Brain penetration of local anaesthetics in the rat: Implications for experimental neuroscience (original) (raw)
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Neuroprotective Effects of Intravenous Anesthetics: A New Critical Perspective
Current Pharmaceutical Design, 2014
Perioperative cerebral damage can result in various clinical sequela ranging from minor neurocognitive deficits to catastrophic neurological morbidity with permanent impairment and death. The goal of neuroprotective treatments is to reduce the clinical effects of cerebral damage through two major mechanisms: increased tolerance of neurological tissue to ischemia and changes in intra-cellular responses to energy supply deprivation. In this review, we present the clinical evidence of intravenous anesthetics on perioperative neuroprotection, and we also provide a critical perspective for future studies. The neuroprotective efficacy of the intravenous anesthetics thiopental, propofol and etomidate is unproven. Lidocaine may be neuroprotective in non-diabetic patients who have undergoing cardiac surgery with cardiopulmonary bypass (CBP) or with a 48hour infusion, but conclusive data are lacking. There are several limitations of clinical studies that evaluate postoperative cognitive dysfunction (POCD), including difficulties in identifying patients at high-risk and a lack of consensus for defining the "gold-standard" neuropsychological testing. Although a battery of neurocognitive tests remains the primary method for diagnosing POCD, recent evidence suggests a role for novel biomarkers and neuroimaging to preemptively identify patients more susceptible to cognitive decline in the perioperative period. Current evidence, while inconclusive, suggest that intravenous anesthetics may be both neuroprotective and neurotoxic in the perioperative period. A critical analysis on data recorded from randomized control trials (RCTs) is essential in identifying patients who may benefit or be harmed by a particular anesthetic. RCTs will also contribute to defining methodologies for future studies on the neuroprotective effects of intravenous anesthetics.
Anaesthetic mechanisms: update on the challenge of unravelling the mystery of anaesthesia
European Journal of Anaesthesiology, 2009
General anaesthesia is administered each day to thousands of patients worldwide. Although more than 160 years have passed since the first successful public demonstration of anaesthesia, a detailed understanding of the anaesthetic mechanism of action of these drugs is still lacking. An important early observation was the Meyer-Overton correlation, which associated the potency of an anaesthetic with its lipid solubility. This work focuses attention on the lipid membrane as a likely location for anaesthetic action. With the advent of cellular electrophysiology and molecular biology techniques, tools to dissect the components of the lipid membrane have led, in recent years, to the widespread acceptance of proteins, namely receptors and ion channels, as more likely targets for the anaesthetic effect. Yet these accumulated data have not produced a comprehensive explanation for how these drugs produce CNS depression. In this review, we follow the story of anaesthesia mechanisms research from its historical roots to the intensely neurophysiologic inquiries regarding it today. We will also describe recent findings that identify specific neuroanatomical locations mediating the actions of some anaesthetic agents. Keywords anaesthetic mechanisms; anaesthetic targets; anaesthetics; ion channels; receptors Introduction`H ealthy discontent is a prelude to progress'-Mahatma Gandhi Over time humankind has employed an array of natural medicines and physical methods to alleviate pain and suffering. Ancient Indian and Chinese texts record the beneficial analgesic effects of cannabis and henbane. In Egypt around 3000 B.C., the opium poppy, hellebore, beer, and the legendary mandrake were used for similar purposes [1]. Other approaches to deal with surgical trauma and pain relied on physical methods such as cold, nerve compression, carotid artery occlusion or infliction of a cerebral concussion. The effectiveness of these historical agents is unknown but allude to an ever present need.
Acta Anaesthesiologica Scandinavica, 1985
Subarachnoid anesthesia with lidocaine, mepivacaine, or tetracaine with and without added epinephrine (1:100000) produced no demonstrable changes in average cerebral (CBF) or segmental spinal cord blood flow (SCBF) in 38 cats anesthetized with pentobarbital. Blood flow was measured by the injection of radioactive microspheres. Seven groups of cats received either lidocaine 15 mg, lidocainr 15 mg with epinephrine, mepivacaine 10 mg, mepivacaine 10 mg with epinephrine, tetracaine 5 mg, tetracaine 5 mg with epinephrine, or saline with epinephrine 1: 100 000. Mean arterial pressure (MAP) decreased significantly (PiO.05) in Groups I-VI. Added epinephrine had no effect on the decrease in MAP. Amplitude of the somatosensory cortical evoked response decreased significantly in Groups I-VI, but did not change from control in Group VII. No significant change in CBF or SCBF was demonstrated in any group at any time. Plasma lidocaine and mepivacaine levels were significantly less at 5 min after subarachnoid injection in the groups receiving epinephrine compared to those not receiving epinephrine (P< 0.05). The data appear to support the hypothesis of a vasoconstrictive reduction in systemic absorption of intrathecal local anesthetics, but suggest that significant segmental spinal cord ischemia does not occur. Maintenance of total flow in the face of a decrease in MAP suggests that autoregulation in brain and spinal cord may be maintained. Changes in regional SCBF or CBF may have been present but were not examined in this study. Further studies of brain and spinal cord blood flow dynamics, regional flow changes, and regulation of flow after intrathecal agents are necessary.
Local Anesthetic Neurotoxicity Does Not Result from Blockade of Voltage-Gated Sodium Channels
Anesthesia & Analgesia, 1995
To investigate whether local anesthetic neurotoxicity results from sodium channel blockade, we compared the effects of intrathecally administered lidocaine, bupivacaine, and tetrodotoxin (TTX), the latter a highly selective sodium channel blocker, on sensory function and spinal cord morphology in a rat model. First, to determine relative anesthetic potency, 25 rats implanted with intrathecal catheters were subjected to infusions of lidocaine (n = 8), bupivacaine (n = 81, or TTX (n = 9). The three drugs produced parallel dose-effect curves that differed significantly from one another: the EC,, values for lidocaine, bupivacaine, and TTX were 28.2 mM (0.66%), 6.6 mM (0.19%), and 462 nM, respectively. Twenty-five additional rats were then given intrathecal lidocaine (n = 8), bupivacaine (n = 8), or TTX (n = 9) at concentrations 10 times the calculated EC,, for sensory block. Lidocaine and bupivacaine induced persistent sensory impairment, whereas TTX did not. Finally, 28 rats were given either intrathecal bupivacaine (n = 10) or TTX (n = 9) at 10 times the EC,,, or normal saline (n = 9). Significant sensory impairment again occurred after infusion of bupivacaine, but not after infusion of TTX or saline. Neuropathologic evaluation revealed moderate to severe nerve root injury in bupivacaine-treated animals; histologic changes in TTX-and saline-treated animals were minimal, similar, and restricted to the area adjacent to the catheter. These results indicate that local anesthetic neurotoxicity does not result from blockade of the sodium channel, and suggest that development of a safer anesthetic is a realistic goal.
Anesthesia & Analgesia, 1983
Recent case reports describing prolonged neurologic deficit after accidental spinal anesthesia with large volumes of 2chloroprocaine have led to the suggestion that chloroprocaine may be more likely to cause such complications than other local anesthetics. We evaluated the neurologic effects of lumbar puncture alone and of large-volume subarachnoid administration of 2-chloroprocaine (370), bupivacaine (0.75%), lidocaine (2%), Elliott's solution B (which is similar to CSF), or the carrier solution of 2-chloroprocaine (Nesacaine) in 48 sheep and 8 monkeys. Cerebrospinal fluid of sheep was collected on days 7 and 7 for biochemical and biological analyses, and CSF pressures of monkeys were recorded before and after injection. Animals were obserzvd for tieurologic deficits for seven days. Twelve sheep were unable to stand. Monkeys, on the other hand, had no apparent neurologic deficits. Autopsies revealed that 5 of the 12 sheep had lumbar subpial demyelination with macrophage infiltration: two of the five had received lidocaine; two received 2-chloroprocaine; and one had only a lumbar puncture. Two other sheep also had subpial demyelination: one had receizied lidocaine and one received 2-chloroprocaine. Three of the eight monkeys had lumbar subpial demyelination with macrophage invasion; two had received bupiziacaine, and one received 2-chloroprocaine. No solution produced significant abnormalities in sheep CSF composition. We conclude that no local anesthetic or solution was more neurotoxic than another when injected in large volumes into the subarachnoid space of sheep or monkeys.
Journal of Perianesthesia Nursing, 2002
Nurses working in the PACU are occupationally exposed to volatile anesthetics that are exhaled by patients. Few studies have quantified this exposure using breath analysis or have characterized biological effects associated with this exposure. Isoflurane is a widely used anesthetic and is a strong respiratory depressant. Exposure to isoflurane has been shown to cause changes in breathing patterns at low doses. However, biological effects of isoflurane exposure have never been addressed in the occupational setting. This study investigates whether occupational exposure to anesthetic gases has a depressive effect on central neural control of breathing. In this study, concentrations of halogenated anesthetics were quantified in pre-and postshift breath samples of nurses working in the PACU on a Friday and the following Monday. After each breath sample was collected, an occlusion pressure measurement was taken as an indicator of central inspiratory drive. Cumulative nitrous oxide and halogenated anesthetics exposure was measured each day using personal sampling monitors placed close to the nurse's mouth. Exposure to nitrous oxide and isoflurane was significantly higher on Monday than on Friday (P Ͻ .001). Monday breath isoflurane concentrations (mean Ϯ SD) increased significantly from 43 Ϯ 30 parts per billion (ppb) in preshift breath samples to 124 Ϯ 57 ppb in postshift breath samples (P Ͻ .002). On Monday, there was a significant decrease in occlusion pressure from 1.2 Ϯ 0.37 cm H 2 O in preshift samples to 0.85 Ϯ 0.43 cm H 2 O in postshift samples (P ϭ .05).
Controversial Issues in Neuroanaesthesia
2012
1. Controversies related to use of drugs in neuroanaesthesia: Controversies regarding the provision of anaesthesia for intracranial neurosurgery remain, with no ideal technique identified Despite the theoretical benefits of intravenous agents, volatile agents remain popular. In a study comparing desflurane, isoflurane and sevoflurane in a porcine model of intracranial hypertension, at equipotent doses and normocapnia, cerebral blood flow (CBF) and intracranial pressure (ICP) were greatest with desflurane and least with sevoflurane The same authors also confirmed that sevoflurane also caused least vasodilation In two separate studies, isoflurane was seen to impair autoregulation, although reversible with hyperventilation, while autoregulation was virtually intact with sevoflurane 1 – 1.2 % at normocapnia Although large studies may be needed, sevoflurane appears to be the most suitable volatile agent for neuroanaesthesia practice.
Anesthetics and cerebral metabolism
Current Opinion in Anaesthesiology, 2004
Purpose of review This review focuses on the utilization of the effects of general anesthetics on cerebral metabolism as revealed by imaging for therapeutic and preventive purposes, for understanding mechanisms of anesthetic action, and for elucidating mechanisms of cerebral processing in humans. Recent findings General anesthetics suppress cerebral metabolism significantly. This effect has been used for neuroprotection during inadequate cerebral blood flow. With the advent of noninvasive imaging techniques, this suppression has also been used to image and map the sites of anesthetic action in the living human brain. Volatile agents, intravenous anesthetics, and analgesics have all begun to be explored using mostly positron emission tomography. The ability of anesthetics to change global baseline brain metabolism has created the opportunity to examine the relevance of global baseline (resting) brain activity in terms of region-specific cerebral processing. Summary Anesthetics experimentally appear to be useful for neuroprotection, at least during the early post-ischemic period. Identification of the cerebral sites of anesthetic action by in vivo human brain imaging provides new insights into the mechanism of action of these agents. Anesthetic-related manipulation of baseline brain metabolism demonstrates the significant contribution of this global activity to regional cerebral processing.