Astrid Chiari

Analgesic and Hemodynamic Effects of Intrathecal Clonidine as the Sole Analgesic Agent during First Stage of Labor A Dose-Response Study

BACKGROUNDnIntrathecal clonidine produces dose-dependent postoperative analgesia and enhances labor analgesia from intrathecal sufentanil. The authors evaluated the dose-response potency of intrathecally administered clonidine by itself during first stage of labor with respect to analgesia and maternal and fetal side effects.nnnMETHODSnThirty-six parturients requesting labor analgesia were included in this prospective, randomized, double-blind study. Parturients with < 6 cm cervical dilatation received either 50, 100, or 200 microg intrathecal clonidine. The authors recorded visual analog pain score (VAPS), maternal blood pressure and heart rate, ephedrine requirements, and sedation at regular intervals and fetal heart rate tracings continuously. Duration of analgesia was defined as time from intrathecal clonidine administration until request for additional analgesia.nnnRESULTSnClonidine produced a reduction in VAPS with all three doses. The duration of analgesia was significantly longer in patients receiving 200 microg (median, 143; range, 75-210 min) and 100 microg (median, 118; range, 60-180 min) than 50 microg (median, 45; range, 25-150 min), and VAPS was lower in the 200-microg than in the 50-microg group. In the 200-microg group, hypotension required significantly more often treatment with ephedrine than in the other groups. No adverse events or fetal heart rate abnormalities occurred.nnnCONCLUSIONSnFifty to 200 microg intrathecal clonidine produces dose-dependent analgesia during first stage of labor. Although duration and quality of analgesia were more pronounced with 100 and 200 microg than with 50 microg, the high incidence of hypotension requires caution with the use of 200 microg for labor analgesia.

Intrathecal adenosine: interactions with spinal clonidine and neostigmine in rat models of acute nociception and postoperative hypersensitivity.

BACKGROUNDnSpinal adenosine receptor agonists exert antinociception in animal models of acute and chronic pain, but adenosine itself has not been examined. The authors tested the antinociceptive and antihypersensitivity interactions of intrathecal adenosine and its interactions with intrathecal clonidine and neostigmine in rat models of acute thermal nociception and postoperative hypersensitivity.nnnMETHODSnRats were prepared with lumbar intrathecal catheters. Responses to acute noxious stimulation were evaluated by latency to paw withdrawal from a radiant heat source focused on the hind paw. Postoperative hypersensitivity was measured after an incision in the rat hind paw by application of von Frey filaments to the heel adjacent to the wound. An isobolographic design was used to distinguish between additive and synergistic drug interactions.nnnRESULTSnSpinal administration of clonidine and neostigmine, but not adenosine, produced dose-dependent antinociception to noxious thermal stimulation. Addition of adenosine enhanced the antinociceptive effect of clonidine but not neostigmine. In contrast, each of these three agents alone reversed postoperative hypersensitivity. Pretreatment with the alpha-adrenergic antagonist phentolamine completely reversed adenosines antihypersensitivity action. Adenosine interacted synergistically with neostigmine and additively with clonidine in reducing postoperative hypersensitivity.nnnCONCLUSIONSnThese data indicate that intrathecal adenosine by itself has no antinociceptive properties to acute noxious thermal stimulation in rats, but enhances clonidines antinociception. In contrast, intrathecal adenosine is active against postoperative hypersensitivity by an adrenergic mechanism. Different interactions between adenosine, clonidine, and neostigmine in acute nociception and postoperative hypersensitivity models are consistent with altered central processing of sensory information after peripheral injury.

Resistive-Polymer Versus Forced-Air Warming: Comparable Efficacy in Orthopedic Patients

BACKGROUND: Several adverse consequences are caused by mild perioperative hypothermia. Maintaining normothermia with patient warming systems, today mostly with forced air (FA), has thus become a standard procedure during anesthesia. Recently, a polymer-based resistive patient warming system was developed. We compared the efficacy of a widely distributed FA system with the resistive-polymer (RP) system in a prospective, randomized clinical study. METHODS: Eighty patients scheduled for orthopedic surgery were randomized to either FA warming (Bair Hugger warming blanket #522 and blower #750, Arizant, Eden Prairie, MN) or RP warming (Hot Dog Multi-Position Blanket and Hot Dog controller, Augustine Biomedical, Eden Prairie, MN). Core temperature, skin temperature (head, upper and lower arm, chest, abdomen, back, thigh, and calf), and room temperature (general and near the patient) were recorded continuously. RESULTS: After an initial decrease, core temperatures increased in both groups at comparable rates (FA: 0.33°C/h ± 0.34°C/h; RP: 0.29°C/h ± 0.35°C/h; P = 0.6). There was also no difference in the course of mean skin and mean body (core) temperature. FA warming increased the environment close to the patient (the workplace of anesthesiologists and surgeons) more than RP warming (24.4°C ± 5.2°C for FA vs 22.6 °C ± 1.9°C for RP at 30 minutes; PAUC <0.01). CONCLUSION: RP warming performed as efficiently as FA warming in patients undergoing orthopedic surgery.

Morphine-induced spinal cholinergic activation: in vivo imaging with positron emission tomography.

&NA; Positron emission tomography (PET) imaging of spinal cord in monkeys with a cholinergic tracer demonstrates increased spinal cholinergic activity in response to an analgesic dose of morphine, and this PET result correlates with measurement of acetylcholine spillover into spinal cord extracellular space induced by morphine, as measured by microdialysis. Previous studies in rats, mice, and sheep demonstrate activation of spinal cholinergic neurons by systemic opioid administration, and participation of this cholinergic activity in opioid‐induced analgesia. Testing the relevance of this observation in humans has been limited to measurement of acetylcholine spillover into lumbar cerebrospinal fluid. The purpose of this study was to apply a recently developed method to image spinal cholinergic terminals non‐invasively via PET and to test the hypothesis that the tracer utilized would reflect changes in local cholinergic activity. Following Animal Care and Use Committee approval, seven adult male rhesus monkeys were anesthetized on three separate occasions. On two of the occasions PET scans were performed using [18F] (+)‐4‐fluorobenzyltrozamicol ([18F]FBT), which selectively binds to the vesicular acetylcholine (ACh) transporter in the presynaptic cholinergic terminals. PET scans were preceded by injection of either saline or an analgesic dose of IV morphine (10 mg/kg). On the third occasion, microdialysis catheters were inserted in the spinal cord dorsal horn and acetylcholine concentrations in dialysates determined before and after IV morphine injection. Morphine increased cholinergic activity in the spinal cord, as determined by blood flow corrected distribution volume of [18F]FBT in the cervical cord compared to the cerebellum. Morphine also increased acetylcholine concentrations in microdialysates from the cervical cord dorsal horn. The one animal which did not show increased spinal cholinergic activity by PET from this dose of morphine also did not show increased acetylcholine from this morphine dose in the microdialysis experiment. These data confirm the ability to use PET to image spinal cholinergic terminals in the monkey spinal cord and suggest that acute changes in cholinergic activity can be imaged with this non‐invasive technique. Following preclinical screening, PET scanning with [18F]FBT may be useful to investigate mechanisms of analgesic action in normal humans and in those with pain.

Spinal anesthesia: Mechanisms, agents, methods, and safety

Abstract Recent advances in our understanding of neurotransmitter and receptor pharmacology in the spinal cord have provided new directions for the development of novel analgesic compounds. Although IT opioids provide effective analgesia for most patients, limited duration of action, tolerance, and side effects represent a limitation. Nonopioids such as alpha-2 adrenergic and cholinergic agonists may be more suited as adjuvants rather than sole analgesic agents. N-methyl-D-aspartate antagonists could be used to treat centrally mediated hyperalgesia, although ketamine might have a neurotoxic potential. The role of other agents in pain management, such as somatostatin analogs, calcitonin, and calcium channel blockers, which all act by different pathways, remains to be determined. It is essential that appropriate animal neurotoxicity studies followed by controlled clinical trials are performed before widespread spinal administration of new drugs. The combined use of low doses of drugs with separate but synergistic mechanisms of analgesia can reduce the required dose as well as unwanted side effects.

Formation of 6-nitro-norepinephrine from nitric oxide and norepinephrine in the spinal cord and its role in spinal analgesia

Spinally released norepinephrine is thought to produce analgesia in part by stimulating alpha(2)-adrenergic receptors, which in turn leads to nitric oxide synthesis. Also, nitric oxide is known to react with norepinephrine in vivo in the brain to form 6-nitro-norepinephrine, which inhibits neuronal norepinephrine reuptake. In the present study, we tested the hypothesis that formation of 6-nitro-norepinephrine occurs in the spinal cord and that intrathecal administration of 6-nitro-norepinephrine produces analgesia by stimulating norepinephrine release. 6-Nitro-norepinephrine was present in rat spinal cord tissue and microdialysates of the dorsal horn and intrathecal space. Intrathecal norepinephrine injection increased 6-nitro-norepinephrine. 6-Nitro-norepinephrine also stimulated norepinephrine release in dorsal spinal cord in vitro. Intrathecal injection of 6-nitro-norepinephrine produced antinociception and interacted additively with norepinephrine for antinociception. Spinal noradrenergic nerve destruction increased antinociception from intrathecally injected norepinephrine, but decreased antinociception from 6-nitro-norepinephrine. These results suggest a functional interaction between spinal nitric oxide and norepinephrine in analgesia, mediated in part by formation of 6-nitro-norepinephrine. Stimulation of auto-inhibitory alpha(2)-adrenergic receptors at noradrenergic synapses decreases norepinephrine release. Paradoxically, alpha(2)-adrenergic agonist injection increases and alpha(2)-adrenergic antagonist injection decreases norepinephrine release in the spinal cord. 6-Nitro-norepinephrine may be an important regulator of spinal norepinephrine release and could explain the positive feedback on norepinephrine release after activation of spinal alpha(2)-adrenergic receptors.

Intrathecal Clonidine for Postoperative Analgesia in Elderly Patients: The Influence of Baricity on Hemodynamic and Analgesic Effects

Intrathecal (IT) clonidine is an effective analgesic, but it also produces hemodynamic depression and sedation which are likely to be related to IT clonidine’s cephalad spread within the cerebrospinal fluid. We hypothesized that IT clonidine’s side effects could be reduced without compromising the duration and quality of analgesia by injecting clonidine IT in a hyperbaric solution and elevating the patient’s trunk. We prospectively randomized 30 elderly patients to receive IT150μ gofeitherisobaric(ISO) or hyperbaric (HYPER) clonidine for postoperative analgesia after surgical repair of traumatichip fracture.Hemodynamics, IV fluid administration, visual analog pain scores, sedation scores, and clonidine cerebrospinal fluid levels were recorded at fixed intervals. Patients in the ISO group required significantly more crystalloid fluid administration (median, 2500 mL; range, 1500–3000 mL) than those in the HYPER group (median, 1500; range, 500–3000 mL) to maintain adequate arterial blood pressure (P < 0.01). Also, the decrease in heart rate was significantly more pronounced in the ISO than in the HYPER group (P < 0.01). The duration of analgesia was significantly larger in the ISO (median, 400 min; range, 115–400 min) than in the HYPER (median, 265 min; range, 205–400 min) group (P < 0.05). Sedation scores did not differ between groups. We conclude that increasing the baricity of IT clonidine solution in the conditions of our experiment reduces hemodynamic side effects but also analgesia from IT administered clonidine.

In vivo imaging of the spinal cord cholinergic system with PET.

PURPOSEnOur goal was to demonstrate the feasibility of an in vivo noninvasive method for imaging spinal cord cholinergic terminals using (+)-4-[18F]fluorobenzyltrozamicol ([18F]FBT) and PET.nnnMETHODnIn vitro and in vivo experiments in rats were conducted to demonstrate the specific binding characteristics, localization, and time course of [3H]FBT binding in the spinal cord. PET imaging was then performed on seven rhesus monkeys.nnnRESULTSnThe rat studies demonstrate high specific binding in the spinal cord with a distribution coinciding with the known distribution of cholinergic terminals. In vivo tracer concentrations in the spinal cord and basal ganglia were of the same magnitude. With use of [18F]FBT and PET in the rhesus monkey, the spinal cord was clearly visualized, with tracer concentration in the spinal cord being approximately one-fourth of that seen in the basal ganglia.nnnCONCLUSIONnThis work demonstrates the feasibility of imaging cholinergic terminals in vivo in the spinal cord using [18F]FBT and PET.