressor response in rabbits Tatsuya Ichinohe ) , Hideharu Agata, Hidetaka Aida, Yuzuru Kaneko Department of Dental Anesthesiology, Tokyo Dental College, 1-2-2 Masago, Mihama-ku, Chiba 261, Japan Received 13 May 1997; revised 12 June 1997; accepted 13 June 1997
Abstract The trigeminal depressor response ŽTDR. is characterized with profound hypotension caused by sympathetic outflow decreases. The purpose of this study was: Ž1. to compare the hemodynamic changes during acute hypotension induced by the TDR with those induced by electrical stimulation of the vagal nerve ŽVS. as models of sympathetic inhibition and vagal activation and Ž2. to investigate the effects of nitrous oxide ŽN2 O., a well-known sympathomimetic, on the hemodynamic changes during the TDR. Male Japan White rabbits were anesthetized with halothane in oxygen and mechanically ventilated. The electrode pair for the TDR was inserted into the submucosal tissue of the animal’s tongue. The pair for the VS was applied to the isolated left vagal trunk. Both the TDR and the VS produced similar decreases in mean arterial pressure ŽMAP. and cerebral cortex regional blood flow ŽrCBF., although the decreases in heart rate ŽHR. and aortic blood flow were greater during the VS. Cerebral cortex tissue oxygen tension in both groups decreased slightly. 50% N2 O, producing MAP elevation and HR decrease, ameliorated the hemodynamic changes including rCBF reduction during the TDR. A sudden diminution of sympathetic tone following noxious stimulation of the orofacial area, as in the case of the TDR, may be a possible trigger mechanism for vasodepressor reactions in dental patients. The sympathomimetic and possible antinociceptive effects of N2 O may explain, at least in part, the preventive effects on vasodepressor reactions during dental procedures. q 1997 Elsevier Science B.V. Keywords: Trigeminal depressor response; Vagal nerve; Cerebral cortex regional blood flow; Cerebral cortex regional tissue oxygen tension; Nitrous oxide; Vasodepressor reactions
1. Introduction Electrical stimulations, especially trains of low frequency stimulations, of the spinal trigeminal complex or the branches of the trigeminal nerve in rabbits produce profound hypotension known as the trigeminal depressor response ŽTDR. w22,23x. Because vagotomy, atropine and propranolol do not inhibit, although phentolamine does inhibit, this hypotension, it is speculated that the hypotension in TDR is caused, not by an increase in vagal tone, but by a decrease in sympathetic vasoconstrictor outflow w23x. The determinants for blood pressure are cardiac output and total peripheral resistance. Hypotension occurs through decreased cardiac output mainly due to hemorrhage or vagal activation, or through reduced total peripheral resistance mainly due to sympathetic inhibition including the TDR. The first purpose of this study was, therefore, to )
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investigate the changes in cerebral cortex regional blood flow ŽrCBF. and tissue oxygen tension Ž PtO 2 . as well as in systemic hemodynamic parameters, including heart rate ŽHR., blood pressure, and aortic blood flow ŽAoF., during the TDR. We compared these hemodynamic changes with those during electrical stimulation of the vagal nerve ŽVS. which causes hypotension by the other mechanisms. Since vasodepressor reactions, including fainting, develop from inadequate cerebral blood flow due to systemic hypotension w16,38x, a sudden diminution of sympathetic tone following noxious stimulation of the orofacial area, as in the case of the TDR, may be a possible mechanism for them. Therefore, we discuss the significance of sympathetic inhibition like the TDR as a mechanism for vasodepressor reactions. In routine dental practice, 20–30% nitrous oxide ŽN2 O. in balance oxygen has been administered to patients with dentalphobia or prone to faint. N2 O inhalation lessens the occurrence of vasodepressor reactions in clinical dentistry. The second purpose of this study was to investigate the
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effects of N2 O, a well-known sympathomimetic w3,14x, on the hemodynamic changes including rCBF during the TDR.
beneath the rCBF measurement probe. The diameter of the electrode was 0.2 mm. The inserted length of the electrode was approximately 10 mm.
2. Materials and methods
2.3. Electrical stimulation
After approval by our Animal Care and Use Committee, we utilized male Japan White rabbits Ž2.2–2.7 kg.. All animals were allowed food and water ad libitum until the morning of the experiment.
Two pairs of stainless needle electrodes were used for the delivery of an electrical current. The pair for the TDR was inserted into the submucosal tissue of the animal’s tongue 4 mm apart, with the cathode at the left side and the anode at the right side of the tongue. Square wave pulses were delivered using a stimulation unit ŽSEN-7203, Nihon Kohden, Tokyo. and an isolation unit ŽSS-104J, Nihon Kohden, Tokyo.. The stimulating condition for the TDR was 20 V in intensity, 10 Hz in frequency and 0.5 ms in duration for 3 s. The second pair for the VS applied to the isolated left vagal trunk distal to the emerging site of the depressor nerve. The electrodes were 4 mm apart, with the cathode at the distal site. The vagal nerve was covered with a layer of liquid paraffin. Bilateral vagal nerves were kept intact to prevent vagotomy-induced modification of the HR during the TDR. The stimulating condition for the VS was the same as for the TDR except for the intensity, which was adjusted to produce a similar decrease in mean arterial pressure ŽMAP. to that during the TDR. After the completion of experimental preparations, the halothane concentration was reduced to 0.5 vrv% and maintained at that level for more than 60 min to stabilize the animal’s hemodynamic parameters. Nitrogen was added to the anesthetic gas mixture to keep PaO 2 at 100–150 mm Hg throughout the experiment. Each animal received the electrical stimulations for the TDR and the VS in a randomized crossover manner.
2.1. Surgical procedures Anesthesia was induced by inhalation of halothane Ž2.5 vrv%. in oxygen delivered via a mask. Before skin incisions for each of the experimental procedures described below, appropriate doses of lidocaine were infiltrated into the surgical field. A a20 French size non-cuffed pediatric endotracheal tube was inserted into the trachea via a tracheostomy. The left auricular marginal vein and right femoral artery were cannulated with 22 and 20 gauge Teflon indwelling catheters. After intravenous lactated Ringer’s solution was started at 10 ml kgy1 hy1 , the animals were paralyzed with 1 mgrkg alcuronium chloride ŽDialferin, Roche, Tokyo. and mechanically ventilated. The femoral artery blood pressure was continuously monitored with a pressure transducer ŽP23ID; Gould, Oxnard, California.. HR was recorded by a tachograph triggered by the blood pressure wave. AoF was measured with an ultrasound flowmeter ŽT108; Transonic, Ithaca, New York. via a left-sided thracotomy. A flow probe Žtype 3SB; Transonic, Ithaca, New York. was applied to the isolated ascending aorta. 2.2. Study 1. Comparison of rCBF and PtO 2 between the TDR and the VS In the first study, we compared the hemodynamic changes during the TDR with those during the VS. In 10 rabbits, rCBF and PtO 2 in the left parietal region were measured with a laser-Doppler flowmeter ŽALF21; Unique Medical, Tokyo. and a PO 2 monitor Ž PO 2-100DW; Inter Medical, Tokyo. via a left-sided craniotomy. The time constant for these devices was 1 s. The animal was fixed in a supine position with the head turned right. After a midline incision of the shaved scalp, the left temporal muscle was stripped off with the parietal periosteum. The left parietal bone was removed with an approximate size of 14 = 14 mm with the dura mater kept intact. The contact type probe Žtype C; Unique Medical, Tokyo. for rCBF measurement was placed at the dorsolateral surface of the left cerebral hemisphere. Care was taken not to place the probe above the pial vessels. A polarographic needle electrode ŽPOE-10N; Inter Medical, Tokyo, Japan. for PO 2 measurement was inserted from the dorsocaudal corner of the exposed dura mater into the cerebral cortex with its tip
2.4. Study 2. Effect of N2 O on the TDR In the second study, we investigated the effects of N2 O on the hemodynamic changes during the TDR. In nine rabbits, experimental preparations including rCBF measurement and electrical stimulation for the TDR were performed in the same manner as in the first study. The animals who participated in the second study did not undergo PtO 2 measurements. The stimulating condition for the TDR was also the same as in the first study. After the completion of experimental preparations and hemodynamic stabilization under inhalation of 0.5 vrv% halothane for more than 60 min, the control measurement was performed. Following the control measurement, the animals inhaled 50 vrv% N2 O for 15 min and the hemodynamic variables were reevaluated. 2.5. Hemodynamic monitoring In both studies, hemodynamic changes were continuously recorded ŽPolygraph series 360; NEC San-ei, Tokyo.. Hemodynamic variables for the TDR and the VS were
T. Ichinohe et al.r Journal of the Autonomic NerÕous System 66 (1997) 111–118
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recorded immediately prior to the nerve stimulation and at maximum change following electrical stimulation. The data for the TDR and the VS were obtained by averaging three consecutive values in each animal. At least 3 min intervals were allowed between each electrical stimulation of the TDR and the VS. Total peripheral resistance ŽTPR. was calculated as MAP divided by AoF. TPR and rCBF were expressed as percentages of the control values. In the first study, prestimulation values of the TDR and the VS were independently served as the respective control values for these parameters. In the second study, in contrast, the prestimulation value of the TDR without N2 O served as the control value throughout the study except for Fig. 4, in which the prestimulation values of the TDR without N2 O and with N2 O independently served as the respective control values. End-tidal halothane concentration Ž0.5 vrv%. and PaCO 2 Ž35–40 mm Hg. were kept constant throughout the experiment. The halothane concentration was continuously monitored with an anesthetic gas monitor ŽCapnomac; Datex, Helsinki, Finland.. Blood gases were analyzed with a pH–blood gas–electrolytes analyzer ŽStat Profile 5; Nova Biomedical, Boston, MA.. Body temperature was continuously monitored by a rectal probe and maintained between 39.0–39.58C with the aid of a heating lamp. At the end of the experiment, the responses of rCBF to hypercapnia or hypocapnia were confirmed to ascertain normal cerebrovascular reactivity in each animal. 2.6. Statistical analysis Data are expressed as the mean " SD. One way analysis of variance for repeated measurements followed by Student–Newman–Keuls test for multiple comparisons was used in this study. P-values less than 0.05 indicated statistical significance.
3. Results
Fig. 1. A typical recording of the hemodynamic changes during the trigeminal depressor response ŽTDR. and the vagal nerve stimulation ŽVS.. Arrows indicate 3 s electrical stimulation for the TDR and the VS. Both stimulations produced long-lasting hypotension Ž15–30 s in general. and rCBF reductions which led to the decrease in PtO 2 . HR: heart rate; BP: blood pressure; MAP: mean arterial pressure; AoF: aortic blood flow; rCBF: cerebral cortex regional blood flow; PtO 2 : cerebral cortex tissue oxygen tension.
Table 1 Hemodynamic changes during the trigeminal depressor response ŽTDR. and the vagal nerve stimulation ŽVS. TDR
3.1. Study 1. Comparison of rCBF and Pt O 2 between the TDR and the VS Fig. 1 shows a typical recording of the hemodynamic changes during the TDR and the VS. Electrical stimulations for 3 s for the TDR and the VS produced arterial hypotension which lasted for 15–30 s. Likewise, the rCBF was reduced after the electrical stimulations. The duration of rCBF reduction, however, was shorter than that of MAP reduction Žless than 15 s in general.. rCBF reduction was followed by a PtO 2 decrease which lasted as long as MAP reduction. Table 1 and Fig. 2 summarize the hemodynamic changes during the TDR and the VS. The laser-Doppler flowmeter readings before electrical stimulations for the TDR and the
CONT HR MAP AoF TPR rCBF Pt O 2
VS ES
264.5"28.6 240.8"34.2 75.2"10.0 60.3"10.0 325.0"42.8 298.5"37.9 100.0" 0.0 86.8" 4.4 100.0" 0.0 86.1" 5.2 28.5" 6.5 27.7" 6.8
CONT )a ) )a )a ) )
ES
267.1"27.3 232.5"36.5 75.3"10.5 59.3"11.3 329.0"44.6 278.5"27.9 100.0" 0.0 92.7"12.6 100.0" 0.0 85.1" 6.7 29.1" 6.1 28.3" 6.0
)a ) )a )a ) )
Values are expressed as the mean"SD. HR: heart rate Žbpm.; MAP: mean arterial pressure Žmm Hg.; AoF: aortic blood flow Žmlrmin.; TRP: total peripheral resistance Ž s MAPrAoF, expressed as a percentage of the control value.; rCBF: cerebral cortex regional blood flow Žexpressed as a percentage of the control value.; PtO 2 : cerebral cortex tissue oxygen tension Žmm Hg.. CONT and ES represent the control value and the value at maximum change following electrical stimulation, respectively. ) Significantly different Ž p- 0.05. from CONT. a Significantly different Ž p- 0.05. between two groups.
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T. Ichinohe et al.r Journal of the Autonomic NerÕous System 66 (1997) 111–118 Table 2 Hemodynamic changes during the trigeminal depressor response ŽTDR. with or without nitrous oxide ŽN2 O.
HR MAP AoF TPR rCBF Fig. 2. The hemodynamic changes during the trigeminal depressor response ŽTDR; open column. and the vagal nerve stimulation ŽVS; hatched column.. Both the TDR and the VS produced similar decreases in mean arterial pressure and cerebral cortex regional blood flow. The decreases in heart rate and aortic blood flow were greater during the VS, while the decrease in total peripheral resistance was greater during the TDR. Cerebral cortex tissue oxygen tension in both groups showed slight but statistically significant decreases. Data are shown as percentages of the respective pre-stimulation control values Žmean"SD.. HR: heart rate; MAP: mean arterial pressure; AoF: aortic blood flow; TPR: total peripheral resistance Ž s MAPrAoF.; rCBF: cerebral cortex regional blood flow; PtO 2 : cerebral cortex tissue oxygen tension. a Significantly different Ž p- 0.05. between two groups.
TDR without N2 O
TDR with N2 O
CONT
CONT
ES
ES
269.6"33.8 a 243.2"37.0 ) 248.4"32.0 a 234.9"29.6 74.6"15.1 a 55.9"16.1 ) a 79.4"16.7 a 66.9"18.3 ) a 290.6"55.4 260.6"35.0 ) a 310.0"48.1 291.7"35.2 ) a 100.0" 0.0 81.9" 8.4 ) a 99.5" 8.4 87.6" 7.0 ) a 100.0" 0.0 82.1"10.3 ) a 101.1" 4.3 94.1" 5.7 a
Values are expressed as the mean"SD. HR: heart rate Žbpm.; MAP: mean arterial pressure Žmm Hg.; AoF: aortic blood flow Žmlrmin.; TPR: total peripheral resistance Ž s MAPrAoF, expressed as a percentage of the control value in the TDR without N2 O.; rCBF: cerebral cortex regional blood flow Žexpressed as a percentage of the control value in the TDR without N2 O.. CONT and ES represent the control value and the value at the maximum change during electrical stimulation, respectively. ) Significantly different Ž p- 0.05. from CONT. a Significantly different Ž p- 0.05. between two groups.
VS were almost the same. Both the TDR and the VS produced similar decreases in MAP. The reduction of rCBF in both groups was also similar. The decreases in HR and AoF, on the other hand, were greater during the VS than during the TDR. In contrast, the decrease in TPR was greater during the TDR. PtO 2 in both groups showed slight but statistically significant decreases. 3.2. Study 2. Effect of N2 O on the TDR Fig. 3 shows a typical recording of the hemodynamic changes during the TDR with or without N2 O. These hemodynamic changes were summarized in Table 2 and Fig. 4. N2 O, producing mean arterial pressure ŽMAP. elevation and HR decrease, ameliorated the hemodynamic changes including rCBF reduction during the TDR.
Fig. 3. A typical recording of the hemodynamic changes during the trigeminal depressor response ŽTDR. with Žright. or without Žleft. N2 O. Arrows indicate 3 s electrical stimulation for the TDR. 50% N2 O ameliorated the hemodynamic changes during the TDR. HR: heart rate; BP: blood pressure; MAP: mean arterial pressure; AoF: aortic blood flow; rCBF: cerebral cortex regional blood flow.
Fig. 4. The hemodynamic changes during the trigeminal depressor response ŽTDR; open column. were attenuated by nitrous oxide ŽN2 O; hatched column. inhalation. Data are shown as percentages of the respective control values Žmean"SD.. HR: heart rate; MAP: mean arterial pressure; AoF: aortic blood flow; TPR: total peripheral resistance Ž s MAPrAoF.; rCBF: cerebral cortex regional blood flow. a Significantly different Ž p- 0.05. between two groups.
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4. Discussion Electrical stimulations of the submucosal tissue of the rabbit’s tongue produced arterial hypotension. In our preliminary study, vagotomy, atropine and propranolol did not inhibit this hypotension, whereas phentolamine inhibited it. Accordingly, the hypotension induced by electrical stimulations of the rabbit’s tongue in this study should be a type of the TDR. Since bilateral vagal nerves were kept intact in this study, afferent as well as efferent impulses might be generated during the VS. Accordingly, a compensatory activation of sympathetic nervous system induced by vagal afferent impulses might occur. The changes in hemodynamic variables during the VS however suggest that this sympathetic compensation should be minimal. Therefore, the VS was considered as a model of vagal activation in this study. 4.1. Comparison of rCBF and PtO 2 between the TDR and the VS In the first study, TDR-derived hypotension led to rCBF and PtO 2 reductions. Likewise, the VS produced hypotension followed by rCBF and PtO 2 reductions. Similar decreases in MAP during the TDR and the VS produced similar reductions in rCBF and PtO 2 ; the decreases in HR and AoF were greater during the VS. It is well-known that the blood flow to the brain is well maintained during systemic hypotension through autoregulatory mechanisms w20x. In contrast, a rapid and sustained decrease in blood pressure to a level below the lower limit of autoregulation may result in central nervous system dysfunction due to rCBF reduction w30x. Since hypotension during the TDR and the VS is an abrupt phenomenon with short duration because of its reflex nature, the rCBF reduction should also be transient and soon recover by the autoregulatory compensation in normal conditions. A shorter duration of rCBF reduction than that of MAP decrease suggests intact autoregulatory functions. However, rapid recovery of rCBF reduction was followed by sustained PtO 2 decrease. Clinical significance of this decrease remains to be investigated. Blood flow at internal carotid artery ŽICA. measured by a electromagnetic flowmeter did not change during the TDR produced by electrical stimulation of the tongue in pentobarbital-anesthetized rabbits w27x. The authors concluded that the painful stimulation of the oral receptors produced a blood pressure decrease, which was tolerated by autoregulation of the cerebral blood flow. However, they did not record mean ICA flow but beat to beat ICA flow, which might not necessarily detect the change in cerebral blood flow. The cardiovascular responses produced by electrical stimulation of peripheral nerves depend on several variables, including the stimulation characteristics of intensity, frequency and duration, the type of somatic nerve stimulated, and the anesthetic depth and the drug used
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w5,19,29,32,33,36x. In this study, we delivered electrical current at 10 Hz in frequency during the TDR and the VS, because a train of low frequency stimulation Ž- 20 Hz. elicited the TDR, while high frequency stimulation Ž50 Hz or more. caused a pressor response w23x. In this study, the intervals between each electrical stimulation for the TDR and the VS were at least three minutes. Our preliminary study showed that the electrical stimulations given at these intervals elicited the reproducible responses. An increase in the end-tidal halothane concentration from sub-minimum alveolar concentration ŽMAC. level to supra-MAC level was associated with a depressor response to tail clamping in rats w15x. In addition, although the rCBF increased during 1 MAC halothane anesthesia in rabbits w34x, neither the increase in rCBF nor the impairment of autoregulation were observed in goats w24x and monkeys w25x during 0.5 MAC halothane anesthesia. The animals participating in this study, therefore, were anesthetized with halothane at the end-tidal concentration of 0.5 vrv%, which approximated to 0.5 MAC in rabbits w18x, throughout the experiment. Since 0.5 MAC halothane approximates to its MAC awake level in humans w35x, the animals in this study were considered to be lightly anesthetized or deeply sedated. Even lighter sedation of the experimental animals should be avoided for ethical reasons. In this study, electrical current during the TDR stimulated submucosal nerve receptors and, possibly, some other receptors in the lingual muscle, such as proprioceptors. The lingual proprioceptive afferent fibers occupy the hypoglossal nerve and enter the spinal cord after the connection to the C2–C3 spinal nerve in monkeys w12x. The significance of electrical stimulation of these receptors remains unknown. rCBF was measured using a laser-Doppler flowmeter in this study. Laser-Doppler flowmetry has been reported to allow rapid and instantaneous measurement of rCBF in rabbits w13x. Brain surface PO 2 had a range of 26.5–31.0 mm Hg during isoflurane anesthesia with PaO 2 of 109.2 " 2.2 mm Hg Žmean " SEM. in rabbits w26x. In addition, noncompromised brain tissue PO 2 remained above 20 mm Hg in humans w17x. In the first study, PtO 2 under control conditions was 29 " 6 mm Hg, with a range of 21–38 mm Hg in both groups. These results assured us of the noncompromised cerebral cortical tissue of the experimental animals. 4.2. Effect of N2 O on the TDR In the second study, 50 vrv% N2 O inhalation produced small but significant elevation in MAP and decrease in HR. MAP elevation depended not on TPR increase but on AoF augmentation. The hemodynamic changes during the TDR were attenuated under these conditions. 70% N2 O revealed sympathomimetic effects such as the increases in blood pressure and cardiac output in humans and intact cats, although it produced direct myocardial depression in the decerebrated cats, during halothane in-
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halation as basal anesthesia w3,14x. In human volunteers, 40% N2 O caused the elevation in plasma norepinephrine level which was reflected as an increase in TPR, although it produced blood pressure and HR decreases w10x. In clinical situations, the sympathomimetic effects of N2 O should be balanced more or less by its direct myocardial depressant effects w9x. Thus, hemodynamic parameters such as blood pressure or HR may not be necessarily increased during N2 O inhalation. Although N2 O depressed, but not abolished, the baroreceptor reflex w2,7x, significant HR decrease was observed during small MAP elevation in this study. The change in HR may be partly attributable to direct myocardial depressant effects of N2 O. Decrease in HR was more obvious than in MAP when direct myocardial depression occurred during N2 O inhalation in the decerebrated cats w3x. It is therefore suggested that N2 O produced MAP elevation and AoF augmentation, though not statistically significant, through central sympathetic activation, which were accompanied with HR decrease through the baroreceptor reflex andror direct myocardial depression in the second study. The hemodynamic changes during the TDR were attenuated by N2 O inhalation. Since the TDR is elicited through sympathetic inhibition, N2 O-induced sympathetic activation may counteract the hemodynamic changes during the TDR. Because PaO 2 during N2 O inhalation in each animal was well over 100 mm Hg in the second study Ždata not shown., it was not likely that the hypoxia-induced sympathetic excitation was the primary cause for this sympathetic activation. In the second study, the animals were anesthetized with halothane at the end-tidal concentration of 0.5%, which approximated to 0.5 minimum alveolar concentration ŽMAC. in rabbits w18x, during the control period. An addition of 50% N2 O to 0.5 MAC halothane might attenuate the hemodynamic changes during the TDR because the depth of anesthesia could increase. This was unlikely, however, because hemodynamic responses to noxious stimulation were inhibited at 1.6 or more MAC ŽMAC BAR. level of anesthesia w31x. Although the N2 O MAC value in rabbits has not been determined, we can speculate it between 115–141%. This is based on the N2 Orhalothane MAC ratio in rats w37x and the halothane MAC value in rabbits and is modified with a 10% deviation for the calculations w18x. Therefore, the animals in this study should be anesthetized at a 0.85–0.93 MAC level which is far less than the MAC BAR level. Another possibility is that N2 O might influence several factors in the reflex arc of the TDR including nociceptors, afferent fibers, trigeminal complex, vasomotor centers and efferent fibers. N2 O alters neither axonal transmission of impulses nor impulse generation in cutaneous receptors w4x. In contrast, since 75% N2 O suppressed the spontaneous firing frequency of the central trigeminal nociceptors in the nucleus caudalis w21x, 50% N2 O may also modify noxious input during the TDR. 66 to 75% N2 O releases Met-enkephalin into cerebrospinal fluid in dogs w11x. Since en-
dogenous opioids inhibit the depressor neurons in the caudal ventrolateral medulla of rabbits through d- and k-receptors w6x, N2 O might attenuate the neural activities in the caudal ventrolateral medulla. Further studies on the antinociceptive effects of 50% N2 O during the TDR will be needed. 70% N2 O increases rCBF in rabbits during 1.0 MAC halothane anesthesia w37x. In contrast, at sub-MAC concentrations, inhaled anesthetics including N2 O have minimal or no effects on rCBF w9x. Although rCBF may increase during substantially more than 1.0 MAC anesthesia with the combination of N2 O and potent volatile anesthetic, the animals in the second study were anesthetized at less than 1.0 MAC level. Thus, rCBF should minimally increase during N2 O inhalation in the second study. It is therefore suggested that N2 O ameliorated rCBF reduction during the TDR through sympathomimetic and possible antinociceptive effects rather than direct cerebrovascular effects in this study. 4.3. Clinical consideration In the present study, the duration of the reductions in MAP and PtO 2 during the TDR was 15–30 s at most. In contrast, most cases of vasodepressor reactions in clinical settings continue for more than several minutes. It is therefore speculated that the occurrence of vasodepressor reactions might generally require three factors; Ž1. sudden decrease in blood pressure, Ž2. persistence of hypotension and Ž3. disturbed autoregulation of cerebral blood flow. Since persistent hypotension does not necessarily cause long-lasting reduction in cerebral blood flow under normal autoregulatory mechanism, prolonged vasodepressor reactions may be attributable to disturbed autoregulation of cerebral blood flow. The relative contributions of these factors need to be further investigated. Therefore, sudden onset of hypotension produced by the TDR could be a possible trigger mechanism for vasodepressor reactions. Recent studies have reported that a neurocardiogenic mechanism is responsible for one kind of vasodepressor syncope w1x. However, like the TDR, the neurocardiogenic mechanism is a simple reflex effect and its role remains speculative w16x. In clinical situations, vasodepressor reactions frequently occur during venous cannulation as well as during dental treatment. 15 out of 141 ambulatory surgery patients developed vasodepressor reactions, including feelings of faintness or dizziness and nausea, during venous cannulation w28x. Of those, the minimum MAP in seven patients was over 60 mm Hg; a level at which cerebral blood flow is believed to be kept constant through autoregulatory mechanisms. In the first study, MAP during the TDR was 60 " 10 mm Hg, with a range of 39–72 mm Hg. Therefore, if hemodynamic changes due to sympathetic inhibition like the TDR happened in patients undergoing dental treatment, some near-fainting symptoms could transiently develop following painful stimulation of the orofacial area.
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The second study suggests that N2 O-induced sympathetic activation may explain, at least in part, the preventive effect of N2 O on vasodepressor reactions during dental procedures. Although 20–30% N2 O is commonly used for the sedation of dental patients, the animals in the second study received 50% N2 O. The difference in the effects of 30 and 50% N2 O on sympathetic outflow remains unclear. Nevertheless, striking augmentation of muscle sympathetic outflow was found with increasing concentrations Ž25–40%. of N2 O in humans w8x. Therefore, the significance of N2 O for the patient sedation during dental treatments may be not only to alleviate the patient’s fear and anxiety but also to activate the sympathetic nervous system, to maintain high brain PO 2 and possibly to elicit antinociceptive effects on the nucleus caudalis. The latter three factors may prevent cerebral hypoxia during systemic hypotension caused by sympathetic inhibition.
5. Conclusion Similar abrupt decreases in MAP during the TDR and the VS produced similar reductions in rCBF and PtO 2 . A sudden diminution of sympathetic tone following noxious stimulation of the orofacial area, as in the case of the TDR, may be a possible trigger mechanism for vasodepressor reactions in dental patients. N2 O ameliorates hemodynamic changes during the TDR through sympathomimetic and possible antinociceptive effects. These mechanisms may explain, at least in part, the preventive effects of N2 O on vasodepressor reactions during dental procedures.
References w1x F.M. Abboud, Neurocardiogenic syncope, N. Engl. J. Med. 328 Ž1993. 1117–1120. w2x R.J. Bagshaw, R.H. Cox, Nitrous oxide and the baroreceptor reflexes in the dog, Acta. Anaesth. Scand. 26 Ž1982. 31–38. w3x S.H. Bahlman, E.I. Eger II, N. Ty Smith, W.C. Stevens, T.F. Shakespeare, D.C. Sawyer, M.J. Halsey, T.H. Cromwell, The cardiovascular effects of nitrous oxide-halothane anesthesia in man, Anesthesiology 35 Ž1971. 274–285. w4x R.H. De Jong, R.A. Nace, Nerve impulse conduction and cutaneous receptor responses during general anesthesia, Anesthesiology 28 Ž1967. 851–855. w5x P.G. Dellow, M.J. Morgan, Trigeminal nerve inputs and central blood pressure change in the cat, Arch. Oral Biol. 14 Ž1969. 295–300. w6x G. Drolet, D.A. Morilak, J. Chalmers, Endogenous opioids tonically inhibit the depressor neurons in the caudal ventrolateral medulla of rabbits: Mediation through d- and k-receptors, Neuropharmacology 30 Ž1991. 383–390. w7x P.C. Duke, S. Trosky, The effect of halothane with nitrous oxide on baroreflex control of heart rate in man, Can. Anaesth. Soc. J. 27 Ž1980. 531–534. w8x T.J. Ebert, Differential effects of nitrous oxide on baroflex control of heart rate and peripheral sympathetic nerve activity in humans, Anesthesiology 72 Ž1990. 16–22.
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w9x J.H. Eisele, Cardiovascular effects of nitrous oxide, in: E.I. Eger II ŽEd.., Nitrous Oxide, Edward Arnold, New York, 1985, pp. 125–156. w10x J.H. Eisele, N. Ty Smith, Cardiovascular effects of 40% nitrous oxide in man, Anesth. Analg. 51 Ž1972. 956–963. w11x A.D. Finck, E. Samaniego, S.H. Ngai, Nitrous oxide releases Met 5 enkephalin and Met 5-enkephalin–Arg 6 –Phe7 into canine third ventricular cerebrospinal fluid, Anesth. Analg. 80 Ž1995. 664–670. w12x M.J.T. Fitzgerald, S.R. Sachithanandan, The structure and source of lingual proprioceptors in the monkey, J. Anat. 128 Ž1979. 523–552. w13x G. Florence, J. Seylaz, Rapid autoregulation of cerebral blood flow: A laser-Doppler flowmetry study, J. Cereb. Blood Flow Metab. 12 Ž1992. 674–680. w14x A.F. Fukunaga, R.M. Epstein, Sympathetic excitation during nitrous oxide–halothane anesthesia in the cat, Anesthesiology 39 Ž1973. 23–36. w15x N.M. Gibbs, D.R. Larach, T.M. Skeehan, H.G. Schuler, Halothane induces depressor responses to noxious stimuli in the rat, Anesthesiology 70 Ž1989. 503–510. w16x R. Hainsworth, Syncope and fainting, in: R. Bannister, C.J. Mathias ŽEds.., Autonomic Failure, Oxford Medical Publications, Oxford, 1992, pp. 761–781. w17x W.E. Hoffman, F.T. Charbel, G. Edelman, Brain tissue oxygen, carbon dioxide, and pH in neurosurgical patients at risk for ischemia, Anesth. Analg. 82 Ž1996. 582–586. w18x T. Ichinohe, A. Fukunaga, S. Yamazaki, Determination of minimum alveolar concentration ŽMAC. for halothane, enflurane and isoflurane in the rabbit, Anesthesiology 81 Ž1994. A452. w19x B. Johansson, Circulatory responses to stimulation of somatic afferents, Acta. Physiol. Scand. 57 Ž1962. 1–91. w20x P.C. Johnson, Autoregulation of blood flow, Circ. Res. 59 Ž1986. 483–495. w21x L.M. Kitahata, R.G. McAllister, A. Taub, Identification of central nociceptors and the effects of nitrous oxide, Anesthesiology 38 Ž1973. 12–19. w22x M. Kumada, R.A.L. Dampney, D.J. Reis, The trigeminal depressor response: A cardiovascular reflex originating from the trigeminal system, Brain Res. 92 Ž1975. 485–489. w23x M. Kumada, R.A.L. Dampney, D.J. Reis, The trigeminal depressor response: A novel vasodepressor response originating from the trigeminal system, Brain Res. 119 Ž1977. 305–326. w24x D.J. Miletich, A.D. Ivankovich, R.F. Albrecht, C.R. Reimann, R. Rosenberg, E.D. McKissic, Absence of autoregulation of cerebral blood flow during halothane and enflurane anesthesia, Anesth. Analg. 55 Ž1976. 100–109. w25x H. Morita, E.M. Nemoto, A.L. Bleyaert, S.W. Stezoski, Brain blood flow autoregulation and metabolism during halothane anesthesia in monkeys, Am. J. Physiol. 223 Ž1977. H670–H676. w26x R. Murr, L. Schurer, S. Berger, R. Enzenbach, K. Peter, A. Baeth¨ mann, Effects of isoflurane, fentanyl, or thiopental anesthesia on regional cerebral blood flow and brain surface PO 2 in the presence of a focal lesion in rabbits, Anesth. Analg. 77 Ž1993. 898–907. w27x K. Oi, Y. Yamada, Noxious stimulation reduces blood pressure but not flow in the internal carotid artery as measured in rabbits, Anesth. Prog. 37 Ž1990. 24–28. w28x D.J. Pavlin, S. Links, S.E. Rapp, M.L. Nessly, H.J. Keyes, Vasovagal reactions in an ambulatory surgery center, Anesth. Analg. 76 Ž1993. 931–935. w29x G. Raimondi, J.M. Legramante, S. Cassarino, F. Iellamo, A. Vespa, G. Peruzzi, G. Tallarida, Cardiorespiratory effects evoked by electrical stimulation of somatic afferent fibers, Funct. Neurol. 6 Ž1991. 243–247. w30x W.G. Reed, R.J. Anderson, Effects of rapid blood pressure reduction on cerebral blood flow, Am. Heart J. 111 Ž1986. 226–228. w31x M.F. Roizen, R.W. Horrigan, B.M. Frazer, Anesthetic doses blocking adrenergic Žstress. and cardiovascular responses to incision-MAC BAR, Anesthesiology 54 Ž1981. 390–398. w32x E. Samso, N.E. Farber, J.P. Kampine, W.T. Schmeling, The effects
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of halothane on pressor and depressor responses elicited via the somatosympathetic reflex: A potential antinociceptive action, Anesth. Analg. 79 Ž1994. 971–979. w33x A. Sato, R.F. Schmidt, Somatosympathetic reflexes: Afferent fibers, central pathways, discharge characteristics, Physiol. Rev. 53 Ž1973. 916–947. w34x M.S. Scheller, M.M. Todd, J.C. Drummond, Isoflurane, halothane, and regional cerebral blood flow at various levels of PaCO 2 in rabbits, Anesthesiology 64 Ž1986. 598–604. w35x R.K. Stoelting, D.E. Longnecker, E.I. Eger II, Minimum alveolar concentrations in man on awakening from methoxyflurane,
halothane, ether and fluroxene anesthesia: MAC Awake, Anesthesiology 33 Ž1970. 5–9. w36x N. Terui, Y. Numao, M. Kumada, D.J. Reis, Identification of the primary afferent fiber group and adequate stimulus initiating the trigeminal depressor response, J. Autonom. Nerv. Syst. 4 Ž1981. 1–16. w37x M.M. Todd, The effects of PaCO on the cerebrovascular responses 2 to nitrous oxide in the halothane-anesthetized rabbit, Anesth. Analg. 66 Ž1987. 1090–1095. w38x B.G. Wallin, G. Sundlof, ¨ Sympathetic outflow to muscles during vasovagal syncope, J. Autonom. Nerv. Syst. 6 Ž1982. 287–291.
Cerebral cortex regional blood flow and tissue oxygen tension during the trigeminal depressor response in rabbits Tatsuya Ichinohe ) , Hideharu Agata, Hidetaka Aida, Yuzuru Kaneko Department of Dental Anesthesiology, Tokyo Dental College, 1-2-2 Masago, Mihama-ku, Chiba 261, Japan Received 13 May 1997; revised 12 June 1997; accepted 13 June 1997
Abstract The trigeminal depressor response ŽTDR. is characterized with profound hypotension caused by sympathetic outflow decreases. The purpose of this study was: Ž1. to compare the hemodynamic changes during acute hypotension induced by the TDR with those induced by electrical stimulation of the vagal nerve ŽVS. as models of sympathetic inhibition and vagal activation and Ž2. to investigate the effects of nitrous oxide ŽN2 O., a well-known sympathomimetic, on the hemodynamic changes during the TDR. Male Japan White rabbits were anesthetized with halothane in oxygen and mechanically ventilated. The electrode pair for the TDR was inserted into the submucosal tissue of the animal’s tongue. The pair for the VS was applied to the isolated left vagal trunk. Both the TDR and the VS produced similar decreases in mean arterial pressure ŽMAP. and cerebral cortex regional blood flow ŽrCBF., although the decreases in heart rate ŽHR. and aortic blood flow were greater during the VS. Cerebral cortex tissue oxygen tension in both groups decreased slightly. 50% N2 O, producing MAP elevation and HR decrease, ameliorated the hemodynamic changes including rCBF reduction during the TDR. A sudden diminution of sympathetic tone following noxious stimulation of the orofacial area, as in the case of the TDR, may be a possible trigger mechanism for vasodepressor reactions in dental patients. The sympathomimetic and possible antinociceptive effects of N2 O may explain, at least in part, the preventive effects on vasodepressor reactions during dental procedures. q 1997 Elsevier Science B.V. Keywords: Trigeminal depressor response; Vagal nerve; Cerebral cortex regional blood flow; Cerebral cortex regional tissue oxygen tension; Nitrous oxide; Vasodepressor reactions
1. Introduction Electrical stimulations, especially trains of low frequency stimulations, of the spinal trigeminal complex or the branches of the trigeminal nerve in rabbits produce profound hypotension known as the trigeminal depressor response ŽTDR. w22,23x. Because vagotomy, atropine and propranolol do not inhibit, although phentolamine does inhibit, this hypotension, it is speculated that the hypotension in TDR is caused, not by an increase in vagal tone, but by a decrease in sympathetic vasoconstrictor outflow w23x. The determinants for blood pressure are cardiac output and total peripheral resistance. Hypotension occurs through decreased cardiac output mainly due to hemorrhage or vagal activation, or through reduced total peripheral resistance mainly due to sympathetic inhibition including the TDR. The first purpose of this study was, therefore, to )
Corresponding author. Tel.: q81 43 2703969; fax: q81 43 2703971.
0165-1838r97r$17.00 q 1997 Elsevier Science B.V. All rights reserved. PII S 0 1 6 5 - 1 8 3 8 Ž 9 7 . 0 0 0 7 6 - 3
investigate the changes in cerebral cortex regional blood flow ŽrCBF. and tissue oxygen tension Ž PtO 2 . as well as in systemic hemodynamic parameters, including heart rate ŽHR., blood pressure, and aortic blood flow ŽAoF., during the TDR. We compared these hemodynamic changes with those during electrical stimulation of the vagal nerve ŽVS. which causes hypotension by the other mechanisms. Since vasodepressor reactions, including fainting, develop from inadequate cerebral blood flow due to systemic hypotension w16,38x, a sudden diminution of sympathetic tone following noxious stimulation of the orofacial area, as in the case of the TDR, may be a possible mechanism for them. Therefore, we discuss the significance of sympathetic inhibition like the TDR as a mechanism for vasodepressor reactions. In routine dental practice, 20–30% nitrous oxide ŽN2 O. in balance oxygen has been administered to patients with dentalphobia or prone to faint. N2 O inhalation lessens the occurrence of vasodepressor reactions in clinical dentistry. The second purpose of this study was to investigate the
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effects of N2 O, a well-known sympathomimetic w3,14x, on the hemodynamic changes including rCBF during the TDR.
beneath the rCBF measurement probe. The diameter of the electrode was 0.2 mm. The inserted length of the electrode was approximately 10 mm.
2. Materials and methods
2.3. Electrical stimulation
After approval by our Animal Care and Use Committee, we utilized male Japan White rabbits Ž2.2–2.7 kg.. All animals were allowed food and water ad libitum until the morning of the experiment.
Two pairs of stainless needle electrodes were used for the delivery of an electrical current. The pair for the TDR was inserted into the submucosal tissue of the animal’s tongue 4 mm apart, with the cathode at the left side and the anode at the right side of the tongue. Square wave pulses were delivered using a stimulation unit ŽSEN-7203, Nihon Kohden, Tokyo. and an isolation unit ŽSS-104J, Nihon Kohden, Tokyo.. The stimulating condition for the TDR was 20 V in intensity, 10 Hz in frequency and 0.5 ms in duration for 3 s. The second pair for the VS applied to the isolated left vagal trunk distal to the emerging site of the depressor nerve. The electrodes were 4 mm apart, with the cathode at the distal site. The vagal nerve was covered with a layer of liquid paraffin. Bilateral vagal nerves were kept intact to prevent vagotomy-induced modification of the HR during the TDR. The stimulating condition for the VS was the same as for the TDR except for the intensity, which was adjusted to produce a similar decrease in mean arterial pressure ŽMAP. to that during the TDR. After the completion of experimental preparations, the halothane concentration was reduced to 0.5 vrv% and maintained at that level for more than 60 min to stabilize the animal’s hemodynamic parameters. Nitrogen was added to the anesthetic gas mixture to keep PaO 2 at 100–150 mm Hg throughout the experiment. Each animal received the electrical stimulations for the TDR and the VS in a randomized crossover manner.
2.1. Surgical procedures Anesthesia was induced by inhalation of halothane Ž2.5 vrv%. in oxygen delivered via a mask. Before skin incisions for each of the experimental procedures described below, appropriate doses of lidocaine were infiltrated into the surgical field. A a20 French size non-cuffed pediatric endotracheal tube was inserted into the trachea via a tracheostomy. The left auricular marginal vein and right femoral artery were cannulated with 22 and 20 gauge Teflon indwelling catheters. After intravenous lactated Ringer’s solution was started at 10 ml kgy1 hy1 , the animals were paralyzed with 1 mgrkg alcuronium chloride ŽDialferin, Roche, Tokyo. and mechanically ventilated. The femoral artery blood pressure was continuously monitored with a pressure transducer ŽP23ID; Gould, Oxnard, California.. HR was recorded by a tachograph triggered by the blood pressure wave. AoF was measured with an ultrasound flowmeter ŽT108; Transonic, Ithaca, New York. via a left-sided thracotomy. A flow probe Žtype 3SB; Transonic, Ithaca, New York. was applied to the isolated ascending aorta. 2.2. Study 1. Comparison of rCBF and PtO 2 between the TDR and the VS In the first study, we compared the hemodynamic changes during the TDR with those during the VS. In 10 rabbits, rCBF and PtO 2 in the left parietal region were measured with a laser-Doppler flowmeter ŽALF21; Unique Medical, Tokyo. and a PO 2 monitor Ž PO 2-100DW; Inter Medical, Tokyo. via a left-sided craniotomy. The time constant for these devices was 1 s. The animal was fixed in a supine position with the head turned right. After a midline incision of the shaved scalp, the left temporal muscle was stripped off with the parietal periosteum. The left parietal bone was removed with an approximate size of 14 = 14 mm with the dura mater kept intact. The contact type probe Žtype C; Unique Medical, Tokyo. for rCBF measurement was placed at the dorsolateral surface of the left cerebral hemisphere. Care was taken not to place the probe above the pial vessels. A polarographic needle electrode ŽPOE-10N; Inter Medical, Tokyo, Japan. for PO 2 measurement was inserted from the dorsocaudal corner of the exposed dura mater into the cerebral cortex with its tip
2.4. Study 2. Effect of N2 O on the TDR In the second study, we investigated the effects of N2 O on the hemodynamic changes during the TDR. In nine rabbits, experimental preparations including rCBF measurement and electrical stimulation for the TDR were performed in the same manner as in the first study. The animals who participated in the second study did not undergo PtO 2 measurements. The stimulating condition for the TDR was also the same as in the first study. After the completion of experimental preparations and hemodynamic stabilization under inhalation of 0.5 vrv% halothane for more than 60 min, the control measurement was performed. Following the control measurement, the animals inhaled 50 vrv% N2 O for 15 min and the hemodynamic variables were reevaluated. 2.5. Hemodynamic monitoring In both studies, hemodynamic changes were continuously recorded ŽPolygraph series 360; NEC San-ei, Tokyo.. Hemodynamic variables for the TDR and the VS were
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recorded immediately prior to the nerve stimulation and at maximum change following electrical stimulation. The data for the TDR and the VS were obtained by averaging three consecutive values in each animal. At least 3 min intervals were allowed between each electrical stimulation of the TDR and the VS. Total peripheral resistance ŽTPR. was calculated as MAP divided by AoF. TPR and rCBF were expressed as percentages of the control values. In the first study, prestimulation values of the TDR and the VS were independently served as the respective control values for these parameters. In the second study, in contrast, the prestimulation value of the TDR without N2 O served as the control value throughout the study except for Fig. 4, in which the prestimulation values of the TDR without N2 O and with N2 O independently served as the respective control values. End-tidal halothane concentration Ž0.5 vrv%. and PaCO 2 Ž35–40 mm Hg. were kept constant throughout the experiment. The halothane concentration was continuously monitored with an anesthetic gas monitor ŽCapnomac; Datex, Helsinki, Finland.. Blood gases were analyzed with a pH–blood gas–electrolytes analyzer ŽStat Profile 5; Nova Biomedical, Boston, MA.. Body temperature was continuously monitored by a rectal probe and maintained between 39.0–39.58C with the aid of a heating lamp. At the end of the experiment, the responses of rCBF to hypercapnia or hypocapnia were confirmed to ascertain normal cerebrovascular reactivity in each animal. 2.6. Statistical analysis Data are expressed as the mean " SD. One way analysis of variance for repeated measurements followed by Student–Newman–Keuls test for multiple comparisons was used in this study. P-values less than 0.05 indicated statistical significance.
3. Results
Fig. 1. A typical recording of the hemodynamic changes during the trigeminal depressor response ŽTDR. and the vagal nerve stimulation ŽVS.. Arrows indicate 3 s electrical stimulation for the TDR and the VS. Both stimulations produced long-lasting hypotension Ž15–30 s in general. and rCBF reductions which led to the decrease in PtO 2 . HR: heart rate; BP: blood pressure; MAP: mean arterial pressure; AoF: aortic blood flow; rCBF: cerebral cortex regional blood flow; PtO 2 : cerebral cortex tissue oxygen tension.
Table 1 Hemodynamic changes during the trigeminal depressor response ŽTDR. and the vagal nerve stimulation ŽVS. TDR
3.1. Study 1. Comparison of rCBF and Pt O 2 between the TDR and the VS Fig. 1 shows a typical recording of the hemodynamic changes during the TDR and the VS. Electrical stimulations for 3 s for the TDR and the VS produced arterial hypotension which lasted for 15–30 s. Likewise, the rCBF was reduced after the electrical stimulations. The duration of rCBF reduction, however, was shorter than that of MAP reduction Žless than 15 s in general.. rCBF reduction was followed by a PtO 2 decrease which lasted as long as MAP reduction. Table 1 and Fig. 2 summarize the hemodynamic changes during the TDR and the VS. The laser-Doppler flowmeter readings before electrical stimulations for the TDR and the
CONT HR MAP AoF TPR rCBF Pt O 2
VS ES
264.5"28.6 240.8"34.2 75.2"10.0 60.3"10.0 325.0"42.8 298.5"37.9 100.0" 0.0 86.8" 4.4 100.0" 0.0 86.1" 5.2 28.5" 6.5 27.7" 6.8
CONT )a ) )a )a ) )
ES
267.1"27.3 232.5"36.5 75.3"10.5 59.3"11.3 329.0"44.6 278.5"27.9 100.0" 0.0 92.7"12.6 100.0" 0.0 85.1" 6.7 29.1" 6.1 28.3" 6.0
)a ) )a )a ) )
Values are expressed as the mean"SD. HR: heart rate Žbpm.; MAP: mean arterial pressure Žmm Hg.; AoF: aortic blood flow Žmlrmin.; TRP: total peripheral resistance Ž s MAPrAoF, expressed as a percentage of the control value.; rCBF: cerebral cortex regional blood flow Žexpressed as a percentage of the control value.; PtO 2 : cerebral cortex tissue oxygen tension Žmm Hg.. CONT and ES represent the control value and the value at maximum change following electrical stimulation, respectively. ) Significantly different Ž p- 0.05. from CONT. a Significantly different Ž p- 0.05. between two groups.
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T. Ichinohe et al.r Journal of the Autonomic NerÕous System 66 (1997) 111–118 Table 2 Hemodynamic changes during the trigeminal depressor response ŽTDR. with or without nitrous oxide ŽN2 O.
HR MAP AoF TPR rCBF Fig. 2. The hemodynamic changes during the trigeminal depressor response ŽTDR; open column. and the vagal nerve stimulation ŽVS; hatched column.. Both the TDR and the VS produced similar decreases in mean arterial pressure and cerebral cortex regional blood flow. The decreases in heart rate and aortic blood flow were greater during the VS, while the decrease in total peripheral resistance was greater during the TDR. Cerebral cortex tissue oxygen tension in both groups showed slight but statistically significant decreases. Data are shown as percentages of the respective pre-stimulation control values Žmean"SD.. HR: heart rate; MAP: mean arterial pressure; AoF: aortic blood flow; TPR: total peripheral resistance Ž s MAPrAoF.; rCBF: cerebral cortex regional blood flow; PtO 2 : cerebral cortex tissue oxygen tension. a Significantly different Ž p- 0.05. between two groups.
TDR without N2 O
TDR with N2 O
CONT
CONT
ES
ES
269.6"33.8 a 243.2"37.0 ) 248.4"32.0 a 234.9"29.6 74.6"15.1 a 55.9"16.1 ) a 79.4"16.7 a 66.9"18.3 ) a 290.6"55.4 260.6"35.0 ) a 310.0"48.1 291.7"35.2 ) a 100.0" 0.0 81.9" 8.4 ) a 99.5" 8.4 87.6" 7.0 ) a 100.0" 0.0 82.1"10.3 ) a 101.1" 4.3 94.1" 5.7 a
Values are expressed as the mean"SD. HR: heart rate Žbpm.; MAP: mean arterial pressure Žmm Hg.; AoF: aortic blood flow Žmlrmin.; TPR: total peripheral resistance Ž s MAPrAoF, expressed as a percentage of the control value in the TDR without N2 O.; rCBF: cerebral cortex regional blood flow Žexpressed as a percentage of the control value in the TDR without N2 O.. CONT and ES represent the control value and the value at the maximum change during electrical stimulation, respectively. ) Significantly different Ž p- 0.05. from CONT. a Significantly different Ž p- 0.05. between two groups.
VS were almost the same. Both the TDR and the VS produced similar decreases in MAP. The reduction of rCBF in both groups was also similar. The decreases in HR and AoF, on the other hand, were greater during the VS than during the TDR. In contrast, the decrease in TPR was greater during the TDR. PtO 2 in both groups showed slight but statistically significant decreases. 3.2. Study 2. Effect of N2 O on the TDR Fig. 3 shows a typical recording of the hemodynamic changes during the TDR with or without N2 O. These hemodynamic changes were summarized in Table 2 and Fig. 4. N2 O, producing mean arterial pressure ŽMAP. elevation and HR decrease, ameliorated the hemodynamic changes including rCBF reduction during the TDR.
Fig. 3. A typical recording of the hemodynamic changes during the trigeminal depressor response ŽTDR. with Žright. or without Žleft. N2 O. Arrows indicate 3 s electrical stimulation for the TDR. 50% N2 O ameliorated the hemodynamic changes during the TDR. HR: heart rate; BP: blood pressure; MAP: mean arterial pressure; AoF: aortic blood flow; rCBF: cerebral cortex regional blood flow.
Fig. 4. The hemodynamic changes during the trigeminal depressor response ŽTDR; open column. were attenuated by nitrous oxide ŽN2 O; hatched column. inhalation. Data are shown as percentages of the respective control values Žmean"SD.. HR: heart rate; MAP: mean arterial pressure; AoF: aortic blood flow; TPR: total peripheral resistance Ž s MAPrAoF.; rCBF: cerebral cortex regional blood flow. a Significantly different Ž p- 0.05. between two groups.
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4. Discussion Electrical stimulations of the submucosal tissue of the rabbit’s tongue produced arterial hypotension. In our preliminary study, vagotomy, atropine and propranolol did not inhibit this hypotension, whereas phentolamine inhibited it. Accordingly, the hypotension induced by electrical stimulations of the rabbit’s tongue in this study should be a type of the TDR. Since bilateral vagal nerves were kept intact in this study, afferent as well as efferent impulses might be generated during the VS. Accordingly, a compensatory activation of sympathetic nervous system induced by vagal afferent impulses might occur. The changes in hemodynamic variables during the VS however suggest that this sympathetic compensation should be minimal. Therefore, the VS was considered as a model of vagal activation in this study. 4.1. Comparison of rCBF and PtO 2 between the TDR and the VS In the first study, TDR-derived hypotension led to rCBF and PtO 2 reductions. Likewise, the VS produced hypotension followed by rCBF and PtO 2 reductions. Similar decreases in MAP during the TDR and the VS produced similar reductions in rCBF and PtO 2 ; the decreases in HR and AoF were greater during the VS. It is well-known that the blood flow to the brain is well maintained during systemic hypotension through autoregulatory mechanisms w20x. In contrast, a rapid and sustained decrease in blood pressure to a level below the lower limit of autoregulation may result in central nervous system dysfunction due to rCBF reduction w30x. Since hypotension during the TDR and the VS is an abrupt phenomenon with short duration because of its reflex nature, the rCBF reduction should also be transient and soon recover by the autoregulatory compensation in normal conditions. A shorter duration of rCBF reduction than that of MAP decrease suggests intact autoregulatory functions. However, rapid recovery of rCBF reduction was followed by sustained PtO 2 decrease. Clinical significance of this decrease remains to be investigated. Blood flow at internal carotid artery ŽICA. measured by a electromagnetic flowmeter did not change during the TDR produced by electrical stimulation of the tongue in pentobarbital-anesthetized rabbits w27x. The authors concluded that the painful stimulation of the oral receptors produced a blood pressure decrease, which was tolerated by autoregulation of the cerebral blood flow. However, they did not record mean ICA flow but beat to beat ICA flow, which might not necessarily detect the change in cerebral blood flow. The cardiovascular responses produced by electrical stimulation of peripheral nerves depend on several variables, including the stimulation characteristics of intensity, frequency and duration, the type of somatic nerve stimulated, and the anesthetic depth and the drug used
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w5,19,29,32,33,36x. In this study, we delivered electrical current at 10 Hz in frequency during the TDR and the VS, because a train of low frequency stimulation Ž- 20 Hz. elicited the TDR, while high frequency stimulation Ž50 Hz or more. caused a pressor response w23x. In this study, the intervals between each electrical stimulation for the TDR and the VS were at least three minutes. Our preliminary study showed that the electrical stimulations given at these intervals elicited the reproducible responses. An increase in the end-tidal halothane concentration from sub-minimum alveolar concentration ŽMAC. level to supra-MAC level was associated with a depressor response to tail clamping in rats w15x. In addition, although the rCBF increased during 1 MAC halothane anesthesia in rabbits w34x, neither the increase in rCBF nor the impairment of autoregulation were observed in goats w24x and monkeys w25x during 0.5 MAC halothane anesthesia. The animals participating in this study, therefore, were anesthetized with halothane at the end-tidal concentration of 0.5 vrv%, which approximated to 0.5 MAC in rabbits w18x, throughout the experiment. Since 0.5 MAC halothane approximates to its MAC awake level in humans w35x, the animals in this study were considered to be lightly anesthetized or deeply sedated. Even lighter sedation of the experimental animals should be avoided for ethical reasons. In this study, electrical current during the TDR stimulated submucosal nerve receptors and, possibly, some other receptors in the lingual muscle, such as proprioceptors. The lingual proprioceptive afferent fibers occupy the hypoglossal nerve and enter the spinal cord after the connection to the C2–C3 spinal nerve in monkeys w12x. The significance of electrical stimulation of these receptors remains unknown. rCBF was measured using a laser-Doppler flowmeter in this study. Laser-Doppler flowmetry has been reported to allow rapid and instantaneous measurement of rCBF in rabbits w13x. Brain surface PO 2 had a range of 26.5–31.0 mm Hg during isoflurane anesthesia with PaO 2 of 109.2 " 2.2 mm Hg Žmean " SEM. in rabbits w26x. In addition, noncompromised brain tissue PO 2 remained above 20 mm Hg in humans w17x. In the first study, PtO 2 under control conditions was 29 " 6 mm Hg, with a range of 21–38 mm Hg in both groups. These results assured us of the noncompromised cerebral cortical tissue of the experimental animals. 4.2. Effect of N2 O on the TDR In the second study, 50 vrv% N2 O inhalation produced small but significant elevation in MAP and decrease in HR. MAP elevation depended not on TPR increase but on AoF augmentation. The hemodynamic changes during the TDR were attenuated under these conditions. 70% N2 O revealed sympathomimetic effects such as the increases in blood pressure and cardiac output in humans and intact cats, although it produced direct myocardial depression in the decerebrated cats, during halothane in-
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halation as basal anesthesia w3,14x. In human volunteers, 40% N2 O caused the elevation in plasma norepinephrine level which was reflected as an increase in TPR, although it produced blood pressure and HR decreases w10x. In clinical situations, the sympathomimetic effects of N2 O should be balanced more or less by its direct myocardial depressant effects w9x. Thus, hemodynamic parameters such as blood pressure or HR may not be necessarily increased during N2 O inhalation. Although N2 O depressed, but not abolished, the baroreceptor reflex w2,7x, significant HR decrease was observed during small MAP elevation in this study. The change in HR may be partly attributable to direct myocardial depressant effects of N2 O. Decrease in HR was more obvious than in MAP when direct myocardial depression occurred during N2 O inhalation in the decerebrated cats w3x. It is therefore suggested that N2 O produced MAP elevation and AoF augmentation, though not statistically significant, through central sympathetic activation, which were accompanied with HR decrease through the baroreceptor reflex andror direct myocardial depression in the second study. The hemodynamic changes during the TDR were attenuated by N2 O inhalation. Since the TDR is elicited through sympathetic inhibition, N2 O-induced sympathetic activation may counteract the hemodynamic changes during the TDR. Because PaO 2 during N2 O inhalation in each animal was well over 100 mm Hg in the second study Ždata not shown., it was not likely that the hypoxia-induced sympathetic excitation was the primary cause for this sympathetic activation. In the second study, the animals were anesthetized with halothane at the end-tidal concentration of 0.5%, which approximated to 0.5 minimum alveolar concentration ŽMAC. in rabbits w18x, during the control period. An addition of 50% N2 O to 0.5 MAC halothane might attenuate the hemodynamic changes during the TDR because the depth of anesthesia could increase. This was unlikely, however, because hemodynamic responses to noxious stimulation were inhibited at 1.6 or more MAC ŽMAC BAR. level of anesthesia w31x. Although the N2 O MAC value in rabbits has not been determined, we can speculate it between 115–141%. This is based on the N2 Orhalothane MAC ratio in rats w37x and the halothane MAC value in rabbits and is modified with a 10% deviation for the calculations w18x. Therefore, the animals in this study should be anesthetized at a 0.85–0.93 MAC level which is far less than the MAC BAR level. Another possibility is that N2 O might influence several factors in the reflex arc of the TDR including nociceptors, afferent fibers, trigeminal complex, vasomotor centers and efferent fibers. N2 O alters neither axonal transmission of impulses nor impulse generation in cutaneous receptors w4x. In contrast, since 75% N2 O suppressed the spontaneous firing frequency of the central trigeminal nociceptors in the nucleus caudalis w21x, 50% N2 O may also modify noxious input during the TDR. 66 to 75% N2 O releases Met-enkephalin into cerebrospinal fluid in dogs w11x. Since en-
dogenous opioids inhibit the depressor neurons in the caudal ventrolateral medulla of rabbits through d- and k-receptors w6x, N2 O might attenuate the neural activities in the caudal ventrolateral medulla. Further studies on the antinociceptive effects of 50% N2 O during the TDR will be needed. 70% N2 O increases rCBF in rabbits during 1.0 MAC halothane anesthesia w37x. In contrast, at sub-MAC concentrations, inhaled anesthetics including N2 O have minimal or no effects on rCBF w9x. Although rCBF may increase during substantially more than 1.0 MAC anesthesia with the combination of N2 O and potent volatile anesthetic, the animals in the second study were anesthetized at less than 1.0 MAC level. Thus, rCBF should minimally increase during N2 O inhalation in the second study. It is therefore suggested that N2 O ameliorated rCBF reduction during the TDR through sympathomimetic and possible antinociceptive effects rather than direct cerebrovascular effects in this study. 4.3. Clinical consideration In the present study, the duration of the reductions in MAP and PtO 2 during the TDR was 15–30 s at most. In contrast, most cases of vasodepressor reactions in clinical settings continue for more than several minutes. It is therefore speculated that the occurrence of vasodepressor reactions might generally require three factors; Ž1. sudden decrease in blood pressure, Ž2. persistence of hypotension and Ž3. disturbed autoregulation of cerebral blood flow. Since persistent hypotension does not necessarily cause long-lasting reduction in cerebral blood flow under normal autoregulatory mechanism, prolonged vasodepressor reactions may be attributable to disturbed autoregulation of cerebral blood flow. The relative contributions of these factors need to be further investigated. Therefore, sudden onset of hypotension produced by the TDR could be a possible trigger mechanism for vasodepressor reactions. Recent studies have reported that a neurocardiogenic mechanism is responsible for one kind of vasodepressor syncope w1x. However, like the TDR, the neurocardiogenic mechanism is a simple reflex effect and its role remains speculative w16x. In clinical situations, vasodepressor reactions frequently occur during venous cannulation as well as during dental treatment. 15 out of 141 ambulatory surgery patients developed vasodepressor reactions, including feelings of faintness or dizziness and nausea, during venous cannulation w28x. Of those, the minimum MAP in seven patients was over 60 mm Hg; a level at which cerebral blood flow is believed to be kept constant through autoregulatory mechanisms. In the first study, MAP during the TDR was 60 " 10 mm Hg, with a range of 39–72 mm Hg. Therefore, if hemodynamic changes due to sympathetic inhibition like the TDR happened in patients undergoing dental treatment, some near-fainting symptoms could transiently develop following painful stimulation of the orofacial area.
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The second study suggests that N2 O-induced sympathetic activation may explain, at least in part, the preventive effect of N2 O on vasodepressor reactions during dental procedures. Although 20–30% N2 O is commonly used for the sedation of dental patients, the animals in the second study received 50% N2 O. The difference in the effects of 30 and 50% N2 O on sympathetic outflow remains unclear. Nevertheless, striking augmentation of muscle sympathetic outflow was found with increasing concentrations Ž25–40%. of N2 O in humans w8x. Therefore, the significance of N2 O for the patient sedation during dental treatments may be not only to alleviate the patient’s fear and anxiety but also to activate the sympathetic nervous system, to maintain high brain PO 2 and possibly to elicit antinociceptive effects on the nucleus caudalis. The latter three factors may prevent cerebral hypoxia during systemic hypotension caused by sympathetic inhibition.
5. Conclusion Similar abrupt decreases in MAP during the TDR and the VS produced similar reductions in rCBF and PtO 2 . A sudden diminution of sympathetic tone following noxious stimulation of the orofacial area, as in the case of the TDR, may be a possible trigger mechanism for vasodepressor reactions in dental patients. N2 O ameliorates hemodynamic changes during the TDR through sympathomimetic and possible antinociceptive effects. These mechanisms may explain, at least in part, the preventive effects of N2 O on vasodepressor reactions during dental procedures.
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