Medullary and spinal cord projections from cardiovascular responsive sites in the rostral ventromedial medulla

The rostral ventromedial medulla (RVMM) is a sympathoexcitatory area. However, little is known about its efferent projections. In this study, biotinylated dextran amine (BDA) or Phaseolus vulgaris leucoagglutinin (PHA-L) were used to investigate the medullary and spinal cord projections from pressor sites in RVMM. Initially, RVMM was systematically explored in urethane-anesthetized rats using microinjection of L-glutamate for sites that elicited increases in arterial pressure. A pressor area was identified that included the rostral magnocellular reticular and rostral lateral paragigantocellular reticular nuclei. In the second series of experiments, BDA or PHA-L was iontophoretically injected into RVMM pressor sites. Anterograde labeling was observed throughout the brainstem and spinal cord, bilaterally, but with an ipsilateral predominance. Dense labeling was observed within the nucleus of the solitary tract (NTS); the greatest density of labeling was observed in the caudal dorsolateral, medial, and ventrolateral subnuclei. Additionally, light to moderately dense labeling was found within the nucleus substantia gelatinosus and commissural nucleus. In the nucleus ambiguus/ventrolateral medullary (Amb/VLM) region, the density of labeling was greatest in caudal regions. Within Amb, most of the labeling was localized to its external formation. Anterograde labeling was also found throughout the spinal cord. In the thoracolumbar segments, dense axonal labeling was observed within the dorsolateral funiculus. These labeled axons innervated the intermediolateral nucleus and the central autonomic area. Taken together, these data suggest that RVMM neurons elicit increases in sympathetic activity by likely providing a direct excitatory input to spinal sympathetic preganglionic neurons, and by a direct inhibitory input to medullary cardioinhibitory and depressor areas.     

Differential development of 5-HT receptor and the serotonin transporter binding in the human infant medulla

Tissue receptor autoradiography with 3H-lysergic acid diethylamide (3H-LSD), 3H-8-hydroxy-2-[di-N-propylamine] tetralin (3H-8-OH-DPAT), and 125I-RTI-55 was used to map the distribution and developmental profile of 5-HT(1A-1D) and 5-HT2 receptors, 5-HT1A receptors, and the serotonin (5-HT) transporter (SERT), respectively, to nuclei with cardiorespiratory function in the human medulla from midgestation to maturity. The distribution pattern of the 5-HT markers was heterogeneous, with variable densities of binding of each observed both in nuclei with and without 5-HT cell bodies. The highest density of binding for each marker was observed in the raphé nuclei, the site of the highest density of 5-HT cell bodies. A significant reduction in 5-HT receptor binding measured with 3H-LSD was observed between midgestation and infancy, and between infancy and maturity in multiple nuclei, but no changes were observed across infancy. A significant increase in 5-HT1A receptor binding density was observed across infancy in the hypoglossal nucleus (regression slope coefficient = 0.008 +/- 0.002, P = 0.02), and a marginally significant increase was observed in the raphé obscurus (regression slope coefficient = 0.061 +/- 0.026 [mean +/- SEM], P = 0.05). No significant age-related changes in SERT binding were observed at any time. With the exception of the hypoglossal nucleus, where 5-HT1A receptor binding increases while SERT binding remains stable, the medullary 5-HT markers analyzed in the study are essentially "in place" at birth. This study provides important baseline data that serve as a foundation for future work in pediatric 5-HT brainstem disorders, including sudden infant death syndrome.     

Comparison of fentanyl-bupivacaine or midazolam-bupivacaine mixtures with plain bupivacaine for caudal anaesthesia in children

BACKGROUND: The aim of this study was to evaluate the intensity and effectiveness of 0.75 ml.kg-1 bupivacaine 0.25% with the addition of fentanyl or midazolam for caudal block in children undergoing inguinal herniorrhaphy. METHODS: Seventy-five children were allocated randomly to three groups to receive a caudal block with either 0.25% bupivacaine with fentanyl 1 microg.kg(-1) (group BF) or with midazolam 50 microg.kg(-1) (group BM) or bupivacaine alone (group B) after induction of anaesthesia. Haemodynamic parameters, degree of pain, additional analgesic requirements and side-effects were evaluated. RESULTS: The mean systolic arterial pressure at 10, 20, 30 min after caudal block was higher in group B compared with groups BF and BM. Mean intraoperative heart rate was lower in group BF than the other groups. Adequate analgesia was obtained in all patients (100%) in group BF, 23 patients (92%) in group BM and 21 patients (84%) in group B (P > 0.05). The time to recovery to an Aldrete score of 10 was significantly shorter in group B than group BM (P < 0.05). Although not significant, it was also shorter in group B than group BF. There was no difference in additional analgesic requirements between the groups in the first 24 h. Sedation score was higher in the midazolam group at 60 and 90 min postoperatively than the other groups. CONCLUSIONS: Caudal block with 0.75 ml.kg(-1) 0.25% bupivacaine and 50 microg.kg(-1) midazolam or 1 microg.kg(-1) fentanyl provides no further analgesic advantages to bupivacaine alone when administered immediately after induction of anaesthesia in children undergoing unilateral inguinal herniorrhaphy.     

Nonopioid additives to local anaesthetics for caudal blockade in children: a systematic review

BACKGROUND: Caudal epidural injection with local anaesthetics is a popular regional technique used in infants and children. A disadvantage of caudal blockade is the relatively short duration of postoperative analgesia. Opioids have traditionally been added to increase the duration of analgesia but have been associated with unacceptable side-effects. A number of nonopioid additives have been suggested to increase the duration of analgesia. METHODS: A systematic review was conducted to identify randomized control trials comparing the use of local anaesthetic to local anaesthetic with nonopioid additives for caudal blockade in children. The increase in duration of analgesia and side-effects were compared. RESULTS: The addition of clonidine to the local anaesthetic solution produces an increase in the duration of analgesia following caudal blockade in children (pooled weighted mean difference of 145 min with 95% confidence interval of 132-157 min). Side-effects include sedation and the potential for neonatal respiratory depression. Ketamine and midazolam further increase the duration of analgesia, however, the potential for neurotoxicity remains a concern. CONCLUSION: The evidence examined shows an increased duration of analgesia with clonidine, ketamine and midazolam. However, we are not convinced that the routine use of these adjuvants in the setting of elective outpatient surgery shows improved patient outcome. It is unclear if the potential for neurotoxicity is outweighed by clinical benefits. Further testing, including large clinical trials, is required before recommending routine use of nonopioid additives for caudal blockade in children.     

A randomized trial of caudal block with bupivacaine 4 mg x kg-1 (1.8 ml x kg-1) plus morphine (150 microg x kg-1) vs general anaesthesia with fentanyl for cardiac surgery

BACKGROUND: Regional anaesthesia has been used effectively in paediatric patients undergoing cardiac surgery and is thought to be safe. METHODS: Thirty patients ASA physical status II-III undergoing scheduled palliative or corrective cardiac surgery, receiving premedication with midazolam and anaesthetic induction with sevoflurane, fentanyl and pancuronium were randomly allocated to two groups. In group 1, patients received bupivacaine 0.22% 4 mg.kg-1 (1.8 ml.kg-1) and morphine 150 microg x kg-1 by the caudal route. After a 20-min period for the block to take effect, sevoflurane 0.5-1.0% and fentanyl 5 microg x kg-1 were administered for maintenance of anaesthesia. In group 2, the anaesthetic technique was the same as in group 1, without a caudal block and fentanyl 25 microg x kg-1 was administered at the moment of surgical incision. RESULTS: Cardiovascular and haemodynamic responses of patients receiving caudal block showed minor variations during the 20-min period between caudal and general anaesthesia. Fentanyl requirements during surgery were lower (P = 0.001) in patients with caudal block than patients with general anaesthesia. Extubation time was shorter (P = 0.034) in the caudal group. Two patients in the general anaesthesia group and one in the caudal group died because of postoperative complications. CONCLUSIONS: Caudal block with bupivacaine 0.22% 4 mg.kg-1 (1.8 ml.kg-1) and morphine 150 microg x kg-1 was safe and effective for paediatric patients undergoing cardiac surgery. However, patients might have a better outcome with a reduction of morphine dosage and administration of a muscle relaxant of shorter duration of action than pancuronium.     

Motor cortical control of cardiovascular bulbar neurones projecting to spinal autonomic areas

There is evidence that the motor cortex is involved in cardiovascular adjustments associated with somatic motor activity, as it has functional connections with the ventrolateral medulla, a brainstem region critically involved in the control of blood pressure and the regulation of plasma catecholamine levels. The ventrolateral medulla sends projections to the spinal intermediolateral nucleus, where preganglionic neurones controlling heart and blood vessels (T2 segment) and adrenal medulla (T8 segment) are found. The aim of the present study was to determine whether electrical stimulation of the rat motor cortex induces cardiovascular responses and Fos expression in ventrolateral medulla neurones projecting to the T2 and T8 segments. After a set of experiments designed to record cardiovascular parameters (blood pressure and plasma catecholamine levels), injections of retrograde tracer (Fluorogold) were performed in the intermediolateral nucleus of two groups of rats, at the T2 or at the T8 segmental levels. Five days later, the motor cortex was stimulated in order to induce Fos expression in the ventrolateral medulla. Stimulation of the motor cortex induced: (1). hypotension and a significant decrease in plasma noradrenaline levels, and (2). a significant increase in the number of the double-labelled neurones in the rostral ventrolateral medulla projecting to T2. These data demonstrate that cardiovascular adjustments, preparatory to, or concomitant with, motor activity may be initiated in the motor cortex and transmitted to cardiac and vasomotor spinal preganglionic neurones, via the ventrolateral medulla.     

Differential regulation of brown adipose and splanchnic sympathetic outflows in rat: roles of raphe and rostral ventrolateral medulla neurons

1. The medullary premotor neurons determining the sympathetic outflow regulating cardiac function and vasoconstriction are located in the rostral ventrolateral medulla (RVLM). The present study sought evidence for an alternative location for the sympathetic premotor neurons determining the sympathetic nerve activity (SNA) controlling brown adipose tissue (BAT) metabolism and thermogenesis. 2. The tonic discharge on sympathetic nerves is determined by the inputs to functionally specific sympathetic preganglionic neurons from supraspinal populations of premotor neurons. Under normothermic conditions, BAT SNA was nearly silent, while splanchnic (SPL) SNA, controlling mesenteric vasoconstriction, exhibited sustained large-amplitude bursts. 3. The rostral raphe pallidus (RPa) contains potential sympathetic premotor neurons that project to the region of sympathetic preganglionic neurons in the thoracic spinal cord. Disinhibition of neurons in RPa elicited a dramatic increase in BAT SNA, with only a small rise in SPL SNA. 4. Splanchnic SNA was strongly influenced by the baroreceptor reflex, as indicated by a high coherence with the arterial pressure wave, a significant amplitude modulation over the time-course of the cardiac cycle and a marked inhibition of SPL SNA during a sustained increase in arterial pressure. When activated, the bursts in BAT SNA exhibited no correlation with arterial pressure and were not affected by increases in arterial pressure. 5. Because these characteristics and reflex responses in sympathetic outflow have been shown to arise from the on-going or altered discharge of sympathetic premotor neurons, the marked differences between SPL and BAT SNA provide strong evidence supporting the hypothesis that vasoconstriction and thermogenesis (metabolism) are controlled by distinct populations of sympathetic premotor neurons, the former in the RVLM and the latter, potentially, in the RPa.     

Evaluation of caudal anaesthesia performed in conscious ex-premature infants for inguinal herniotomies

Ex-premature infants, before 45 weeks postconceptional age, are at high-risk of apnoea after surgery. General anaesthesia increases the risk of apnoea. We evaluated the tolerance and the efficiency of caudal anaesthesia performed in 25 consecutive conscious ex-premature infants for inguinal herniotomies. N2O/O2 and EMLA cream are used to facilitate caudal puncture. Anaesthesia procedure, patient comfort and complications following the 24 postoperative hours were studied. We report good anaesthesia conditions without compromising the baby's comfort and few perioperative complications. Only two infants with a prior history of apnoea or bronchopulmonary dysplasia had apnoea during and after surgery. A total spinal anaesthesia was the major complication in one infant and prolonged surgery requiring general anaesthesia was the main limitation of this technique in another child. The principal advantage of the procedure is to facilitate and simplify the postoperative management of the babies. The anaesthetic technique does not alter surgical conditions. Caudal epidural anaesthesia performed in awake high-risk preterm infants is beneficial for these infants but requires experienced operators.     

A comparison of single dose caudal tramadol, tramadol plus bupivacaine and bupivacaine administration for postoperative analgesia in children

BACKGROUND: Our aim was to compare the effect of single dose caudal tramadol, tramadol plus bupivacaine and bupivacaine on the management of postoperative pain in children. METHODS: Sixty-three children in ASA groups I-II, between the ages of 1 and 5 were evaluated for postoperative pain randomly divided into three groups as follows: In group T, only tramadol was given caudally; in group TB, tramadol-bupivacaine was given caudally; in group B, bupivacaine was given alone. Pain was evaluated by using the paediatric objective pain scale (POPS). Sedation was evaluated with a 5-point test. There were no differences with age, weight, haemodynamic and respiratory parameters between groups. RESULTS: For 24 h postoperatively, the POPS value showed no statistically significant difference among groups (P > 0.05). Postoperative analgesia was maintained for 24 h. Nausea and vomiting was found to be higher in the tramadol group than in the bupivacaine group and tramadol-bupivacaine group (P < 0.001 and P < 0.01, respectively). CONCLUSION: Tramadol used caudally is as effective as bupivacaine in the management of postoperative pain in children and the addition of tramadol to bupivacaine, when both drugs were administered caudally, did not prolong the duration of action of bupivacaine and is a safe agent in children.     

Prefrontal,accumbal [shell] and ventral striatal mechanisms in jaw movements and non-cyclase-coupled dopamine D1-like receptors

The effect on jaw movements of intracerebral injections of the dopamine D1-like receptor agents SK&F 83959 (3-methyl-6-chloro-7,8-dihydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), SK&F 38393 ([R]-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and of injections of the dopamine D2-like receptor agonist quinpirole into the ventrolateral striatum, accumbens shell or prefrontal cortex were studied. SK&F 38393 and SK&F 83959 injected into the ventrolateral striatum synergised with i.v. quinpirole; in the shell of accumbens, SK&F 38393 evidenced weaker synergism with quinpirole, while SK&F 83959 did not synergise with it; neither agent synergised with quinpirole in the prefrontal cortex. Co-injection of SCH 23390 or SK&F 83959 into the prefrontal cortex antagonised jaw movements induced by injection of SK&F 83959 into the ventrolateral striatum in combination with i.v. quinpirole. Injection of SK&F 83959 + quinpirole into the ventrolateral striatum, but not into the accumbens shell, resulted in synergism. These findings indicate a primary, but not exclusive, role for ventral striatal, non-cyclase-coupled dopamine D1-like receptors in the induction of jaw movements. These processes appear to require tonic activity of prefrontal cyclase-linked dopamine D1A [and/or D1B] receptors.