Atul Humar, M.D., M.SC., F.R.C.P. (C)

• Associate Professor of Medicine
• Transplant Infectious Diseases
• University of Alberta
• Director
• Transplant Infectious Diseases
• University of Alberta Hospital
• Edmonton, Alberta, Canada

This effect is likely to be clinically inconsequential unless these muscle relaxants are administered in the large doses necessary to achieve endotracheal intubating conditions rapidly bacteria in water safe 50 mg minocin. Doses of metocurine infection 7 weeks postpartum cheap 50mg minocin overnight delivery, atracurium infection quizlet purchase minocin discount, and mivacurium should be limited to ranges not associated with hypotension treatment for fungal uti order minocin 50 mg amex. Rocuronium will probably be increasingly used for the induction of anesthesia bacteria no estomago 50mg minocin otc, as well as for intraoperative relaxation bacteria 33 000 feet buy minocin 50 mg otc. With sugammadex, even a profound neuromuscular blockade can be rapidly reversed (see Chapters 34 and 35). Their observations are very relevant because it is in precisely this population of patients that the issue of the use of succinylcholine arises most frequently. As with many anesthetics, the concern should not be whether it is used but how it is used. Table 17-3 provides nonquantitative information about the direction of the influences of common anesthetic drugs. All the information has been derived from animals,207-213 and these processes have not been examined in humans. Although probably of minimal relevance to clinical practice, a theoretic concern might be in the setting of a prolonged closed-cranium procedure in a patient with poor intracranial compliance. This pattern occurs with enflurane in the dog, which is perhaps another reason (in addition to the potential for epileptogenesis in the presence of cerebral injury and hypocapnia) for omission of enflurane in this circumstance. At higher doses, isoflurane (3%) significantly increases protein extravasation, not only in the thalamus but also in the cortex. In experimental models of brain injury, isoflurane has been reported to both exacerbate215 and ameliorate216 edema formation in the injured brain. In practice, it appears that spontaneous seizures during or after anesthesia have been extremely rare events. Nonetheless, in patients with processes that might predispose them to seizures, the use of potentially epileptogenic drugs should be avoided in situations during which reasonable alternatives are available. Volatile Anesthetics Enflurane is potentially epileptogenic in the clinical setting. Of particular relevance to neuroanesthesia is the observation that hypocapnia potentiates seizure-type discharges during enflurane anesthesia. Chapter 17: Cerebral Physiology and the Effects of Anesthetic Drugs 409 especially at high doses and with hypocapnia, should probably be avoided in patients predisposed to seizures or those with occlusive cerebrovascular disease. No permanent sequelae appeared to occur as a result of these events, and, in fact, this association is not a rigorously proven one. The clinical experience with isoflurane is extremely large, and unexplained seizurelike activity has been reported in only two patients. One occurrence was intraoperative,225 and the other incidence was immediately postoperative. Of note was the observation that paroxysmal activity was not restricted to the ictal focus and that the administration of sevoflurane did not provide any assistance in localizing the epileptogenic region of the brain. The preceding information notwithstanding, no convincing reports indicate epileptogenesis in subjects who are neurologically normal, and the use of etomidate need not be restricted on this basis. However, systematic studies in both humans243 and animals,244 although identifying the occurrence of occasional dystonic and choreiform movements, have failed to confirm propofol as a proconvulsant. In addition, propofol sedation has been widely used during awake resection of seizure foci and other intracranial lesions. Accordingly, this anesthetic has been used to activate seizure foci during cortical mapping. However, prolonged seizure Narcotics Seizures or limbic system hypermetabolism (or both) can be readily elicited in some animal species with narcotics. Tempelhoff and coauthors250 reported partial complex seizures on the induction of anesthesia with fentanyl in patients undergoing anterior temporal lobectomy. Eight of the nine patients displayed electrical seizure activity at a range of clinically relevant fentanyl doses (mean, 26 g/kg). Models of Cerebral Ischemia How different is complete cerebral ischemia, as occurs during cardiac arrest, and incomplete cerebral ischemia, as may occur during occlusion of a major cerebral vessel or severe hypotension Energy Failure and Excitotoxicity Energy failure is the central event that occurs during cerebral ischemia. Voltage-dependent Ca2+ channels are then activated, and Ca2+ gains entry into the cytosol. The brain is therefore extremely vulnerable in the event of interruption of substrate. Ionic influx is accompanied by an influx of water, and neuronal swelling rapidly occurs after membrane depolarization. The injury that is initiated by excessive mGluR activity is referred to as excitotoxicity. Ca2+ is a ubiquitous second messenger in cells and is a cofactor required for the activation of a number of enzyme systems. The rapid, uncontrolled increase in cytosolic Ca2+ levels initiates the activation of a number of cellular processes that contribute to injury. The latter, in combination with other free radicals generated in response to mitochondrial injury, can lead to lipid peroxidation and membrane injury. Prostaglandins and leukotrienes also evoke an inflammatory response and are powerful chemotactic drugs. Activation of platelets within cerebral microvessels, as well as an influx of white blood cells into damaged areas, aggravates the ischemic injury by occluding the vasculature. Excessive stimulation of ligand-gated channels and the simultaneous opening of voltage-dependent calcium (Ca2+) channels permit rapid entry of Ca2+ into neurons. Injury to the mitochondria leads to energy failure, generation of free radicals, and the release of cytochrome c (cyt c) from the mitochondria; the latter is one of the means by which neuronal apoptosis is initiated. Lactic acid is formed as a result of the anaerobic glycolysis that takes place after failure of the supply of oxygen. The associated decline in pH contributes to the deterioration of the intracellular environment. An increased preischemic serum glucose level may accelerate this process by providing additional substrate for anaerobic glycolysis. Collectively, the simultaneous and unregulated activation of a number of cellular pathways overwhelms the reparative and restorative processes within the neuron and ultimately leads to neuronal death. A characteristic of these necrotic neurons is the presence of acidophilic cytoplasm. Neuronal apoptosis, a form of cellular suicide, has also been demonstrated in a variety of models of cerebral ischemia. Apoptosis is characterized by chromatin condensation, involution of the cell membrane, swelling of mitochondria, and cellular shrinkage. In the later stages of apoptosis, neurons fragment into several apoptotic bodies, which are then cleared from the brain. Initiation of apoptosis by the release of cytochrome c from injured mitochondria has been studied the most. Cytochrome c is restricted from the cytoplasm by the outer mitochondrial membrane. Cytochrome c (cyt c), which is normally restricted to the space between the inner and outer mitochondrial membranes, is released in response to mitochondrial injury. The nature of neuronal death probably encompasses a spectrum in which some neurons undergo necrosis or apoptosis whereas others undergo cell death that has features of both necrosis and apoptosis. Timing of Neuronal Death the traditional concept of ischemic injury was that neuronal death was restricted to the time of ischemia and during the early reperfusion period. However, more recent data indicate that postischemic neuronal injury is a dynamic process during which neurons continue to die for a long period after the initiating ischemic insult. Excitotoxic (glutamate-mediated) injury results in neuronal death within the first few hours after the onset of ischemia. Brain tissue injury elicits an inflammatory responsean important process in the removal of injured tissue and in healing that leads to a substantial amount of collateral damage. Apoptotic neuronal death has been demonstrated to occur for many days after the initiating ischemic insult. It is now apparent that ischemic neuronal death is a dynamic process during which neurons continue to die for a long period. The extent of delayed neuronal death depends on the severity of the ischemic insult. With more moderate insults, neurons that survive the initial insult undergo delayed death. This ongoing neuronal loss contributes to the gradual expansion of cerebral infarction after focal ischemia. In experimental studies, evidence of cerebral inflammation, which can theoretically contribute to further injury, has been demonstrated even 6 to 8 months after the primary ischemia. The occurrence of delayed neuronal death has important implications for the evaluation of studies in which neuroprotective strategies are being investigated. A wide variety of interventions have shown neuroprotective efficacy in studies in which the extent of injury is evaluated within 3 to 4 days after ischemia. Recent data indicate that cerebral infarction undergoes gradual expansion and that a reduction in injury attributed to a particular therapeutic intervention is no longer apparent when the injury is evaluated after a long postischemic recovery period. Much of the literature on the pathophysiologic process of cerebral ischemia has primarily been focused on neuronal injury. However, recent work has highlighted the importance of the contribution of astrocytes, microglia, vascular cells. Hypotension developing after resuscitation from cardiac arrest may aggravate the microcirculatory and vasospastic processes occurring at this time and may increase brain damage. A late phase of intracranial hypertension may occur and is due to the development of extensive cerebral edema (probably both vasogenic and cytotoxic edema) associated with brain necrosis. Attempts to control this type of intracranial hypertension with osmotherapy usually fail. Both barbiturates and calcium channel blockers have been administered after cardiac arrest. This single study cannot serve as justification for the administration of nimodipine after cardiac arrest, especially in the face of the unequivocally negative results of the multicenter lidoflazine cardiac arrest study. Induced mild hypothermia is effective in reducing mortality and morbidity in patients who sustain a cardiac arrest that is followed by altered mental status with a Glasgow coma scale of 7 or less. The incidence of complications was similar to that in the control normothermic group. This important study is one of the first to demonstrate the feasibility and efficacy of induced hypothermia as a treatment to prevent injury from global ischemia. In neonates who sustained hypoxic-ischemic encephalopathy, induction of whole body hypothermia (33. Considerations Relevant to Focal (Incomplete) Ischemia Before discussing individual anesthetics, it should be noted that anesthesia, per se, is protective. For undefined reasons, reducing the level of systemic stress associated with a standardized experimental insult results in an improved outcome. Numerous demonstrations have revealed the protective efficacy of barbiturates in focal cerebral ischemia in animals,283-285 and a single demonstration confirmed the effectiveness in a human. Such regions are likely to be limited in size in the setting of focal ischemia, yet several of the animal investigations suggest a very substantial protective effect. Unrecognized cerebral hypothermia may well have been a factor in some of the cited investigations, and it is therefore possible that the protective efficacy of barbiturates may have been overestimated. Although more recent publications involving suitable temperature control methods do, in fact, indicate a protective effect of barbiturates,288,291,292 the magnitude of that effect was modest when compared with the results of earlier studies. Numerous investigations in animals and humans have failed to demonstrate any protective effect of barbiturates in the setting of global cerebral ischemia. However, data presented by Warner and colleagues288 demonstrated that the same protective benefit (expressed as a reduction of infarct volume) could be achieved with a third of the burst-suppression dose, which raises a clinically important issue. Recent data suggest that the neuroprotective efficacy of barbiturates is not similar. In a direct comparison of three clinically used barbiturates, methohexital and thiopental, but not pentobarbital, reduced injury in an animal model of focal ischemia. These data indicate that neuronal injury continues well into the postischemic recovery period and that the neuroprotective benefit that is evident shortly after ischemia may not persist for the long term. More recent data have shown that isoflurane treatment can improve neuronal survival when the severity of ischemia is limited and the restoration of blood flow after ischemia is complete. Sevoflurane reduces ischemic injury in animal models of focal300 and hemispheric ischemia301; its efficacy is not different from that of halothane. As such, it is logical to suspect that it might provide neuroprotection against excitotoxic injury. Moreover, the administration of xenon has been shown to have a preconditioning effect on the brain307; previous exposure reduces the vulnerability of the brain to ischemic injury. The specific use of xenon for the purpose of neuroprotection awaits results from outcome studies in humans. In experimental models of cerebral ischemia, the extent of neurologic injury in propofol-anesthetized animals was similar to that in halothane-anesthetized animals. In a more recent investigation, cerebral infarction was significantly reduced in propofol-anesthetized animals in comparison with awake animals. Etomidate was proposed as a potential protective anesthetic in the setting of aneurysm surgery. To the contrary, in an experimental model of focal ischemia, the volume of injury was not reduced by etomidate relative to a 1. In fact, the volume of injury with etomidate was significantly larger than that in the control group. In patients subjected to temporary intracranial vessel occlusion, the administration of etomidate results in greater tissue hypoxia and acidosis than does equivalent desflurane anesthesia. Therefore no scientific studies support the current use of etomidate for cerebral protection.

This form of regional anesthesia has been subdivided arbitrarily into minor and major nerve blocks infection 6 weeks after wisdom tooth removal cheap minocin generic. Minor nerve blocks are defined as procedures involving single nerve entities such as the ulnar or radial nerve antibiotic list drugs cheap minocin express, whereas major nerve blocks involve the blockade of two or more distinct nerves or a nerve plexus or the blockade of very large nerves at more proximal sites bacteria h pylori purchase minocin 50 mg without a prescription. The onset of blockade is rapid with most drugs virus removal tools buy discount minocin line, and the choice of drug is determined primarily by the required duration of anesthesia antimicrobial resistance and antibiotic resistance minocin 50 mg low price. A classification of the various drugs according to their duration of action is shown in Table 36-5 antibiotics vs antibacterial buy discount minocin. The duration of both sensory analgesia and motor blockade is prolonged significantly when epinephrine is added to the various local anesthetic solutions in some, but not all applications. Although interpleural analgesia appeared to be useful for unilateral postoperative analgesia after open cholecystectomy, mastectomy, and nephrectomy, its efficacy for post-thoracotomy pain is doubtful. Interpleural analgesia has also been used to provide analgesia for chronic pain conditions as diverse as upper extremity complex regional pain syndromes, pancreatitis, and cancer of the thorax and abdomen. In many centers, interpleural analgesia has largely been supplanted by thoracic epidural analgesia for the majority of thoracic and abdominal procedures. Two related approaches for unilateral somatic blockade in the thorax are continuous extrapleural catheters55 (placed by the surgeon through the chest dorsal to the parietal pleura) and continuous thoracic paravertebral somatic blockade. The risk-benefit ratio of thoracic epidural analgesia versus thoracic paravertebral analgesia or extrapleural analgesia remains controversial. A significant difference exists between the onset times of various agents when these blocks are used (Table 36-6). In general, agents of intermediate potency exhibit a more rapid onset than the more potent compounds do. Onset times of approximately 14 minutes for lidocaine and mepivacaine have been reported, versus approximately 23 minutes for bupivacaine. A variety of approaches to the brachial plexus are available; the choice among these approaches is dictated by several factors, including the site of surgery and the ability of the patient to tolerate spillover to other nerves, including the phrenic nerve. Chapter 36: Local Anesthetics 1043 Similarly, the lumbar plexus can be approached via several routes, including a posterior approach, an anterior perivascular "3 in 1" approach, and an anterior fascia iliaca compartment approach. For example, durations of anesthesia varying from 4 to 30 hours have been reported for bupivacaine. It is prudent to warn patients before a major nerve block about the possibility of prolonged sensory and motor block in the involved region, particularly when agents such as bupivacaine, levobupivacaine, and ropivacaine are used. With prolonged infusions, there is the potential for delayed systemic accumulation and toxicity. The duration of short- and intermediate-acting drugs is significantly prolonged by the addition of epinephrine (1:200,000), but the duration of long-acting drugs is only minimally affected by epinephrine. The onset of lumbar epidural anesthesia occurs within 5 to 15 minutes after the administration of chloroprocaine, lidocaine, mepivacaine, and prilocaine. It should be emphasized that although high concentrations of local anesthetics may be appropriate for episodic bolus dosing for surgery, these concentrations. When concentrated bupivacaine solutions are used for infusions, the potential exists for excessive local effect with an associated risk for unwanted and very prolonged motor blockade. Etidocaine produces adequate sensory analgesia and Drug Lidocaine Mepivacaine Prilocaine Bupivacaine Levobupivacaine Ropivacaine Usual Volume (mL) 30-50 30-50 30-50 30-50 30-50 30-50 Maximum Dose (mg) Without/With Epinephrine 350/500 350/500 400/600 175/225 200/225 200/250 Onset (min) 10-20 10-20 10-20 20-30 20-30 20-30 Duration (min) 120-240 180-300 180-300 360-720 360-720 360-720 *See also Chapter 57. Doses should be reduced, as detailed in Chapter 92, for children, for patients with specific risk factors, and for blocks in specific locations. When two or more blocks are performed together, the sum of the doses for each of the individual blocks should not exceed the max dose listed here. Doses should be reduced, as detailed in Chapter 92, for children, for patients with specific risk factors, and for specific catheter tip locations. Dosing may be reduced during pregnancy (see Chapter 77) and with advancing age (see Chapter 80). Use of etidocaine has decreased in recent years, and currently it is primarily restricted to surgical procedures for which profound muscle relaxation is required. Although lidocaine has long been used for spinal anesthesia as a 5% solution, recent studies of local anesthetic neurotoxicity have led some to question this practice. This issue is discussed later in the chapter in the section on the neurotoxicity of local anesthetics. Tetracaine is available both as crystals and as a 1% solution, which may be diluted with 10% glucose to obtain a 0. Hypobaric solutions of tetracaine (tetracaine in sterile water) can be used for specific operative situations, such as anorectal or hip surgery. Isobaric tetracaine obtained by mixing 1% tetracaine with cerebrospinal fluid or normal saline is useful for lower limb surgical procedures. Bupivacaine is widely used as a spinal anesthetic, either as a hyperbaric solution at a concentration of 0. Intrathecal bupivacaine possesses an anesthetic profile similar to that of tetracaine. The addition of epinephrine to bupivacaine or lidocaine may be more effective in prolonging the duration of spinal anesthesia in lumbosacral segments than in thoracic segments. In general, these preparations provide effective but relatively short durations of analgesia when applied to mucous membranes or abraded skin. Lidocaine and tetracaine sprays are commonly used for endotracheal anesthesia before endotracheal intubation or for mucosal analgesia for bronchoscopy or esophagoscopy. Because of concerns regarding cocaine toxicity and the potential for diversion and abuse, several groups have investigated alternative cocaine-free topical preparations. In recent years, cocaine has increasingly been replaced for nasal application by the combined use of an 1-adrenergic agonist (oxymetazoline or phenylephrine) and a local anesthetic such as 2% to 4% lidocaine, with more dilute solutions being recommended for infants and children (see Chapter 92). Systemic absorption of phenylephrine can cause severe hypertension and reflex bradycardia. Oxymetazoline is associated with much less systemic effect and has a wider margin of safety, although it can still produce peripheral vasoconstriction, hypertension, and reflex bradycardia. Total doses of lidocaine ranging from 35 to 55 mg/kg produce safe plasma concentrations, which can peak more than 8 to 12 hours after infusion. Clinicians should exercise great caution when administering additional local anesthetics by infiltration or other routes for at least 12 to 18 hours after the use of this technique. When the signs of neuropathic pain are reversed by lidocaine infusion, normal nociception and other sensory modalities are unaffected, suggesting that the neurophysiologic correlate of the disease has an unusually high susceptibility to these drugs, present in plasma at concentrations 50- to 100-fold lower than that required to block normal impulses in peripheral fibers. Laboratory studies suggest that ectopic impulse activity arising at a site of injury or elsewhere, such as the dorsal root ganglion, contributes to the neuropathic pain and that such impulses are particularly sensitive to use-dependent Na+ channel blockers. It is noteworthy that relief of preexisting neuropathic pain, both clinically and in animal models,78 can in some cases persist for days, weeks, or months after a single intravenous infusion of drug. Epinephrine decreases the rate of vascular absorption of certain local anesthetics from various sites of administration and thus decreases their potential systemic toxicity. A 5-g/mL concentration of epinephrine (1:200,000) significantly reduces the peak blood levels of lidocaine and mepivacaine irrespective of the site of administration. Peak blood levels of bupivacaine and etidocaine are minimally influenced by the addition of a vasoconstrictor after injection into the lumbar epidural space. However, epinephrine will significantly reduce the rate of vascular absorption of these drugs when they are used for peripheral nerve blocks such as brachial plexus blockade. The slower phase of disappearance from blood is mainly a function of the particular compound. In general, more highly perfused organs show higher concentrations of local anesthetic drug than less well-perfused organs do. Because local anesthetics are rapidly extracted by lung tissue, the whole blood concentration of local anesthetics decreases markedly as they pass through the pulmonary vasculature. When a local anesthetic solution is exposed to an area of greater vascularity, a greater rate and degree of absorption occur. This relationship is of clinical significance because use of a fixed dose of a local anesthetic agent can be potentially toxic in one area of administration but not in others. By comparison, this same dose of lidocaine used for a brachial plexus block yields a mean maximum blood level of approximately 3 g/mL, which is rarely associated with signs of toxicity. The maximum blood concentration of local anesthetic drugs is related to the total dose of drug administered for any particular site of administration. The ester, or procainelike, drugs undergo hydrolysis in plasma by the pseudocholinesterase enzymes; clearance of chloroprocaine is especially rapid. Lidocaine is metabolized somewhat more rapidly than mepivacaine, which in turn is more rapidly metabolized than bupivacaine. In a report by Nation and colleagues,88 the half-life of lidocaine after intravenous administration averaged 80 minutes in human volunteers varying in age from 22 to 26 years, whereas volunteers 61 to 71 years of age demonstrated a significantly prolonged lidocaine half-life that averaged 138 minutes. Chapter 36: Local Anesthetics 1047 Newborn infants have immature hepatic enzyme systems and hence prolonged elimination of lidocaine, bupivacaine, and ropivacaine. In neonates and some younger infants, terminal elimination half-lives can be as long as 8 to 12 hours. Prolonged elimination is particularly an issue for continuous infusions of local anesthetics in infants, and seizures have been associated with high bupivacaine infusion rates. The potential for toxicity with lidocaine infusions in neonates is also increased by the accumulation of its principal metabolite, monoethylglycinexylidide, which can cause seizures. Chloroprocaine may offer unique advantages for epidural infusion in neonates in that it is rapidly cleared from plasma, even in preterm neonates. The rate of disappearance of lidocaine from blood is markedly prolonged in patients with congestive heart failure. However, systemic and localized toxic reactions can occur because of accidental intravascular or intrathecal injection or administration of an unwanted excessive dose. In addition, specific adverse effects are associated with the use of certain drugs, such as allergic reactions to the aminoester drugs and methemoglobinemia after the use of prilocaine. Seizure activity ceases, and respiratory depression and ultimately respiratory arrest may occur. Blockade of inhibitory pathways allows facilitatory neurons to function in an unopposed fashion, which results in an increase in excitatory activity leading to convulsions. Hypercapnia and acidosis also decrease the plasma protein binding of local anesthetic agents. On the other hand, acidosis increases the cationic form of the local anesthetic, which should decrease the rate of diffusion through lipid barriers. The clinical implication of this effect of hypercapnia and acidosis on toxicity deserves emphasis. Based on the preceding discussion and a number of national guidelines for safe perioperative care, it is generally agreed that clinicians performing major conduction blockade should make a routine practice of having the following ready at hand: 1. Airway equipment, including a bag-mask circuit for delivery of positive-pressure ventilation 4. Drugs to terminate convulsions, should they occur, preferably midazolam, lorazepam, diazepam, or thiopental. The cardiotoxicity of bupivacaine appears to differ from that of lidocaine in the following manner: 1. Ventricular arrhythmias and fatal ventricular fibrillation can occur more often after the rapid intravenous administration of a large dose of bupivacaine, but far less frequently with lidocaine. A pregnant animal or patient may be more sensitive to the cardiotoxic effects of bupivacaine than a nonpregnant animal or patient105 (see Chapter 77). Cardiac resuscitation is more difficult after bupivacaine-induced cardiovascular collapse, and acidosis and hypoxia markedly potentiate the cardiotoxicity of bupivacaine. It is not recommended to treat bupivacaineinduced ventricular arrhythmias with lidocaine or amiodarone. Rapid institution of extracorporeal cardiopulmonary support has been lifesaving in a small number of cases of bupivacaine cardiotoxicity. There is a growing use of rapid-response extracorporeal membrane oxygenator and/ or cardiopulmonary bypass teams in some tertiary hospitals. The clinical implications for cardiac resuscitation after intravascular injection or overdose of local anesthetic are the following: 1. No medications are uniformly effective in facilitating resuscitation from bupivacaine-induced cardiac arrest or severe ventricular tachycardia (despite our recommendations regarding Intralipid later). Basic principles of cardiopulmonary resuscitation should be Cardiovascular System Toxicity Local anesthetics can exert direct actions on both the heart and peripheral blood vessels, as well as indirect actions on the circulation by blockade of sympathetic or parasympathetic efferent activity. The primary cardiac electrophysiologic effect of local anesthetics is a decrease in the rate of depolarization in the fast conducting tissues of Purkinje fibers and ventricular muscle. Action potential duration and the effective refractory period are also decreased by local anesthetics. Bupivacaine depresses the rapid phase of depolarization (Vmax) in Purkinje fibers and ventricular muscle more than lidocaine does. In addition, the rate of recovery from a use-dependent block is slower in bupivacaine-treated papillary muscles than in lidocaine-treated muscles. This slow rate of recovery results in incomplete restoration of Na+ channel availability between action potentials, particularly at high heart rates. These differential effects of lidocaine and bupivacaine have been advanced as explanations of the antiarrhythmic properties of lidocaine and the arrhythmogenic potential of bupivacaine. Extremely high concentrations of local anesthetics depress spontaneous pacemaker activity in the sinus node, thereby resulting in sinus bradycardia and sinus arrest. All local anesthetics exert dose-dependent negative inotropic action on cardiac muscle102; the depression of cardiac contractility is roughly proportional to conduction blocking potency. Thus, bupivacaine and tetracaine are more potent cardiodepressants than lidocaine is. Local anesthetics may depress myocardial contractility by affecting calcium influx and triggered release from the sarcoplasmic reticulum,97 as well as by inhibiting cardiac sarcolemmal Ca2+ currents and Na+ currents. Cocaine is the only local anesthetic that consistently causes vasoconstriction at all concentrations because of its ability to inhibit the uptake of norepinephrine by premotor neurons and thus to potentiate neurogenic vasoconstriction. Chapter 36: Local Anesthetics 1049 emphasized first, including attention to securing the airway, providing oxygenation and ventilation, and performing chest compressions if needed. Because resuscitation after local anesthetic-induced circulatory collapse is so difficult, prevention of massive intravascular injection or excessive dosing is crucial. Negative aspiration of the syringe does not always exclude intravascular placement. Incremental, fractionated dosing should be the rule for all patients undergoing major conduction blockade.

A questionnaire sent to German anesthesiologists in 2003 revealed routine reversal with neostigmine at the end of surgery was not practiced in 75% of anesthesia departments antimicrobial vinyl purchase minocin australia. The findings from these surveys suggest that there is little agreement about best practices related to reversal of neuromuscular blockade antibiotics simplified pdf minocin 50mg without prescription. Despite perioperative guidelines from several national organizations antibiotic resistance mortality generic minocin 50 mg line, surveys from many countries reveal that most clinicians do not monitor or reverse a neuromuscular blockade in the operating room antibiotic mode of action cheap 50mg minocin amex. Surprisingly bacteria that causes diarrhea buy generic minocin line, most anesthesiologists have not witnessed obvious adverse events directly attributable to incomplete recovery from neuromuscular blockade antibiotics for acne safe while breastfeeding order 50 mg minocin with mastercard. In the following sections, the definitions, incidence, and clinical implications of residual neuromuscular blockade are reviewed. Three methods are commonly used in the operating room to determine the presence or absence of residual neuromuscular blockade: clinical evaluations for signs of muscle weakness, qualitative neuromuscular monitors, and quantitative neuromuscular monitors. A more detailed description of the types of neuromuscular monitors used perioperatively is provided in Chapter 53. Following the introduction of d-tubocurarine into clinical practice, residual paralysis and the need for neostigmine was determined primarily by the observation of "shallow, jerky movements of the diaphragm" at the end of surgery. A peripheral nerve stimulator was first used in the 1960s by Harry Churchill-Davidson in the United Kingdom and later in the United States. In fact, several decades later, the most commonly applied technique for evaluation of recovery of neuromuscular function continues to be the use of clinical tests for signs of apparent muscle weakness. The most commonly applied criteria used to determine suitability for extubation of the trachea are a "normal" pattern of ventilation and a sustained head lift. At a level of neuromuscular recovery that allows for adequate ventilation in a patient whose trachea is intubated, the muscles responsible for maintaining airway patency and protection are significantly impaired. Qualitative neuromuscular monitors-or more accurately, peripheral nerve stimulators-deliver an electrical stimulus to a peripheral nerve, and the response to nerve stimulation is subjectively assessed by clinicians either visually or tactilely. The presence of fade with these patterns of nerve stimulation indicates incomplete neuromuscular recovery. A positive test result means inability to smile, swallow and speak, general muscular weakness, and so on. Example of a qualitative neuromuscular monitor (or more appropriately, a peripheral nerve stimulator). A peripheral nerve is stimulated, and the response to nerve stimulation is subjectively (qualitatively) assessed using either visual or tactile (hand placed on the muscle) means. In this illustration, the ulnar nerve is stimulated, and movement of the thumb subjectively evaluated. Ulnar nerve stimulation results in thumb movement, which is sensed by a piezoelectric sensor attached to the thumb. To improve the consistency of responses, a hand adapter applies a constant preload. Acceleration of the thumb is sensed by the piezoelectric sensor, and is proportional to the force of muscle contraction. Quantitative neuromuscular monitors are instruments that permit both stimulation of a peripheral nerve and the quantification and recording of the evoked response to nerve stimulation. During recovery, a blinded observer estimated tactile fade in the other extremity. A careful evaluation of the degree of residual blockade at the conclusion of a general anesthetic is essential in order to avoid the potential hazards of incomplete neuromuscular recovery following tracheal extubation. At the present time, quantitative neuromuscular monitoring is the only method of determining whether full recovery of muscular function has occurred and reversal drugs safely avoided. In order to exclude with certainty the possibility of residual paresis, quantitative monitoring should be used. Traditionally, residual neuromuscular blockade has been defined using quantitative neuromuscular monitoring. Shortly thereafter, these same investigators performed several studies examining the association between the degree of residual blockade in the hand (defined using quantified T4/T1 ratio, i. A variety of clinical signs may be present in patients with residual neuromuscular blockade, including the following: inability to perform a head lift, hand grip, eye opening, or tongue protrusion; inability to clench a tongue depressor between the incisor teeth; inability to smile, swallow, speak, cough, track objects with eyes; or inability to perform a deep or vital capacity breath. In 1979, Viby-Mogensen examined the efficacy of neostigmine in reversing d-tubocurarine, gallamine, or pancuronium blockade. However, incomplete neuromuscular recovery continues to be a common postoperative event. In conclusion, a frequent incidence of residual neuromuscular blockade still occurs worldwide in the immediate postoperative period; with current practice and inadequate monitoring, the incidence of this complication is not decreasing over time. The observed incidence of postoperative residual blockade varies widely between studies, ranging from 5% to 93%. The observed incidence of residual blockade is more frequent if a threshold definition of 0. The following section reviews the effects of residual blockade in both awake volunteer studies and in postoperative surgical patients. The weight in the random-effect model takes into account both between and within studies variation. Inconsistency is the proportion of between studies variability that cannot be explained by chance. Time interval between reversal agent administration and quantification of residual blockade Factors related to measurement oF residual Blockade 1. Surgical patients receive a variety of anesthetics in the perioperative period, which complicates an assessment of the particular effect of residual neuromuscular blockade on clinical outcomes. Return of pharyngeal muscle function is essential for airway control following tracheal extubation. In series of human studies from the Karolinska Institutet, Sweden, a functional assessment of the pharynx, upper esophageal muscles, and the integration of respiration with swallowing was performed during various levels of neuromuscular blockade. An investigation examining the effect of residual neuromuscular blockade on respiratory muscle function in awake volunteers. Supraglottic airway diameter and volume was measured by respiratory-gated magnetic resonance imaging. Images from the volunteer show that a partial paralysis evokes an impairment of upper airway diameter increase during forced inspiration. Clearly, an association exists between neuromuscular management characteristics and postoperative morbidity and mortality. Beecher and colleagues collected data from 10 university hospitals between the years 1948 to 1952 to determine anesthetic-related causes of mortality. In another large-scale study, mortality data associated with anesthesia were collected over a 10-year period (1967-1976) at a single institution in South Africa. Again, data relating to the use of pharmacologic reversal drugs were not provided. A study from the Association of Anaesthetists of Great Britain and Ireland examined deaths that were judged "totally due to anesthesia" and reported that postoperative respiratory failure secondary to neuromuscular management was a primary cause of mortality. Two investigations of anesthetic complications resulting in admissions to the intensive care unit determined that "failure to reverse after muscle relaxants" and "ventilatory inadequacy after reversal of muscle relaxants" were the most common causes of admission. A large case-control investigation was performed of all patients undergoing anesthesia over a 3-year period (n = 869,483) in the Netherlands assessing the impact of anesthetic management characteristics on the risk of coma or death within 24 hours of surgery. Epidemiologic studies thus suggest an association between incomplete neuromuscular recovery and adverse events in the early postoperative period. Notably, an important limitation of these outcome studies is that residual paresis was not quantified at the end of surgery. Therefore, causality (residual blockade results in postoperative complications) can only be suggested but not proven. Several clinical investigations have documented an association between postoperative residual blockade and adverse respiratory events. Because the two cohorts did not differ in any perioperative characteristics with the exception of neuromuscular recovery, these findings suggest that unrecognized residual paralysis is an important contributing factor to postoperative adverse respiratory events. A study of 114 patients randomized to neostigmine reversal or placebo (saline) documented a significantly more frequent incidence of both postoperative residual blockade and hypoxemia in the placebo group. Berg and colleagues randomized 691 patients to receive pancuronium, atracurium, or vecuronium. Notably, the study also demonstrated a continuously increased risk for postoperative pulmonary complications with increased age, a finding of significant clinical relevance for older adult patients, a growing part of the surgical patient population. In conclusion, a number of studies conducted over the past 5 decades have documented the effects of small degrees of residual blockade in human volunteers and surgical patients. Epidemiologic outcome investigations have suggested an association between incomplete neuromuscular recovery and major morbidity and mortality. These data suggest that residual blockade is an important patient safety issue in the early postoperative period. Therefore, appropriate management of reversal of neuromuscular blockade is essential to optimize patient outcomes. The positively charged quaternary nitrogen group on acetylcholine (Ach) binds by electrostatic forces to the negatively charged anionic site on the enzyme. The carbamate group at the opposite end of the Ach molecule forms covalent bonds with and is metabolized at the esteratic site. If larger concentrations of acetylcholine are present at the neuromuscular junction, acetylcholine will attach to the postsynaptic receptor and facilitate neuromuscular transmission and muscle contraction. A more detailed description of the neuromuscular junction is provided in Chapter 18. This can be accomplished using an inhibitor of cholinesterase, which constrains the enzyme that breaks down acetylcholine at the neuromuscular junction (acetylcholinesterase). Three anticholinesterase drugs are commonly used in clinical practice: neostigmine, edrophonium, and pyridostigmine. Over the prior 6 decades, anticholinesterases have been the only drugs used clinically to reverse neuromuscular blockade (until the recent introduction of sugammadex). Mechanism of Action of Anticholinesterases Acetylcholine is the primary neurotransmitter that is synthesized, stored, and released by exocytosis at the distal motor nerve terminal. Acetylcholinesterase is the enzyme responsible for the control of neurotransmission at the neuromuscular junction by hydrolyzing acetylcholine. Rapid hydrolysis of acetylcholine removes excess neurotransmitter from the synapse, preventing overstimulation and tetanic excitation of the postsynaptic muscle. Acetylcholinesterase is concentrated at the neuromuscular junction, and there are approximately 10 enzyme-binding sites for each molecule of acetylcholine released. Each molecule of acetylcholinesterase has an active surface with two important binding sites, an anionic site and an esteratic site. The negatively charged anionic site on the acetylcholinesterase molecule is responsible for electrostatically binding the positively charged quaternary nitrogen group on the acetylcholine molecule. The esteratic site forms covalent bonds with the carbamate group at the opposite end of the acetylcholine molecule and is responsible for the hydrolytic process70. Binding of ligands to the peripheral anionic site results in inactivation of the enzyme. The anticholinesterase drugs used by anesthesiologists interact with the anionic and esteratic sites of acetylcholinesterase. These drugs are characterized as either prosthetic inhibitors (edrophonium) or oxydiaphoretic (acid-transferring) inhibitors (neostigmine, pyridostigmine) of the enzyme. Edrophonium rapidly binds to the anionic site via electrostatic forces and to the esteratic site by hydrogen bonding. During the time edrophonium is bound, the enzyme is inactive and edrophonium is not metabolized. However, the interaction between edrophonium and acetylcholinesterase is weak and short-lived. The dissociation half-life of this interaction is approximately 20 to 30 seconds, and the interaction between drug and enzyme is competitive and reversible. Because the nature of the binding is relatively brief, the efficacy of edrophonium in reversing neuromuscular blockade may be limited. Neostigmine and pyridostigmine are oxydiaphoretic inhibitors of acetylcholinesterase, which also bind to the anionic site. In addition, these drugs transfer a carbamate group to acetylcholinesterase, creating a covalent bond at the esteratic site. The stronger interaction between neostigmine and enzyme results in dissociation half-life of approximately 7 minutes. These interactions at the molecular level likely have little impact on the duration of action in clinical practice. Duration of clinical effect is primarily determined by removal of anticholinesterase from the plasma. Anticholinesterases produce a reversible increase in the duration of the action potential and refractory period of the nerve terminal. Because the quantity of acetylcholine released is a function of the extent and duration of the depolarization of the terminal membrane, the period of acetylcholine release in response to nerve stimulation may be increased by anticholinesterase agents. As concentrations of acetylcholine increase, some of the neurotransmitter diffuses away from the neuromuscular junction, while additional acetylcholine undergoes reuptake into motor nerve terminals. As the processes of diffusion and reuptake reach equilibrium with augmented release by enzyme inhibition, a "peak" level at the neuromuscular junction is reached. Pharmacokinetic and Pharmacodynamic Properties of Anticholinesterases A large number of clinical studies have examined the pharmacokinetic and pharmacodynamic characteristics of neostigmine, pyridostigmine, and edrophonium. Neostigmine has been the most extensively investigated anticholinesterase agent over the past 5 decades. The favorable pharmacokinetic profile of neostigmine likely explains its popularity in clinical practice as a reversal drug.

When phosphorylated antimicrobial gym bag buy generic minocin 50 mg online, it detaches from microtubules antibiotic effects order minocin 50 mg visa, and antibiotics for acne while breastfeeding purchase minocin 50mg with mastercard, if excessive antimicrobial hand wash 50mg minocin mastercard, can stay unattached and form aggregates that eventually become fibrillar and cytotoxic antibiotics for sinus infection and uti order cheapest minocin. This is in addition to leaving microtubules chapter 46 antimicrobial agents discount 50mg minocin mastercard, essential for many cellular functions, destabilized and perhaps dysfunctional. Thus, small molecules that stabilize microtubules have been shown to improve pathogenesis and behavior in animals and are currently in clinical trials in patients. Anesthetics have not been directly implicated in the aggregation process as they have for amyloid-, but features of the anesthetic state have been implicated in phosphorylation and detachment. The protein is attached reversibly to microtubules, an interaction thought to stabilize the microtubule polymer. It has multiple phosphorylation sites, which modulate microtubule binding affinity. This figure emphasizes that amyloidopathy, tauopathy, and structural loss are well advanced before the ability to detect significant cognitive consequences. In addition, it is not clear to what degree pathologic processes and degeneration are reversible once cognitive decline is detected. This recent understanding makes cognitive markers of neurodegeneration of questionable value in judging the effect of interventions, both positive and negative. That anesthetics cause changes in calcium regulation is widely known, and this is likely to occur through interactions with several types of channels79. The neuronal endoplasmic reticulum is a normal cellular store of calcium that is released in a highly regulated fashion through these channels. It is now thought that mutations in either of these channels, or exposure to drugs that interact with either, may lead to an exaggerated release of calcium that could trigger apoptosis. Initial studies of this premise in animals using the ryanodine receptor inhibitor dantrolene are inconsistent, perhaps because of difficulty in getting this drug across the blood-brain barrier. Mitochondria and Anesthesia these small organelles are the powerhouses of cells, and their function is tightly integrated with most cellular functions. Neuroinflammation and Anesthesia That inflammation contributes to cognitive decline is well known. First, it activates calcium channels on the plasma membrane to allow further calcium entry. Perioperative management frequently includes drugs capable of modulating inflammatory cascades. Inhaled anesthetics such as isoflurane and sevoflurane are not likely antiinflammatory, but literature in favor of propofol being antiinflammatory has increased. Certainly, propofol is a radical scavenger, but whether this is responsible for any salutary effects is not yet clear. Second, the inflammatory response to an intervention such as surgery is known to be enormously variable. Understanding both of these features may, in the future, allow us to predict and prevent cognitive decline. Patient Studies As mentioned earlier, patient studies invariably combine both anesthesia and surgery, but serve as the ultimate test of whether the notions described dictate a change in perioperative management. In general, however, it appears from anesthetic-only studies, especially those that examined long-term effects, that anesthetics produce few to no cognitive effects and only small and often reversible pathologic effects. Given that many of these procedures elicit inflammation, they may contribute to cognitive problems, especially in vulnerable populations. That surgery itself can contribute to shortterm cognitive loss was first shown in mice exposed to either an injectable anesthetic alone or combined with an orthopedic operation. Moreover, these animals were healthy and young, a group at infrequent risk for cognitive complications and hardly representative of most of our patients. In this case, desflurane anesthesia alone produced only a transient cognitive consequence whereas the addition of surgery caused a much larger decrement that lasted-essentially unchanged-for at least 3 months. Such a mechanism may explain why everyone does not suffer cognitive decline after surgery. First, patients arrive for Surgery and anesthesia Peripheral inflammatory response Neural afferents Neuroinflammation (Proinflammatory mediators, microglia activation) Vulnerable brain. In these centers, elderly patients with and without cognitive symptoms are recruited and studied extensively with a variety of tests, including cognition, imaging, and biomarker assays. They are then followed longitudinally for many years to seek associations between cognitive decline and the various biomarkers. In a recently published study, the patients from the centers were retrospectively examined for associations between their cognitive trajectory and the occurrence of either a surgical procedure or a serious illness (requiring hospitalization). The small number of surgical procedures in these patients limited power, but the authors were able to conclude an absence of any relationship between cognitive trajectory and either surgery or serious illness. Most interestingly, larger losses of hippocampal and cortical gray matter volume were detected in the surgical group, suggesting a brain structural correlate to the cognitive defect. This work is one of the first to use biomarkers in establishing an effect of surgery and anesthesia on the brain. Biomarkers Especially in disorders with a very long presymptomatic phase, biomarkers are important to understand the linkage between interventions and outcomes. Neurodegeneration begins decades before the first memory complaints, and yet it is likely that this presymptomatic phase is a period of vulnerability, both to therapy and to acceleration by interventions such as surgery. First, to establish this vulnerability preoperatively to tailor perioperative management (when we know how) and, second, to understand the impact of perioperative management on the trajectory of the pathology. The unique skills and opportunity that the anesthesiologist has with respect to lumbar puncture should greatly facilitate generation of the necessary data. Other biomarker modalities that might reflect perioperative neurotoxicity include plasma. Plasma biomarkers of neuronal injury are in their infancy and not yet rigorously validated,101 but significant advances in imaging have occurred. Until such time that this information is available, the cost of routine genetic testing cannot be justified, unless these patients are enrolled in studies. On the other hand, the potential impact of surgery itself, via inflammatory pathways, is more compelling and supported by both preclinical and clinical data. The neuropathologic and behavioral outcome of surgery in the elderly is likely to be strongly modulated by many patient vulnerability factors, in addition to perioperative management decisions. This will require, of course, careful balancing of the risks for cognitive decline against the risk for not receiving needed surgery. In most cases, the latter risk would be higher; thus, elements of perioperative management contributing to cognitive decline need to be identified and managed. The evidence at this point implicates inflammatory pathways and also suggests that anesthetic choice matters. Nothing has been confirmed in prospective clinical trials that strongly emphasizes this need. Finally, reliable biomarkers are needed to stratify patients and follow the effects of interventions. Thus, the Alzheimer brain (left) shows a much lower global signal than the normal brain (right), presumably as a result of both neuron loss and neuronal dysfunction. These imaging biomarkers hold promise for determining vulnerability and the response to therapy (or surgery). However, significant progress in the laboratory has made a compelling case that anesthesia and surgery may indeed be the cause of durable cognitive problems- at both extremes of age. These preclinical studies have allowed more focused clinical studies, many of which are under way. It is too early to make recommendations for detailed changes in perioperative management, but it is not too early to call for more investigation into the causes and prevention of perioperative neurotoxicity. Similar to positron emission tomography, this imaging biomarker has helped establish a link between prior surgery and structural defects in the brain. These data from reference 106 show gray matter loss in both the hippocampus and cortex in a cohort of patients that underwent surgery in contrast to age-matched controls. Shown in the bar graph for comparison are the gray matter changes that occur in patients with mild cognitive impairment and with Alzheimer disease. Kalb C: Kids and anesthesia: a new study raises questions about the risks to young children, Health Section, Newsweek10-20, 2008. Dobbing J, Sands J: Comparative aspects of the brain growth spurt, Early Hum Dev 3:79-83, 1979. Briner A, Nikonenko I, De Roo M, et al: Developmental stagedependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex, Anesthesiology 115: 282-293, 2011. Lunardi N, Ori C, Erisir A, et al: General anesthesia causes longlasting disturbances in the ultrastructural properties of developing synapses in young rats, Neurotox Res 17:179-188, 2010. Halliwell B: Reactive oxygen species and the central nervous system, J Neurochem 59:1609-1623, 1992. Zhao Y, Liang G, Chen Q, et al: Anesthetic-induced neurodegeneration mediated via inositol 1,4,5-trisphosphate receptors, J Pharmacol Exp Ther 333:14-22, 2010. Inan S, Wei H: the cytoprotective effects of dantrolene: a ryanodine receptor antagonist, Anesth Analg 111:1400-1410, 2010. Wei H, Liang G, Yang H: Isoflurane preconditioning inhibited isoflurane-induced neurotoxicity, Neurosci Lett 425:59-62, 2007. Orrenius S, Nicotera P, Zhivotovsky B: Cell death mechanisms and their implications in toxicology, Toxicol Sci 119:3-19, 2011. Gozuacik D, Kimchi A: Autophagy as a cell death and tumor suppressor mechanism, Oncogene 23:2891-2906, 2004. Jevtovic-Todorovic V, Boscolo A, Sanchez V, Lunardi N: Anesthesiainduced developmental neurodegeneration: the role of neuronal organelles, Front Neurol 3:141, 2012. Shu Y, Zhou Z, Wan Y, et al: Nociceptive stimuli enhance anesthetic-induced neuroapoptosis in the rat developing brain, Neurobiol Dis 45:743-750, 2012. Chorne N, Leonard C, Piecuch R, et al: Patent ductus arteriosus and its treatment as risk factors for neonatal and neurodevelopmental morbidity, Pediatrics 119:1165-1174, 2007. Activation of the sympathetic nervous system elicits what is traditionally called the fight-or-flight response, typically including redistribution of blood flow from the viscera to skeletal muscle, increased cardiac function, sweating, and pupillary dilation. The parasympathetic system governs activities of the body more closely associated with maintenance needs, such as digestive and genitourinary function. A major goal of administration of anesthetics is maintaining optimum homeostasis in patients despite powerful challenges to the contrary. Modification or ablation of the stress response may actually improve perioperative outcome. Claude Bernard, a student of Magendie, postulated the theory of transmission by synapses through the release of chemical mediators. Later, Sherrington initiated a systematic study of reflexes and described some characteristics of reflex function. Abel, first synthesized epinephrine in 1899, and his student Langley demonstrated that it caused effects similar to those produced by stimulating postganglionic sympathetic neurons. Furthermore, Langley found that when the nerve was cut and epinephrine was injected, a more profound effect was produced, thus demonstrating denervation supersensitivity. Sir Henry Dale isolated choline and subsequently studied acetylcholine in animals, in which he demonstrated that acetylcholine causes vasodilation and hypotension. Nerves that operate by acetylcholine are called cholinergic, whereas those using norepinephrine are called adrenergic. In addition to classifying nerves, the term cholinergic refers to other structures or functions that relate in some way to acetylcholine. Cholinergic agonists are drugs that act like acetylcholine on cholinoceptors to cause the cell to react in its characteristic way. Cholinergic antagonists are drugs that react with cholinoceptors to block access by acetylcholine and thereby prevent its action. These drugs may also be referred to as cholinolytic, cholinergic-blocking, or anticholinergic drugs. Because muscarine, a chemical isolated from a mushroom, causes effects similar to those produced by activation of the parasympathetic nervous system, it was thought to be the endogenous parasympathetic transmitter. Thus, drugs that mimic the effects of muscarine on parasympathetically innervated structures, including the heart, smooth muscles, and glands, have been called muscarinic drugs. In the early 1900s, nicotine was found to interact with ganglionic and skeletal muscle synapses and on nerve membranes and sensory endings. Accordingly, drugs that act on these parts of the cholinergic system are called nicotinic drugs. Some postganglionic sympathetic neurons, such as those that innervate the sweat glands and certain blood vessels 5. Preganglionic sympathetic neurons that arise from the greater splanchnic nerve and innervate the adrenal medulla 6. Central cholinergic neurons Drugs mimicking the action of norepinephrine are referred to as sympathomimetic, whereas drugs inhibiting the effects of norepinephrine are called sympatholytic. Adrenergic nerves release norepinephrine at the neuroeffector junction, whereas epinephrine and norepinephrine are released by the adrenal medulla. Adrenergic receptors have been identified and subdivided into and receptors and further subdivided into 1, 2, 1, 2, and other types. The underlying theme of the sympathetic nervous system is an amplification response, whereas that of the parasympathetic nervous system is a discrete and narrowly targeted response. The enteric nervous system is arranged nontopographically and relies on the mechanism of chemical coding to differentiate among nerves serving different functions. The preganglionic sympathetic neurons have cell bodies within the horns of the spinal gray matter. Nerve fibers from these cell bodies extend to three types of ganglia grouped as paired sympathetic chains, various unpaired distal plexuses, or terminal or collateral ganglia near the target organ.

These investigations tween 80 antimicrobial activity purchase minocin 50 mg visa, as well as a number of pharmacokinetic and pharmacodynamic studies 90 bacteria 10 human discount minocin 50 mg overnight delivery, demonstrate that the time course of spontaneous neuromuscular recovery is extremely variable from patient to patient antibiotics simplified generic minocin 50 mg on line. In order to detect and appropriately manage patients in whom delayed neuromuscular recovery may be present infection 10 weeks postpartum order 50 mg minocin overnight delivery, quantitative neuromuscular monitoring is required antibiotic resistant sinus infection order minocin cheap. The duration of neuromuscular blockade following the administration of either succinylcholine or mivacurium is primarily determined by their rate of hydrolysis by plasma cholinesterase (also see Chapter 34) bacteria during pregnancy purchase minocin with a visa. Mivacurium is four to five times more potent in patients phenotypically homozygous for the atypical plasma cholinesterase gene than in patients with normal cholinesterase activity. In 1977, Scholler and associates reported data on 15 patients with unexpected prolonged apnea lasting several hours after a dose of succinylcholine. Naguib and associates reported successful reversal of a profound mivacurium-induced neuromuscular blockade with three doses of a purified human plasma cholinesterase preparation and, in a subsequent study, established a dose-response relationship for plasma cholinesterase as a reversal agent for mivacurium in normal subjects. Administration of cholinesterase restored plasma cholinesterase to normal levels, resulting in a 9- to 15-fold increased clearance and a shorter elimination half-life of mivacurium. These data suggest that prolonged neuromuscular blockade secondary to low or abnormal plasma cholinesterase activity can be successfully managed with purified human plasma cholinesterase. Decisions relating to management of prolonged neuromuscular blockade in patients with atypical plasma cholinesterase should be based on the availability and cost of human plasma cholinesterase versus delaying tracheal extubation until spontaneous neuromuscular recovery has occurred. Anticholinesterases can antagonize moderate to shallow levels of neuromuscular blockade. However, if given when neuromuscular function is completely recovered, paradoxical muscle weakness theoretically may be induced. Anticholinesterases should not be given until some evidence of recovery of muscle strength is observed since administration of an anticholinesterase during deep levels of paralysis may delay neuromuscular recovery. Decisions relating to the use or avoidance of anticholinesterases should not be based upon clinical tests of muscle strength (5-second head lift). Other muscle groups may be significantly impaired (pharyngeal muscles) at the time when patients can successfully perform these tests. The clinical implications of administration of neostigmine after neuromuscular recovery has occurred have been examined in studies by Eikermann and colleagues. Neostigmine administration resulted in decreases in upper airway dilator muscle tone and volume, impairment of diaphragmatic function, and reductions in minute ventilation. In contrast, sugammadex does not appear to produce adverse effects on upper airway tone or normal breathing when given after neuromuscular recovery. The impact of anticholinesterases on the incidence of postoperative nausea and vomiting remains controversial (also see Chapter 97). Systemic anticholinesterases produce effects outside of the neuromuscular junction that may influence the risk of unwanted side effects following anesthesia and surgery. In addition to the action within the neuromuscular junction, anticholinesterase drugs result in muscarinic effects on the gastrointestinal tract, resulting in stimulation of secretion of gastric fluid and increases in gastric motility. The use of smaller doses of neostigmine in combination with atropine decreases lower esophageal sphincter tone. Intrathecal neostigmine increases the incidence of nausea and vomiting, likely through a direct effect on the brainstem. Similarly, surgical patients who were randomized to receive atropine had significantly less nausea than those given glycopyrrolate. The beneficial effects of atropine on nausea and vomiting are likely secondary to a central nervous system effect. Several randomized clinical trials have been performed to determine whether anticholinesterase administration results in an increase in the incidence of postoperative nausea and vomiting. However, some evidence in adults suggested that antagonism with larger doses of neostigmine (2. A later systematic review evaluated the effect of neostigmine on postoperative nausea and vomiting while considering the different anticholinergics as confounding variables. The combination of neostigmine with either glycopyrrolate or atropine did not increase the incidence of nausea or vomiting, nor was there an increased risk when large doses of neostigmine were compared with smaller doses (Table 35-6). Atropine was associated with a reduction in the risk of vomiting, but glycopyrrolate was not. In conclusion, there is at present insufficient evidence to conclude that neostigmine or edrophonium is associated with an increased risk of postoperative nausea and vomiting. Pronounced vagal effects are observed following the administration of anticholinesterases-bradycardia and other bradyarrhythmias, such as junctional rhythms, ventricular escape beats, complete heart block, and asystole, have been reported. The time course of these bradyarrhythmias parallels the onset of action of the anticholinesterases, with the most rapid onset observed with edrophonium, slower for neostigmine, and slowest for pyridostigmine. Atropine and glycopyrrolate have muscarinic (parasympathetic) blocking effects, but do not block nicotinic receptors. Atropine has a more rapid onset of action (approximately 1 minute) compared with glycopyrrolate (2 to 3 minutes), although the duration of action of both agents is similar (30 to 60 minutes). Despite the concurrent administration of anticholinergic drugs, a high incidence of bradyarrhythmias is observed following anticholinesterase reversal (up to 50% to 60% of patients in some studies). Several investigations have examined the heart rate and rhythm responses to various anticholinesterase/anticholinergic combinations. In general, it is preferable to use atropine with edrophonium, because the onset of action of both drugs is rapid. Edrophonium-atropine mixtures induced small increases in heart rate, whereas edrophonium-glycopyrrolate mixtures caused decreases in heart rate and occasionally severe bradycardia. During physiologic stressful events, control of heart rate and arterial blood pressure is regulated by the sympathetic and parasympathetic nervous systems. Anticholinergic drugs attenuate the efferent parasympathetic regulation of heart rate and suppress cardiac baroreflex sensitivity and heart rate variability. Marked decreases in baroreflex sensitivity and high-frequency heart rate variability have been observed in healthy volunteers given either atropine (20 g/kg) or glycopyrrolate (7 g/kg). Similar effects have been observed in healthy patients undergoing general anesthesia reversed with neostigmine and anticholinergics. Two hours after giving neostigmine, patients given atropine had persistent impairment of baroreflex sensitivity and high-frequency heart rate variability, whereas these variables had returned to baseline values in patients receiving glycopyrrolate. These investigations demonstrate that the parasympathetic nervous system control of heart rate is less impaired by glycopyrrolate than by atropine. Bronchospasm can occur after the administration of neostigmine in surgical patients. Neostigmine and pyridostigmine induce a phosphatidylinositol response (a reflection of smooth muscle contraction induced by a muscarinic agonist) in airway muscle, which can result in bronchoconstriction. In patients with cervical spinal cord injuries, neostigmine alone caused bronchoconstriction, whereas neostigmine combined with glycopyrrolate caused bronchodilation. This principle for reversal of rocuronium- and vecuronium-induced neuromuscular blockade was first introduced into clinical practice in 2008 and is now available for pediatric and adult anesthesia in most countries worldwide. The complex formation of sugammadex and rocuronium or vecuronium occurs at all levels of neuromuscular blockade (profound through shallow) and results in a more fastacting pharmacologic reversal when compared with anticholinesterase drugs. The structure has a hydrophobic cavity and hydrophilic exterior because of the presence of polar hydroxyl groups. Hydrophobic interactions trap the lipophilic molecules in the cyclodextrin cavity, thereby resulting in the formation of a water-soluble guest-host complex. Sugammadex is built on this principle ring structure but is a modified -cyclodextrin. Furthermore, at the end of these side chains, negatively charged carboxyl groups are added to enhance electrostatic binding to the positively charged quaternary nitrogen of rocuronium. The molecular mass of the sugammadex-rocuronium complex is 2532 g/mol (sugammadex 2002 g/mol and rocuronium 530 g/mol), and that of the sugammadex-vecuronium complex is 2640 g/mol (vecuronium 638 g/mol). This creates a concentration gradient favoring movement of the remaining rocuronium molecules from the effect site at the neuromuscular junction into plasma, where the drug is encapsulated by free sugammadex molecules. Neuromuscular blockade is quickly reversed as rocuronium is removed from the binding sites at the neuromuscular junction. Sugammadex administration results in an increase in the total plasma concentration of rocuronium (free and that bound to sugammadex). During an infusion of rocuronium to maintain a stable depth of neuromuscular blockade, administration of sugammadex increased the measured plasma concentration of rocuronium; rocuronium redistributed from the effect compartment (including the neuromuscular junction) to the central compartment (mostly as the sugammadex complex) as it was encapsulated by sugammadex. In the absence of sugammadex, rocuronium is eliminated mainly by biliary excretion (>75%) and to a lesser degree by renal excretion (10% to 25%). The clearance of rocuronium after binding by sugammadex decreases to a value approaching the glomerular filtration rate (120 mL/min). This results in a concentration gradient between the relatively high level of free rocuronium in the effect compartment (the neuromuscular junction) and the low level in the plasma compartment. Thus, the increase in plasma levels of rocuronium after sugammadex administration illustrates the mechanism responsible for the rapid reversal of neuromuscular blockade by sugammadex. Because renal excretion is the primary route for the elimination of sugammadex and the rocuronium-sugammadex complex, studies on elimination by dialysis have considerable relevance in clinical practice. In a small subset of patients with severe renal impairment, an investigation on dialysis showed that the clearance of sugammadex and rocuronium in blood was 78 and 89 mL/min, respectively. Therefore, hemodialysis using a high-flux dialysis method is effective in removing sugammadex and the sugammadex-rocuronium complex in patients with severe renal impairment. The first human exposure of sugammadex in male volunteers showed a large dose-dependent, more rapid recovery time from a rocuronium-induced neuromuscular blockade with sugammadex (0. The dose-response relation of sugammadex dose and time to recovery of the T4/T1 ratio to 0. Sugammadex allows a profound neuromuscular blockade to continue until the end of surgery. Thus, reversal of large doses of rocuronium with 16 mg/kg sugammadex was significantly faster than spontaneous recovery from succinylcholine. Chapter 35: Reversal (Antagonism) of Neuromuscular Blockade 1017 these findings were confirmed in a randomized trial that assessed how rapidly spontaneous ventilation could be reestablished after rapid sequence induction of anesthesia and intubation of the trachea, using either the combination of rocuronium (1. In clinical practice and during an unexpected difficult airway (cannot intubate, cannot ventilate scenario), a rocuronium neuromuscular blockade may be reversed by sugammadex immediately in order to restore spontaneous ventilation. When sugammadex was compared with neostigmine or edrophonium, the time course of neuromuscular recovery was markedly different. The use of sugammadex in pediatric patients (also see Chapter 93) was examined in a study enrolling 8 infants (28 days to 23 months), 24 children (2 to 11 years), and 31 adolescents (12 to 17 years). Residual neuromuscular blockade or recurarization was not observed, and no side effects were reported. In a more recent case report, sugammadex was used successfully in reversing a vecuronium-induced neuromuscular blockade in a 7-month-old infant. Information on the use of sugammadex in pediatric patients less than 2 years old is still limited. Reversal of neuromuscular blockade by sugammadex has been assessed in older patients (also see Chapter 80). A randomized trial compared the efficacy of sugammadex reversal of a rocuronium (0. In general, a prolonged circulation time secondary to a reduced cardiac output in older patients was anticipated to result in a longer recovery time from neuromuscular blockade after administration of sugammadex. Patients with a history of pulmonary disease have an increased risk of postoperative pulmonary complications such as pneumonia, respiratory failure, and exacerbation of the underlying pulmonary disease. As in other adult patient groups, reversal of a rocuronium-induced neuromuscular blockade was rapid, and there were no signs of residual neuromuscular blockade or recurarization. Both patients were asthmatic, and there was no evidence that these symptoms were related to sugammadex. In other subsets of high-risk pulmonary patients (cystic fibrosis and end-stage lung disease), the successful use of sugammadex has been reported. The use of sugammadex to reverse rocuronium neuromuscular blockade was investigated in 15 patients with severe renal impairment (creatinine clearance <30 mL/min) and compared with 15 patients with normal renal function (creatinine clearance >80 mL/min). There were no differences between groups in the recovery profile or the incidence of residual blockade after sugammadex (Table 35-9). Because complete elimination of the sugammadexrocuronium complex remains poorly understood in renal impairment, sugammadex is at present not recommended for use in patients with severe renal failure. Hemodialysis using a high-flux dialysis method has been demonstrated to be effective in removing sugammadex and the sugammadex-rocuronium complex in patients with severe renal impairment. Sugammadex has not been studied in animal models or in patients with hepatic impairment. However, it is known that the biliary route of excretion becomes unavailable for either sugammadex or the rocuronium/vecuronium-sugammadex complex, because the large size of this complex prohibits such excretion. However, in other scenarios (sugammadex 2 mg/kg at reappearance of T2 and 4 mg/kg after 15 minutes), recovery from a rocuronium-induced (1. The explanation of the slower reversal is not yet fully understood and needs to be investigated in clinical studies. Based on limited available data, sugammadex should be used with caution in patients with hepatobiliary disease. In this setting, sugammadex may have a more favorable recovery profile than traditional anticholinesterase drugs because it provides a more reliable recovery of neuromuscular functions and a less frequent risk of incomplete neuromuscular recovery. In order to ensure complete neuromuscular recovery, the dose of sugammadex must be sufficient to affect the gradient between the peripheral and central compartments and effectively encapsulate all rocuronium molecules. An inadequate dose of sugammadex may be incapable of sustaining this redistribution of rocuronium and lead to reoccurrence of the neuromuscular blockade. The conclusion of the authors was that a sugammadex dose calculated according to lean/ ideal body weight was insufficient for reversing both profound and moderate blockade in a considerable number of morbidly obese patients. This study demonstrated that a moderate rocuronium neuromuscular blockade could be effectively reversed with sugammadex 2. Until more data are available, the dose of sugammadex should be based on the actual body weight.

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