Effect of Pain and Audiovisual Stimulation on the Depression of Acute Hypoxic Ventilatory Response by Low-dose Halothane in Humans

Background: The effects of different low-dose volatile agents in blunting the acute hypoxic ventilatory response (AHVR) are variable. Arousal (due to audiovisual stimulation) may prevent isoflurane-induced blunting of AHVR. The purpose of this study was to assess whether this was also the case for halothane. The authors also assessed the effects of pain on the interaction of halothane and AHVR.

Methods: Step decreases in end-tidal partial pressure of oxygen using dynamic end-tidal forcing were performed from normoxia to hypoxia (50 mmHg) in 10 healthy volunteers, with end-tidal partial pressure of carbon dioxide held 1-2 mmHg above normal, in six protocols: (1) control conditions (darkened, quiet room, eyes closed) without halothane and (2) with 0.1 minimum alveolar concentration (MAC) halothane; (3) audiovisual stimulation (bright room, loud television) without halothane and (4) with 0.1 MAC halothane; (5) pain (electrical stimulation of skin over the tibia to produce a visual analog pain score of 5-6 out of 10) without halothane and (6) with 0.1 MAC halothane. The Bispectral Index of the electroencephalogram was also monitored.

Results: Halothane did not affect normoxic minute ventilation in any arousal state but significantly reduced the magnitude of AHVR by 50% regardless of the background arousal state (P < 0.001). Bispectral Index values were reduced by halothane only in the absence of arousal (P < 0.003). Both pain and audiovisual stimulation modestly increased normoxic minute ventilation (P < 0.002) and AHVR (P < 0.003).     

Sex-related Differences in the Influence of Morphine on Ventilatory Control in Humans

Background: Opiate agonists have different analgesic effects in male and female patients. The authors describe the influence of sex on the respiratory pharmacology of the micro-receptor agonist morphine.

Methods: The study was placebo-controlled, double-blind, and randomized. Steady-state ventilatory responses to carbon dioxide and responses to a step into hypoxia (duration, 3 min; oxygen saturation, [approximately] 82%; end-tidal carbon dioxide tension, 45 mmHg) were obtained before and during intravenous morphine or placebo administration (bolus dose of 100 micro gram/kg, followed by a continuous infusion of 30 micro gram [center dot] kg sup -1 [center dot] h sup -1) in 12 men and 12 women.

Results: In women, morphine reduced the slope of the ventilatory response to carbon dioxide from 1.8 +/- 0.9 to 1.3 +/- 0.7 l [center dot] min sup -1 [center dot] mmHg sup -1 (mean +/- SD; P < 0.05), whereas in men there was no significant effect (control = 2.0 +/- 0.4 vs. morphine = 1.8 +/- 0.4 l [center dot] min sup -1 [center dot] mmHg sup -1). Morphine had no effect on the apneic threshold in women (control = 33.8 +/- 3.8 vs. morphine = 35.3 +/- 5.3 mmHg), but caused an increase in men from 34.5 +/- 2.3 to 38.3 +/- 3 mmHg, P < 0.05). Morphine decreased hypoxic sensitivity in women from 1.0 +/- 0.5 l [center dot] min sup -1 [center dot] % sup -1 to 0.5 +/- 0.4 l [center dot] min sup -1 [center dot] % sup -1 (P < 0.05) but did not cause a decrease in men (control = 1.0 +/- 0.5 l [center dot] min sup -1 [center dot] % sup -1 vs. morphine = 0.9 +/- 0.5 l [center dot] min sup -1 [center dot] % sup -1). Weight, lean body mass, body surface area, and calculated fat mass differed between the sexes, but their inclusion in the analysis as a covariate revealed no influence on the differences between men and women in morphine-induced changes.     

Acute Pain and Central Nervous System Arousal Do Not Restore Impaired Hypoxic Ventilatory Response during Sevoflurane Sedation

Background: To quantify the effects of acute pain on ventilatory control in the awake and sedated human volunteer, the acute hypoxic ventilatory response was studied in the absence and presence of noxious stimulation before and during 0.1 minimum alveolar concentration sevoflurane inhalation.

Methods: Step decreases in end-tidal partial pressure of oxygen from normoxia into hypoxia (approximately 50 mmHg) were performed in 11 healthy volunteers. Four acute hypoxic ventilatory responses were obtained per subject: one in the absence of pain and sevoflurane (C), one in the absence of sevoflurane with noxious stimulation in the form of a 1-Hz electrical current applied to the skin over the tibial bone (C + P), one in the absence of pain during the inhalation of 0.1 minimum alveolar concentration sevoflurane (S), and one during 0.1 minimum alveolar concentration sevoflurane with noxious stimulation (S + P). The end-tidal partial pressure of carbon dioxide was held constant at a value slightly greater than baseline (44 mmHg). To assess the central nervous system arousal state, the bispectral index of the electroencephalogram was monitored. Values are mean+/-SE.

Results: Pain caused an increase in prehypoxic baseline ventilation before and during sevoflurane inhalation: C = 13.7+/-0.9 l *symbol* min-1, C + P = 16.0+/-1.0 l *symbol* min-1 (P < 0.05 vs. C and S), S = 12.7+/-1.2 l *symbol* min-1, and S + P = 15.9+/-1.1 l *symbol* min-1 (P < 0.05 vs. C and S). Sevoflurane decreased the acute hypoxic ventilatory response in the absence and presence of noxious stimulation: C = 0.69+/-0.20 l *symbol* min-1 (% change in arterial hemoglobin-oxygen saturation derived from pulse oximetry [SP O2])-1, C + P = 0.64 +/-0.13 l *symbol* min-1 *symbol* %SP O2-1, S = 0.48+/-0.15 l *symbol* min-1 *symbol* %SP O2-1 (P < 0.05 vs. C and C + P) and S + P = 0.46+/-0.12 l *symbol* min-1 *symbol* %SP O2-1 (P < 0.05 vs. C and C + P). The bispectral indexes were C = 96.2+/-0.7, C + P = 97.1 +/-0.4, S = 86.3+/-1.3 (P < 0.05), and S + P = 95.0 +/-1.0.     

Activation of the Supraspinal Pain Inhibition System by Ketamine Hydrochloride

The neurophysiologic mechanism of ketamine-induced analgesia was studied in cats under conditions of electrolytic decerebration or pentobarbital anesthesia. Injection of bradykinin into the femoral artery served as the noxious stimulus and the neural response in the lateral funiculus of the spinal cord was recorded by the multi-unit activity technique. Ketamine depressed the bradykinin-induced response more markedly in decerebrate, non-anesthetized cats than in pentobarbital-anesthetized cats. The depressant action disappeared following cervical cord transection at C₁, in both decerebrate non-anesthetized and pentobarbital-anesthetized cats. Thus, the analgesic action of ketamine is probably exerted mainly through activation of the supraspinal pain inhibition system and a direct action on the spinal cord nociceptive neural mechanism, if any, is slight. The excitatory action of ketamine on the supraspinal pain inhibition system is susceptible to the depressant action of pentobarbital.     

Influence of Hydrogen Ion Concentration on Bile Acid Induced Acute Gastric Mucosal Ulcerogenesis

Aggressive treatment with H(2) receptor blocking agents and/or antacids has been advocated as effective prophylaxis against and treatment for "stress ulcer," based on the logical but infrequently tested assumption that the severity of the disease is critically determined by the concentration of intraluminal acid. The present study investigated this assumption in a model which employed topical acid, topical bile acid and mucosal ischemia to induce ulcerogenesis. With vascularized, chambered ex vivo wedges of canine proximal gastric wall, groups of animals were studied during three sequential periods using topical test solutions (TS) containing either 0 mM, 100 mM or 160 mM HCI. During period 1, mucosae were exposed to TS alone; during period 2, either to TS containing 1 mM sodium taurocholate (TC) or to TS and concomitant vasopressin infusion (VP); and during period 3, to TS + TC + VP. Parameters evaluated included net H(+) flux ( big up tri, openH(+)), aminopyrine clearance (AC), a measure of mucosal blood flow, net TC flux ( big up tri, openTC) and the lesion index, graded 0-5. The data indicate that in nonischemic mucosa exposed to constant [TC], AC was significantly increased, big up tri, openH(+) ("back-diffusion") increased as a linear function of [H(+)] and no lesions were observed. Under the same circumstances in ischemic mucosa, big up tri, openH(+) increased as linear function of [H(+)]. As a consequence, lesion severity was also a linear function of [H(+)]. big up tri, openTC was enhanced at low pH but bore no relation to the degree of mucosal damage induced. Assuming applicability of the model, these studies provide support for the use of H(2) receptor blocking agents and/or antacids to prevent or ameliorate "stress ulcer" disease.     

清胰汤对大鼠急性胰腺炎肺损伤中水通道蛋白-1(AQP-1)表达的影响

目的:探讨清胰汤对大鼠急性胰腺炎肺损伤时水通道蛋白-1(AQP-1)表达的影响。方法:将Wistar大鼠分为假手术组(SHAM)、肺损伤组(ALI)、地塞米松组(DEX)与清胰汤组(QYT)。采用逆行胰胆管注射去氧胆酸诱发大鼠急性胰腺炎肺损伤模型,SHAM组仅翻动胰腺,DEX组于造模后立即于股静脉注射地塞米松,QYT组于造模后立即予清胰汤灌胃治疗。各组于造模后8h取血及肺组织。检测血淀粉酶、血气、肺干/湿比值和肺组织病理切片,放免法测血清TNF-α水平,RT-PCR检测肺组织AQP-1 mRNA的表达,免疫组化法检测肺组织AQP-1的表达。结果:胰腺炎ALI组血清淀粉酶、TNF-α明显升高,DEX组与QYT组则明显下降。ALI组AQP-1mRNA和AQP-1的蛋白表达显著下调,DEX组与QYT组较肺损伤组呈显著上调。DEX组与QYT组低氧血症、肺干/湿比值、肺组织病理损害程度较ALI组明显减轻。AQP-1mRNA和AQP-1的蛋白表达与TNF-α的水平呈负相关性。结论:清胰汤通过抑制TNF-α的释放,上调水通道蛋白-1表达,从而减轻急性胰腺炎的肺损伤。     

The Pharmacodynamic Effect of a Remifentanil Bolus on Ventilatory Control

Background: In doses typically administered during conscious sedation, remifentanil may be associated with ventilatory depression. However, the time course of ventilatory depression after an initial dose of remifentanil has not been determined previously.

Methods: In eight healthy volunteers, the authors determined the time course of the ventilatory response to carbon dioxide using the dual isohypercapnic technique. Subjects breathed via mask from a to-and-fro circuit with variable carbon dioxide absorption, allowing the authors to maintain end-tidal pressure of carbon dioxide (PETCO2) at approximately 46 or 56 mmHg (alternate subjects). After 6 min of equilibration, subjects received 0.5 [mu]g/kg remifentanil over 5 s, and minute ventilation ([latin capital V with dot above]E) was recorded during the next 20 min. Two hours later, the study was repeated using the other carbon dioxide tension (56 or 46 mmHg). The [latin capital V with dot above]E data were used to construct two-point carbon dioxide response curves at 30-s intervals after remifentanil administration. Using published pharmacokinetic values for remifentanil and the method of collapsing hysteresis loops, the authors estimated the effect-site equilibration rate constant (keo), the effect-site concentration producing 50% respiratory depression (EC50), and the shape parameter of the concentration-response curve ([gamma]).

Results: The slope of the carbon dioxide response decreased from 0.99 [95% confidence limits 0.72 to 1.26] to a nadir of 0.27 l [middle dot] min-1 [middle dot] mmHg-1 [-0.12 to 0.66] 2 min after remifentanil (P < 0.001); within 5 min, it recovered to approximately 0.6l [middle dot] min-1 [middle dot] mmHg-1, and within 15 min of injection, slope returned to baseline. The computed ventilation at PET = 50 mmHg ([latin capital V with dot above]E50) decreased from 12.9 [9.8 to 15.9] to 6.1 l/min [4.8 to 7.4] 2.5 min after remifentanil injection (P < 0.001). This was caused primarily by a decrease in tidal volume rather than in respiratory rate. Estimated pharmacodynamic parameters based on computed mean values of [latin capital V with dot above]E50 included keo = 0.24 min-1 (T1/2 = 2.9 min), EC50 = 1.12 ng/ml, and [gamma] = 1.74.     

Effects of Pain and Audiovisual Stimulation on the Opioid-induced Depression of the Hypoxic Ventilatory Response

Background: Normoxic and hypoxic ventilation are influenced by chemoreceptor and nonchemoreceptor drives. Although inhalational anesthetics blunt hypoxic ventilation, this effect is reversed by audiovisual stimulation but not by pain. Opioids reduce both normoxic and hypoxic ventilation, but their interaction with pain and audiovisual stimulation has not been fully reported.

Methods: Isocapnic, acute hypoxic ventilatory responses (AHRs) were measured in 11 volunteers. AHR and normoxic ventilation were measured under the following conditions: (1) eyes closed, no audio stimulation (low wakefulness); (2) low wakefulness conditions plus painful thermal stimulation; and (3) playing a computer game (high wakefulness), each with and without remifentanil infusion.

Results: The average (+/- sd) remifentanil dose was 0.035 +/- 0.012 [mu]g [middle dot] kg-1 [middle dot] min-1. Both normoxic and hypoxic ventilation were significantly reduced by the remifentanil infusion under all three conditions. The AHR values under low wakefulness conditions were 0.33 +/- 0.19 and 0.89 +/- 0.49 l [middle dot] min-1 [middle dot] sat-1 with and without remifentanil, respectively (P < 0.05). High wakefulness significantly increased AHR with and without remifentanil, whereas low wakefulness with pain did not. However, high wakefulness with remifentanil did not increase the AHR back to what was observed during low wakefulness without remifentanil.     

Tourniquet Constriction Exacerbates Hyperalgesia-related Pain Induced by Intradermal Capsaicin Injection

Background: When capsaicin is injected intradermally, hyperalgesia develops around the injection site. The authors observed that volunteers report painful sensations in the skin remote from the injection site during tourniquet constriction of the affected extremity.

Methods: Each volunteer received an intradermal injection of capsaicin on the volar forearm, followed by intermittent tourniquet constriction of the extremity. In some participants, the tourniquet position was rotated between different sites on the upper extremities. Laser Doppler measurements were made in the skin to measure capillary blood flow during pain magnification.

Results: Hyperalgesia developed in the volunteers who were tested after the capsaicin injection. Blood flow increased three times in the dermal capillaries remote from the injection site after capsaicin injection. The tourniquet-induced pain reached peak intensity soon after tourniquet inflation. Tourniquet constriction of the arm on the affected side reliably induced painful exacerbation in each person tested. The quality of the sensation was described as burning and extended across the arm in most volunteers. Only when pinprick hyperalgesia was detectable did the volunteers experience the diffuse, immediate pain sensation. The pain initiated by the tourniquet constriction likely is related to changes in skin capillary blood flow.     

Cutaneous versus Muscular Perception of Electrically Evoked Tetanic Pain

This work was supported in part by Laval University (sabbatical leave of Dr. A.Y. Bélanger), the School of Kinesiology at Simon Fraser University, and Medtronic of Canada Inc. There is much speculation in athletic, physical therapy, and sports medicine circles about the relative cutaneous (superficial) vs. muscular (deep) perception of pain felt during maximum electrically evoked tetanic muscle contraction. To date, very few studies have addressed the basic question of whether pain perception during electrical stimulation is more superficial (cutaneous) or deep in muscular tissue. The purpose of this study was to determine, in a group of 10 healthy male subjects, the effect of a complete sensory nerve block at the thigh on the qualities (intensity, sensory, affective) of pain (elicited by electrically induced tetanic muscle contraction) as measured by the Short-Form McGill Pain Questionnaire felt during high amplitude, 50-Hz electrical stimulation (ES) of the vastus lateralis muscle. The findings from this study provide clear evidence that a healthy individual's tolerance level to pain induced during electrically evoked maximum tetanic muscle contraction depends as much on deep muscle stimulation as it does on cutaneous or superficial stimulation. Indeed, the results show a statistically significant decrease of approximately 50% in all three qualities of pain (intensity, sensory, and affective) following the elimination of cutaneous pain pathways via the nerve blocking procedure (p < 0.05). Until it is demonstrated that the same results hold for patients who often experience pain prior to ES treatments, any clinical implications would seem to be premature. For now, clinicians must be aware that muscle, as much as skin, may limit one's ability to tolerate high amplitude ES treatments. Further research is needed on the cutaneous vs. muscular perception of electrically evoked pain in healthy and diseased populations as well as on the issue of subject and patient experience vs. nonexperience with ES. J Orthop Sports Phys Ther 1992;16(4):162-168.     

基质金属蛋白酶对狼疮性肾炎Fas介导凋亡的影响

目的 :通过检测 30例活动期狼疮性肾炎 (LN)患者肾小球中PCNA、Fas、P2 7、MMP - 2、MMP - 3蛋白的表达 ,以探讨基质金属蛋白酶对狼疮性肾炎肾小球系膜细胞凋亡的影响。方法 :30例患者全部行肾活检 ,分别进行常规病理检查 ,并通过连续切片和免疫组化SP法 ,测定PCNA、Fas、MMP - 2、MMP - 3在肾小球中的表达。结果 :30例患者 ,LNⅠ～Ⅱ型 10例 ,LNⅢ～Ⅳ型 2 0例 ,2组病例肾小球中MMP - 3表达无统计学差异 ,Fas、MMP - 2表达P <0 .0 5 ,PCNA表达P <0 .0 1。所有病例 ,肾小球中PCNA/P2 7比值 >1。结论 :活动期狼疮性肾炎肾小球中系膜细胞处于促凋亡状态 ,Fas介导的凋亡过程受到抑制 ,MMPs可在受体水平调节FasL抑制凋亡 ,也通过MMPs直接蛋白水解酶的作用 ,诱导细胞外基质积聚成分的改变 ,而存活信号的改变 ,会影响细胞凋亡。