Continuous Systemic Administration Research Articles

Effect of Continuous Systemic Administration of Esmolol on Intraocular Pressure During Surgery in a Sustained Steep Trendelenburg Position.

To investigate the effects of continuous systemic administration of esmolol on intraocular pressure (IOP) during laparoscopic and robotic surgeries for recto-sigmoid cancer in a steep Trendelenburg position. A total of 50 patients undergoing laparoscopic surgery in a steep Trendelenburg position were included. Patients in the esmolol (E) group received a 0.25 mg/kg IV loading dose of esmolol before anesthesia, followed by an infusion of 15 μg/kg/min throughout the operation. Patients in the saline (S) group were infused with the same volume of normal saline. IOP and ocular perfusion pressure were measured 16 times: before anesthetic induction (T1), before administration of the study drug (T2), after administration of anesthetic induction agents (T3), after tracheal intubation (T4), 1, 3, 5, and 10 minutes after tracheal intubation (T5-T8), immediately after intraperitoneal CO2 insufflation (T9), immediately after the steep Trendelenburg position (T10), 1, 2, and 4 hours after the steep Trendelenburg position (T11-T13), just before the supine position (T14), and 10 and 30 minutes after the supine position (T15, T16). The IOP increased markedly after adopting the steep Trendelenburg position, reaching 28.8±4.4 mm Hg in group S. The IOP at T13 in group S was ∼5.7 mm Hg higher than in group E. The IOP at T13 was ∼10.6 mm Hg higher than in T1 in group S, but only ∼4.4 mm Hg higher than in group E. Continuous systemic administration of esmolol can alleviate the increase in IOP during a sustained steep Trendelenburg position without adverse cardiovascular effects.

Lidocaine overdose after continuous systemic administration for postoperative analgesia

SummaryWe report the case of a 77‐year‐old male who had elective duodenopancreatectomy surgery. As part of a multimodal analgesia strategy a continuous infusion of lidocaine was administered peri‐operatively. Surgery was uneventful. On admission to post‐operative Intensive Care Unit (ICU), the patient presented with progressive neurological and haemodynamic failure due to a lidocaine overdose made by an error in the continuous systemic administration. Once the diagnosis was established, an infusion of lipid emulsion resulted in almost immediate haemodynamic recovery; full neurological recovery was however delayed for some hours. Continuous intravenous infusions of lidocaine can lead to systemic toxicity, therefore training in lidocaine administration, diagnosis of toxicity and its management are essential for all staff involved in the care of these patients.

Lidocaine Attenuates the Development of Diabetic-Induced Tactile Allodynia by Inhibiting Microglial Activation

Lidocaine is used clinically for tactile allodynia associated with diabetes-induced neuropathy. Although the analgesic effect of lidocaine through suppression of microglial activation has been implicated in the development of injury-induced neuropathic pain, its mechanism of action in diabetes-induced tactile allodynia has not yet been completely elucidated. To evaluate the effects of lidocaine on microglial response in diabetic neuropathy, streptozotocin (STZ)-injected mice received a continuous infusion of lidocaine (vehicle, 2, or 10%) from day 14 to day 21 after STZ injection. On day 21, microglial accumulation and p38 mitogen-activated protein kinase activation in the dorsal horn were evaluated. In vitro, the effects of lidocaine on cell viability, chemotactic response to monocyte chemotactic protein-1, and induction of proinflammatory mediators were examined in interferon (IFN)-γ-stimulated primary microglial cells. Continuous systemic administration of lidocaine in the early progression of tactile allodynia produced long-lasting analgesic effects in STZ-treated mice. Lidocaine significantly reduced accumulation and p38 phosphorylation of microglial cells in the dorsal horn. In vitro, lidocaine down-regulated IFN-γ-induced gene induction of inducible oxide synthase and interleukin-1β. Pretreatment with lidocaine significantly reduced chemotactic response to monocyte chemotactic protein-1 of IFN-γ-activated microglial cells. Lidocaine alleviates STZ-induced tactile allodynia, possibly by modulating the p38 pathway in spinal microglial cells. Inhibiting microglial activation by lidocaine treatment early in the course of diabetes-induced neuropathy represents a potential therapeutic strategy for tactile allodynia.

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Cerebrovascular inflammation contributes to secondary brain injury following ischemia. Recent in vitro studies of cell migration and molecular guidance mechanisms have indicated that the Slit family of secreted proteins can exert repellant effects on leukocyte recruitment in response to chemoattractants. Utilizing intravital microscopy, we addressed the role of Slit in modulating leukocyte dynamics in the mouse cortical venular microcirculation in vivo following TNFα application or global cerebral ischemia. We also studied whether Slit affected neuronal survival in the mouse global ischemia model as well as in mixed neuronal–glial cultures subjected to oxygen–glucose deprivation. We found that systemically administered Slit significantly attenuated cerebral microvessel leukocyte–endothelial adherence occurring 4 h after TNFα and 24 h after global cerebral ischemia. Administration of RoboN, the soluble receptor for Slit, exacerbated the acute chemotactic response to TNFα. These findings are indicative of a tonic repellant effect of endogenous Slit in brain under acute proinflammatory conditions. Three days of continuous systemic administration of Slit following global ischemia significantly attenuated the delayed neuronal death of hippocampal CA1 pyramidal cells. Moreover, Slit abrogated neuronal death in mixed neuronal–glial cultures exposed to oxygen–glucose deprivation. The ability of Slit to reduce the recruitment of immune cells to ischemic brain and to provide cytoprotective effects suggests that this protein may serve as a novel anti-inflammatory and neuroprotective target for stroke therapy.

Tramadol relieves thermal hyperalgesia in rats with chronic constriction injury of the sciatic nerve.

The present study was designed to test whether tramadol is effective in the control of neuropathic pain in rats. Chronic constriction injury (CCI) of the sciatic nerve was induced over the left hind limb in male Sprague-Dawley rats. Identical surgery was performed on the opposite side except that the sciatic nerve was not ligated (sham surgery). Paw withdrawal latency (PWL) to heat was tested for each hind paw 1 day before surgery and on the 4th day after surgery to ensure the development of thermal hyperalgesia. In the acute treatment groups, saline or tramadol was administered subcutaneously at doses of 10, 20 or 30 mg/kg, and PWLs were measured 30, 60, 90, 120, 150 and 180 min after treatment. In the semi-chronic treatment groups, continuous systemic administration of tramadol 40 mg/kg/day or saline for 7 days was provided at a uniform rate via osmotic mini pumps. Tramadol reversed PWL in a dose-dependent manner in the acute treatment groups. PWLs were significantly reversed at 2 days after tramadol infusion, and this effect was sustained throughout the remainder of the treatment period in comparison with the saline group. Tramadol also resulted in a decreased sensitivity to thermal stimulus on the sham limb both in acute and semi-chronic administration. We conclude that both acute and semi-chronic tramadol treatment relieves thermal hyperalgesia effectively in rats with CCI of the sciatic nerve. This indicates that tramadol shows promise as a potential treatment for relief of neuropathic pain in humans.

Taurine amplifies renal kallikrein and prevents salt-induced hypertension in Dahl rats

To determine whether taurine reduces blood pressure by stimulating the renal kallikrein-kinin system. The effects of taurine on blood pressure, urinary kallikrein activity and renal kallikrein gene expression were investigated in Dahl salt-sensitive (Dahl-S) rats. The specificity of the action of taurine was verified by comparison with the action of beta-alanine, a carboxylic analogue of taurine. The effect of co-administration of the specific bradykinin B2 receptor antagonist Hoe 140 was also examined. Administration of taurine (3% in drinking water) for 4 weeks retarded the development of salt (4% sodium chloride diet)-induced hypertension. Systolic blood pressure at the end of the experiment was significantly higher in control rats than in taurine-treated rats. Urinary sodium excretion was not decreased by the reduction in blood pressure. The heart weight:body weight ratio was significantly lower, and urinary volume and kallikrein excretion were significantly higher, in taurine-treated rats. Renal kallikrein gene expression at weeks 1 and 4 was higher in taurine-treated rats. Systolic blood pressure 3 and 4 weeks after the administration of beta-alanine was slightly, but not significantly, lower than that of untreated rats on a high-salt diet, and was accompanied by a significantly lower body weight. Urinary kallikrein excretion decreased with a high-salt diet regardless of beta-alanine administration. Continuous systemic administration of Hoe 140 did not cause any significant alteration in blood pressure in Dahl-S rats that received taurine with a high-salt diet. Taurine also showed a renoprotective effect, as judged by a reduction in proteinuria. These results suggest that taurine is an effective antihypertensive agent for salt-induced hypertension. Although taurine activated renal kallikrein, further studies are required to confirm the participation of activated kallikrein in the antihypertensive, cardioprotective and renoprotective effects of taurine.

β-Adrenergic Receptor Blockade Suppresses Glial Scar Formation

Several laboratories have shown that isoproterenol induces or accelerates cell process formation in primary astrocyte cultures. These observations, together with the demonstration of β-adrenergic receptors in astrocytes isolated from adult rat brain, led us to test the hypothesis that β-antagonists prevent astrocyte hypertrophy in the injured spinal cord. Since blood-borne macrophages express β-adrenergic receptors and release cytokines acting on glial cells, we avoided physical trauma and induced glial scar formation indirectly by injecting the cytotoxic ligand Ricinus communis into the sciatic nerve. Seven days later sections of the lumbar spinal cord in regions of motor neuron degeneration were processed for glial fibrillary acidic protein (GFAP) immunocytochemistry. Astrocyte hypertrophy was evaluated by optical density measurements of immunolabeled GFAP. Seven days after ricin treatment there is a mean increase of GFAP in the ventral horn of 11.8 ± 4.4% (P < 0.0001) compared to the intact side. When l -propranolol is continuously infused from a subcutaneously implanted osmotic pump at a concentration calculated to produce a free plasma level of 4.4 nM, the GFAP increase is only 3.2 ± 3%, reflecting a 73% reduction in astrocyte hypertrophy (P < 0.001). Receptor autoradiography with the ligand [125I] iodocyanopindolol showed a 26% increase in β-adrenergic receptor density on the gliotic side. After propranolol treatment, there was only a 3.5% increase in ventral horn β-adrenergic receptor density in the region of the glial scar. In the dorsal horn laminae II and III the GFAP increase was similar to that in the ventral horn, but β-adrenergic receptor binding was markedly reduced, in contrast to the increase observed in the ventral horn. l-Propranolol treatment suppressed the dorsal horn GFAP increase and diminished the extent β-receptor loss. HPLC measurements in tissue punches taken from the normal and gliotic ventral horn showed no differences in norepinephrine content up to 5 days following ricin treatment. The continuous systemic administration of propranolol for 7 days from the time of injury greatly reduces astrocyte hypertrophy. The demonstration that β-adrenergic receptor blockade can reduce reactive gliosis in vivo encourages the further investigation of β-antagonists in the restoration of function following spinal cord injury.

Age‐Dependent Vulnerability of the Striatum to the Mitochondrial Toxin 3‐Nitropropionic Acid

The mechanisms of delayed onset and cell death in Huntington's disease (HD) are unknown. One possibility is that a genetic defect in energy metabolism may result in slow excitotoxic neuronal death. Therefore, we examined the effects of age on striatal lesions produced by local administration of the mitochondrial toxin 3-nitropropionic acid in rats. In vivo chemical shift magnetic resonance imaging showed marked increases in striatal lactate concentrations that significantly correlated with increasing age. Histologic and neurochemical studies showed a striking age dependence of the lesions, with 4- and 12-month-old animals being much more susceptible than 1-month-old animals. Continuous systemic administration of low doses of 3-nitropropionic acid for 1 month resulted in striatal lesions showing growth-related changes in dendrites of striatal spiny neurons using the Golgi technique. These results show that a known mitochondrial toxin can produce selective axon-sparing striatal lesions showing both the age dependence and striatal spiny neuron dendritic changes that characterize HD.

No effect of systemic administration of somatomedin C on bone repair in rats

The effect of somatomedin C on the bone repair process was studied in a rat femoral osteotomy. We used continuous systemic administration of human recombinant somatomedin C (110 micrograms/100 g per day). Radiographic evaluation after 4 weeks showed no effect of somatomedin C on the healing. There was no effect on mechanical strength, and no effect was found on callus vascularization or mineralization. The weight of the callus was slightly reduced in the somatomedin C treated rats. The results were not suggestive of any acceleration with systemic somatomedin C treatment in the early phase of cortical bone repair.

Activity of cholinesterase in the retina with different levels of physiological stimulation.

SummaryRats with an opaque lens over one eye for 15 days have a depressed cholinesterase activity in that retina. Cholinesterase activity returns to normal 4 days after the opaque lens is removed. An opaque lens decreases the rate of return of cholinesterase activity after diisopropyl fluorophosphate administration. Variation in light stimulation does not significantly alter the rate of return of cholinesterase activity. Despite its pupil‐enlarging effect, continuous systemic administration of atropine depresses the rate of return of cholinesterase activity in the light‐stimulated eyes of diisopropyl fluorophosphate‐treated rats. In these animals atropine also depresses the ratio of cholinesterase content of the visual cortex to whole brain.