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Clonidine has comparable effects on spontaneous sympathetic activity and afferent A delta and C-fiber-mediated somatosympathetic reflexes in dogs.

BACKGROUND: Clonidine, an alpha 2-adrenergic agonist, has been studied as an adjunct or alternative to spinal opioids in the management of moderate to severe pain. This study examined the relative effects of clonidine on efferent spontaneous sympathetic activity and afferent A delta and C fiber-mediated somatosympathetic responses. METHODS: Spontaneous and evoked sympathetic activity in renal sympathetic nerves, mediated by A delta and C fibers by means of supramaximal electrical stimulation of the radial and tibial nerves, were observed in anesthetized dogs. Incremental doses of clonidine were administered intrathecally or intravenously in each of five preparations followed by intravenous naloxone 2 mg and yohimbine 5 mg. RESULTS: Both spontaneous sympathetic outflow and afferent A delta- and C fiber-mediated somatosympathetic responses evoked by tibial nerve stimulation were depressed in a similar dose dependent manner by clonidine administered intrathecally or intravenously in a dose ratio of approximately 1:4. Intrathecal clonidine inhibited and eliminated both local spontaneous sympathetic outflow and tibial nerve evoked sympathetic responses but had no significant depressant effect on the radial nerve evoked sympathetic reflexes. When administered intravenously clonidine had a similar depressant effect on both radial and tibial nerve elicited reflexes and spontaneous sympathetic activity. CONCLUSIONS: Clonidine, administered intrathecally or intravenously, has a similar depressant effect on both spontaneous sympathetic outflow and afferent A delta- and C fiber-mediated somatosympathetic reflexes. When administered intrathecally it has little effect on reflexes evoked via the descending pathway by radial nerve stimulation.

Animals↗

Epidural sufentanil for postoperative patient-controlled analgesia (PCA) with or without background infusion: a double-blind comparison.

To evaluate the usefulness of a concurrent infusion in patient-controlled epidural analgesia (PCEA), 40 patients scheduled for elective cesarean section under a combined spinal-epidural technique were assigned randomly in a double-blind fashion to receive sufentanil by PCEA with a concomitant infusion of either sufentanil or saline. The sufentanil 24-h consumption was significantly (P < 0.001) higher in those patients receiving the opioid-containing infusion (212.7 +/- 9.5 vs 128.4 +/- 10.8 micrograms, SEM). The number of additional demands and the quality of sleep did not differ between the two groups. The degree of sedation was significantly less pronounced in patients treated with incremental sufentanil doses only. The visual analog scale (VAS) pain scores at rest were identical in both groups except at 6 h (2.5 +/- 0.4 vs 3.7 +/- 0.3, in favor of the patients treated with the sufentanil background infusion). We conclude that, except for a lower pain score during the initial hours, a background infusion in PCEA with sufentanil does not offer major advantages in terms of sleep quality or sufentanil consumption. Side effects may be more pronounced owing to increased drug administration.

Adult↗

Intraosseous infusions: effects on the immature physis--an experimental model in rabbits.

Intraosseous infusions are becoming more popular in critical care and emergency room settings in pediatric patients. Spinal needles are introduced in metaphyseal bone to establish intravenous (i.v.) access when standard i.v. routes are not accessible. An experimental rabbit model was constructed to simulate intraosseous infusion in human infants to determine effects on the physis and growth rate of the infused bone. Twenty immature rabbits were infused with saline, bicarbonate, or dopamine solutions. Rabbits were killed and tibias harvested at 24 h and 3 weeks, and gross and histologic sections were examined. No growth disturbance occurred in any of the infused tibias. Gross and microscopic changes were confined to metaphyseal bone and had completely resolved after 3 weeks. There was no evidence of physeal injury.

Animals↗

Evolving spinal analgesia practice in palliative care.

Intraspinal analgesia can be helpful in some patients with intractable pain. Over 15 years palliative care professionals evolved their spinals policy through a repeated series of evaluations, discussions and literature reviews. One hundred intraspinal lines were then reviewed. Notable changes in policy were the switch from epidurals to intrathecals, and the insertion of lines during working hours rather than as emergencies. Our efficacy, and frequency of adverse effects, is equal or better to published studies. Key issues in reducing adverse effects were the improved care of the spinal line exit site, a change from bolus administration to continuous infusions, and modifying line insertion techniques. Current policy is to use continuous infusions of diamorphine and bupivacaine in a 1:5 ratio through externalized intrathecal lines. The lines are effective in approximately two thirds of patients and can be kept in place for up to 18 months. The policy continues to be updated and common documentation is now in place.

Adult↗

Alfentanil as an adjuvant to epidural bupivacaine in the management of postoperative pain after laparotomies: lack of evidence of spinal action.

UNLABELLED: In this double-blind study, we compared the efficacy of epidural versus i.v. administration of alfentanil in combination with small-dose bupivacaine for postoperative pain relief. Thirty-two patients were randomly allocated to one of two study groups. Patients from both groups received an epidural loading dose of 60 mg of bupivacaine (12 mL of 0.5%). Subsequently, patients in the epidural (EPI) group received an infusion (8 mL/h) of 0.125% bupivacaine (10 mg/h) plus alfentanil (0.36 mg/h) and an i.v. infusion (8 mL/h) of NaCl 0.9%. Patients in the i.v. group received an epidural infusion (8 mL/h) of 0.125% bupivacaine (10 mg/h) and an i.v. infusion (8 mL/h) of alfentanil (0.36 mg/h). Infusions were maintained for 24 h. These dose regimens were such that equivalent subanalgesic plasma concentrations of alfentanil were obtained. Patient-controlled analgesia with morphine was available to both groups. Time to onset of postoperative pain and morphine consumption were used as variables to compare the two regimens. Measured plasma concentrations of alfentanil during the postoperative observation period were similar (< 20 ng/mL) in both groups. Median times to onset of postoperative pain (EPI 600 min, i.v. 360 min) and total morphine consumption (EPI 11 mg, i.v. 10 mg) did not differ between the groups (P > 0.2). We conclude that, in combination with epidural bupivacaine 0.125%, an i.v. infusion of alfentanil is equally effective as an epidural infusion of alfentanil if the plasma concentrations are the same. The study did not demonstrate a spinal mechanism of action for alfentanil. IMPLICATIONS: This randomized, double-blind study showed that, when combined with small-dose bupivacaine (0.125%), epidurally administered alfentanil is not more effective than i.v. administered alfentanil for postoperative pain management when the regimens are such that equivalent subanalgesic plasma alfentanil concentrations are obtained. A spinal mechanism of action for alfentanil could therefore not be demonstrated.

Adult↗

Anesthetic management of a labouring parturient with urticaria pigmentosa.

PURPOSE: To report the anesthetic management of labour pain and Cesarean section in a patient with urticaria pigmentosa at risk for systemic mastocytosis. CLINICAL: A 37-yr-old patient with a history of urticaria pigmentosa and an allergic reaction to a local anesthetic agent was seen in consultation at 36 weeks gestation. She previously tested negative for an allergy test to lidocaine. Recommendations to avoid systemic mastocytosis included: avoidance of histamine-releasing drugs, using lidocaine for labour epidural, and regional anesthesia in case of a Cesarean section. The patient presented at term in labour. Intravenous fentanyl was used for early labour, followed by a combined spinal-epidural. The spinal contained lidocaine and fentanyl, but because of pruritus, the epidural infusion contained lidocaine only. Most likely because of tachyphylaxis to lidocaine, an epidural bolus of lidocaine with epinephrine failed to provide adequate anesthesia for a Cesarean section. The block was supplemented with nitrous oxide by mask, with fentanyl postdelivery. Postoperative pain control was managed with an epidural infusion of lidocaine and fentanyl for three days. The patient was discharged without complications four days postsurgery. CONCLUSION: Proper allergy testing prior to pregnancy is important to help the management of labour pain and anesthesia for Cesarean section in a patient at risk for systemic mastocytosis.

Adult↗

Hierarchy of blood pressure control mechanisms after spinal sympathectomy.

We have investigated the relative importance of angiotensin and vasopressin in the regulation of arterial pressure following permanent interruption of supraspinal sympathetic influences. To accomplish this aim, the spinal cord of 12 dogs was transected just above the intervertebral foramen of C-6; several days later, we gave first a potent blocker of the vasculotropic actions of vasopressin and 40 min later captopril. The same experiment was performed in other dogs with the drug order reversed. Mean arterial pressure and heart rate were recorded continuously and blood samples were taken to measure plasma renin activity and plasma catecholamines. All studies were carried out at three levels of hydration: normal, after 36 h water deprivation and following an overnight infusion of 0.9% saline. Conscious dogs with complete surgical sympathectomy by spinal cord section had normal mean arterial pressure, heart rate and plasma renin activity but undetectable levels of catecholamines. Captopril produced significant falls in mean arterial pressure that were greatest in water deprivation and least in volume loading, whether the drug was given before or after treatment with the vasopressin antagonist. On the other hand, the vasopressin antagonist modified mean arterial pressure only in the water deprived state. In spinal dogs the renin angiotensin system assumes a primary role in maintaining normal mean arterial pressure at various extremes of body fluid volumes. Vasopressin plays a role only after removal of the two dominant systems.

Animals↗

Protection against ischemic spinal cord injury: one-shot perfusion cooling and percutaneous topical cooling.

PURPOSE: We investigated the protective effect of two methods of hypothermia against ischemic spinal cord injury: one-shot perfusion cooling and percutaneous topical cooling. METHODS: Twenty-five rabbits were divided into five equal groups. The abdominal aorta was isolated proximally by a vascular clamp and distally by an inflated balloon catheter for 60 minutes. Group I served as control. In groups II (2.5 ml/min) and III (5.0 ml/min), hypothermic lactated Ringer's solution was infused for 3 minutes from the distal end of the catheter. Ice blocks were placed behind the backs of rabbits 30 minutes before ischemia in group IV. Group V underwent the procedures combined with those in groups II and IV (infusion of hypothermic solution plus placement of ice blocks). Another 15 rabbits underwent laminectomy at the L2 or L3 level. A temperature probe was inserted into the spinal cord to monitor cord temperature continuously during the procedures in all five groups (three rabbits per group). RESULTS: Neurologic status on the second postoperative day in groups IV and V was significantly superior to that in group I (p < 0.01), but the neurologic status of groups II and III did not differ significantly from the neurologic status of group I. The spinal cord temperature in groups II and III dropped rapidly with the infusion, but it rose again quickly. In contrast, the spinal cord was kept sufficiently hypothermic during ischemia in groups IV and V. CONCLUSIONS: We concluded that the percutaneous cooling method can keep the spinal cord sufficiently hypothermic during ischemia to lead to a significantly superior neurologic outcome.

Analysis of Variance↗

Effects of sodium pentobarbital anesthesia and neurotrophic factor on the maintenance of acetylcholinesterase and butyrylcholinesterase in the preganglionically denervated superior cervical ganglion of the cat.

In continuation of a previously reported study, the superior cervical ganglia of cats were preganglionically denervated bilaterally under sodium pentobarbital anesthesia. The following day cats were reanesthetized and infused via the common carotid artery with an aqueous extract of cat brain, spinal cord, and sciatic nerves for periods of 24, 12, 6, and 3 hr, without ligation of the external carotid or lingual arteries as was done previously. Values for acetylcholinesterase and butyrylcholinesterase of superior cervical ganglia at 48 hr postdenervation were all considerably above those of denervated controls. However, values for cats infused with 0.9% NaCl solution and for noninfused cats in which sodium pentobarbital anesthesia was maintained during the 24- to 48-hr postdenervation period were similarly elevated, to approximately twice the values in denervated controls. Ligation of the external carotid and lingual arteries at 24 hr postdenervation was found to oppose the preservation of acetylcholinesterase and butyrylcholinesterase contents of the ganglia induced by barbiturate anesthesia. When arterially ligated cats were infused with extract for periods of 12, 6, or 3 hr, beginning 24 hr postdenervation, acetylcholinesterase contents of superior cervical ganglia were elevated significantly above those of reanesthetized, arterially ligated controls after 12 and 6 hr but not after 3 hr of infusion, at 48 hr postdenervation.

Acetylcholinesterase↗

[Intrathecal therapy for bladder hyperreflexia].

Intrathecal clonidine was tested for the control of bladder hyperreflexia resistant to pararsympathicolytic drugs in spinal cord injured patients. Urodynamic parameters were significantly improved after acute bolus of intrathecal low doses of clonidine. Unfortunately, the chronic intrathecal infusion of clonidine induced cardiovascular side-effects. Intrathecal baclofen did not modified significantly neurogenic bladder dysfunction from spinal lesion. But intrathecal baclofen modified penile erection quality and impaired the ejaculation reflex induced by penile vibratory stimulation in the same population.

Adrenergic alpha-Agonists↗

[Maternal-fetal cardiovascular effect of spinal anesthesia].

Despite of a chronic volume overload the left ventricle function of pregnant women is preserved by both afterload reduction (arterial vasodilatation) and a facilitation of heart filling through an increase in peripheral venous tone. Fetal oxygenation results from an equilibrium between placental and umbilical blood flows. During regional anaesthesia the sympathetic blockade leads to a peripheral vasodilatation (mainly in the capacitive territories) which is the cause of arterial hypotension through a decrease in cardiac output. Placental flow may therefore be altered by the reduced perfusion pressure and/or a reflex or pharmacological vasoconstriction. Hypotension is an infrequent event during labor epidural analgesia. However the incidence of hypotension is higher during regional anaesthesia for cesarean section, up to 35% following intrathecal injection of local anaesthetic. Prevention of hypotension requires (i) release of aortocaval compression by gravid uterus (ii) volume preloading (15 min i.v. infusion of crystalloid, 20 ml.kg-1 with ephedrine, 15 mg if spinal anaesthesia is chosen), and (iii) limitation of plain local anaesthetic dosage (epinephrine, 1:200,000 with fentanyl, sufentanil or clonidine). Hypotension must be promptly reversed to avoid placental and umbilical flow alteration. Titrated doses of vasopressors are useful, either ephedrine or phenylephrine. Finally regional anaesthesia is beneficial for the mother and the fetus through a reduction in plasma catecholamines, provided that arterial pressure remains unchanged. Thus during pregnancy-induced hypertension (PIH) epidural analgesia leads to an improvement of the reduced placental blood flow. However PIH renders the women susceptible to sympathetic blockade and the fetus easily vulnerable to an additional stress factor like acute decrease in placental flow due to hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity.

Tolerance to the analgesic effects of an opioid occurs after its chronic administration, a pharmacological phenomenon that has been associated with the development of abnormal pain sensitivity such as hyperalgesia. In the present study, we examined the role of spinal glutamate transporters (GTs) in the development of both morphine tolerance and associated thermal hyperalgesia. Chronic morphine administered through either intrathecal boluses or continuous infusion induced a dose-dependent downregulation of GTs (EAAC1 and GLAST) in the rat's superficial spinal cord dorsal horn. This GT downregulation was mediated through opioid receptors because naloxone blocked such GT changes. Morphine-induced GT downregulation reduced the ability to maintain in vivo glutamate homeostasis at the spinal level, because the hyperalgesic response to exogenous glutamate was enhanced, including an increased magnitude and a prolonged time course, in morphine-treated rats with reduced spinal GTs. Moreover, the downregulation of spinal GTs exhibited a temporal correlation with the development of morphine tolerance and thermal hyperalgesia. Consistently, the GT inhibitor l-trans-pyrrolidine-2-4-dicarboxylate (PDC) potentiated, whereas the positive GT regulator riluzole reduced, the development of both morphine tolerance and thermal hyperalgesia. The effects from regulating spinal GT activity by PDC were at least in part mediated through activation of the NMDA receptor (NMDAR), because the noncompetitive NMDAR antagonist MK-801 blocked both morphine tolerance and thermal hyperalgesia that were potentiated by PDC. These results indicate that spinal GTs may contribute to the neural mechanisms of morphine tolerance and associated abnormal pain sensitivity by means of regulating regional glutamate homeostasis.

Amino Acid Transport System X-AG↗

The effect of glucose infusion on survival after acute mesenteric ischemia/reperfusion.

Perfusion of ischemic tissue with glucose has been shown to be deleterious to heart, spinal cord, and kidney. Observations that glucagon improves survival after acute mesenteric ischemia, however, suggest that hyperglycemia may not be deleterious during bowel ischemia. This experiment examined the effect of glucose infusion on survival in an established rat model of acute mesenteric ischemia. The superior (cranial) mesenteric artery (SMA) was occluded for 85 min in 36 anesthetized Sprague-Dawley rats. Animals were randomized to receive 5% glucose in normal saline (n = 15; 16.5 mL/kg.min iv), normal saline alone (n = 13; 16.4 mL/kg.min iv), or no intravenous fluid (n = 8). Ninety-minute intravenous infusions were initiated 10 min after SMA occlusion. Survival to 48 h was 47% in glucose-saline-treated rats, 31% in saline-only-treated rats, and 12.5% in control rats. These results demonstrate no deleterious effect of glucose infusion on mortality after acute mesenteric ischemia in this model.

Animals↗

[Identification of the peridural space with the infusion method in relation to the incidence of inadvertent puncture of the dura].

In 868 cases the identification of the epidural space was performed by plugging a running infusion drip. After accurate identification of the epidural space the patient received either 0.5% or 0.75% bupivacaine without adrenalin for operations on the lower extremities, at the perineum and for lower and upper abdominal surgery. Analgesia was adequate . The only disadvantage of this method as with the "loss of resistance" technique consists in the fact that, if inadvertent dural puncture occurs, it is impossible to recognize the difference between the epidural and spinal space, because the saline solution might reach in any case into the spinal space. In the last 512 cases in which we used the "infusion" technique we observed only 5 patients with an inadvertent dural puncture. Thus the frequency of this complication was below 1%. This is - even according to the latest publications - quite a satisfactory result. An unidentified accidental dural puncture and associated complication did not occur.

Adolescent↗

Repetitive low dose oral methotrexate and intravenous mercaptopurine treatment for patients with lower risk B-lineage acute lymphoblastic leukemia. A Pediatric Oncology Group pilot study.

BACKGROUND: This trial evaluated the toxicity and preliminary efficacy of a repeated oral low dose (LD) methotrexate schedule with intravenous mercaptopurine infusions as intensification therapy for children with lower risk B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS. From December 1986 to January 1991, 96 children with newly diagnosed, lower risk ALL were enrolled. Vincristine, L-asparaginase, and prednisone were used for remission induction. Age-based methotrexate was administered intrathecally (IT) for central nervous system (CNS) prophylaxis. An outpatient-based intensification treatment included LD methotrexate 30 mg/M2 every 6 hours for 5 doses, followed by intravenous mercaptopurine 1000 mg/M2 for 6 hours every 2 weeks for 12 courses. Leucovorin rescue was administered 48 hours after methotrexate treatment was begun. Maintenance therapy included standard daily oral mercaptopurine, weekly intramuscular methotrexate, and IT methotrexate every 12 weeks, for 2 years. RESULTS: All patients had disease remission. Thirty-two patients relapsed; there were 17 isolated bone marrow relapses, 10 isolated CNS relapses, 2 isolated testicular relapses, 1 marrow plus CNS relapse, 1 marrow plus testicular relapse, and 1 CNS plus testicular relapse. Event free survival (EFS) at 4 years was 66% (standard error, 7%) by Kaplan-Meier analysis. Complications associated with LD methotrexate/mercaptopurine courses were few and resulted in hospital readmissions in 2.4% of courses. Two patients were unable to comply with the oral LD methotrexate schedule and received intravenous methotrexate. Three patients were unable to complete scheduled maintenance because of hepatic or hematopoietic dysfunction. CONCLUSIONS: Low dose methotrexate/mercaptopurine can be administered safely on an outpatient basis to children with lower risk B-lineage ALL. However, there was a higher than expected incidence of bone marrow and CNS relapse. The reasons for this outcome were not completely clear but raise the possibility that LD methotrexate therapy may be less effective in preventing relapse than are higher dose, parenteral methotrexate regimens.

Administration, Oral↗

Effect of probenecid on ventricular cerebrospinal fluid methotrexate pharmacokinetics after intralumbar administration in nonhuman primates.

PURPOSE: Intrathecal methotrexate (MTX) achieves high concentrations in the cerebrospinal fluid (CSF) following intralumbar administration. However, peak ventricular CSF MTX concentrations are highly variable and are < 10% of those achieved with intraventricular dosing. The objectives of this study were to evaluate the effect of intralumbar and intravenous probenecid on ventricular CSF MTX concentrations after intralumbar administration of MTX, and to compare the pharmacokinetics of MTX after intralumbar and intraventricular administration. METHODS: Nonhuman primates (Macaca mulatta) with permanently implanted catheters in the lateral and fourth ventricles received 0.5 mg intraventricular (lateral ventricle) MTX, or 0.5 mg intralumbar MTX with and without intralumbar or intravenous probenecid. Animals were kept prone for 1 h after MTX administration, and ventricular CSF was sampled up to 48 h from a fourth ventricular Ommaya reservoir. MTX concentrations were measured using the dihydrofolate reductase enzyme inhibition assay. Area under the ventricular CSF MTX concentration-time curve (AUC) was used as a measure of MTX exposure. RESULTS: Peak ventricular CSF MTX concentrations and AUCs were highly variable after intralumbar MTX administration. Ventricular CSF MTX AUCs increased by a mean of 3.2-fold after the addition of intralumbar probenecid. Intravenous administration of probenecid did not result in an increase in ventricular CSF MTX AUCs. Asymptomatic pleocytosis was observed in all animals after intralumbar probenecid administration. Ventricular CSF MTX concentrations and AUCs were less variable after intraventricular administration of MTX. CONCLUSION: The administration of intralumbar but not intravenous probenecid increases the ventricular CSF MTX exposure after intralumbar MTX administration.

Animals↗