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Frequent advantages cited included preserved hemodynamic stability order indocin now arthritis headache back head, decreased nausea and vomiting order 75mg indocin with amex arthritis in fingers nz, improved procedural conditions cheap indocin 75mg mastercard arthritis diet patrick holford, and decreased airway complications. The effect of ketamine may outlast the effects of propofol under these conditions. Patient movement may make ketamine less than ideal for procedures requiring a completely motionless patient. Ketamine can elevate intracranial and intraocular pressure and is thus relatively contraindicated in patients with increased intracranial pressure and with glaucoma or open-globe injuries. Although it has been suggested that airway reflexes are relatively90 2067 preserved with ketamine, there is no convincing evidence to support this notion. Table 30-5 Typical Dose Ranges of Sedative, Hypnotic, and Analgesic Drugs Ketamine can be also administered orally or intramuscularly. The onset of action typically occurs within 20 to 30 minutes and the duration of effect is between 60 and 90 minutes. The intramuscular dose is 2 to 4 mg/kg with an onset of action of 5 to 10 minutes and typically has a duration of effect of 30 to 120 minutes. Dexmedetomidine Dexmedetomidine is a selective α -receptor agonist that depresses central2 sympathetic function and produces sedation and analgesia. When compared to propofol, use of dexmedetomidine to facilitate sedation may be associated with improved airway patency, particularly in patients with suspected obstructive sleep94 apnea. This consideration is ever important given the increasing prevalence of obesity and associated sleep disordered breathing in our current practice. However, occasional airway intervention to relieve obstruction and apnea may be required during dexmedetomidine administration, particularly when used in combination with other respiratory depressants. Dexmedetomidine95 has been used for sedation during instrumentation of the difficult airway. Patients undergoing fiberoptic intubation who are sedated using dexmedetomidine are generally comfortable yet cooperative. Despite this phenomenon, the incidence of hypertensive episodes requiring intervention is lower when compared with an equivalent propofol-based technique. Under these circumstances, there were fewer fluctuations from the desired sedation level when compared with the combination of midazolam, fentanyl, and propofol. However, when compared 2069 with propofol, the target sedation level takes longer to achieve with dexmedetomidine (25 vs. Although the use of dexmedetomidine may result in greater sedation, lower blood pressure, and improved analgesia in the recovery room when compared with propofol, the time to postanesthesia care unit discharge is not significantly different. Two large retrospective observational studies from a single children’s hospital suggest that dexmedetomidine may be used for sedation for pediatric magnetic resonance imaging and computed tomography studies. However, approximately 15% of patients required a second bolus in order to achieve satisfactory conditions to complete the scan. The analgesic properties of dexmedetomidine may make it a useful alternative to the use of propofol as a sole agent during painful procedures. However, the time taken to deliver the loading dose, the occasional need to rebolus, hypotension, bradycardia, and the relatively long recovery time may limit the utility of dexmedetomidine for very brief procedures such as computed tomography studies. On the other hand, the pain on injection of propofol and the legislative constraints on the administration of propofol by nonanesthesia-trained providers may make dexmedetomidine advantageous in certain circumstances. Amnesia during Sedation with Dexmedetomidine or Propofol Drugs with sedative–hypnotic properties reduce attention to stimuli as a direct consequence of depression of consciousness. Therefore, all sedative– hypnotics have the potential to impair memory formation because attention to stimuli is a crucial element of explicit memory formation. However, like benzodiazepines, propofol has significant amnestic effects at subhypnotic doses, suggesting an additional amnestic mechanism that is separate from its sedative effect. Alternatively, amnestic doses of propofol or a benzodiazepine may be used to supplement 2070 dexmedetomidine. Patient-controlled Sedation and Analgesia Techniques that allow the direct patient control of the level of sedation may positively affect patient satisfaction. These properties have been exploited during vaginal ovum retrieval procedures, when ultrasonically guided needles are passed through the vaginal wall under monitored anesthesia care. Patient acceptability, alfentanil dosage, respiratory variables, and pain scores were similar to those obtained with physician-controlled analgesia. The adverse respiratory effects of sedation administration include adverse effects on respiratory drive, airway patency, and loss of airway protective reflexes. These effects result either directly as a result of sedative–hypnotic or opioid administration or indirectly as a consequence of brain stem hypoperfusion resulting from hypotension. There may also be a marked increase in the work of breathing because of increased upper airway resistance121 and adverse effects on respiratory system mechanics resulting from a decline in functional residual capacity. During inspiration, the pressure within the upper airway is subatmospheric; thus, there is a tendency for the upper airway to collapse under the influence of the surrounding atmospheric pressure. However, in the normal subject this tendency for airway collapse is opposed by upper airway dilator muscle tone. These muscles increase the diameter and reduce the compliance of the upper airway. An increase in upper airway dilator muscle tone occurs during inspiration, commencing just prior to diaphragmatic contraction. However, upper airway dilator muscle control appears to be extremely sensitive to sedative–hypnotic drug administration. The response to this obstruction is a significant increase in intercostal and accessory muscle activity. However, this response is only partially effective because the increase in inspiratory force will further decrease intraluminal upper airway pressure, thus predisposing to further airway collapse. It is likely that these effects will be of greatest significance in patients with pre-existing respiratory compromise, such as elderly patients or those with chronic obstructive pulmonary disease. These patients often have limited respiratory reserve and are unable to increase 2072 their respiratory muscle activity in response to the increased work of breathing induced by sedation and may become hypercarbic, acidotic, and hypoxic. Sedation and Protective Airway Reflexes Competent laryngeal and upper airway reflexes are required to protect the lower airway from aspiration. Protective laryngeal and pharyngeal reflexes are depressed by anesthesia and sedation. Furthermore, it is also well documented that protective airway reflexes are compromised by advanced age and debilitation. Therefore, it is likely that significant further impairment of airway reflexes occurs during sedation in the elderly or debilitated patient. Aspiration of gastric contents can potentially occur any time during the perioperative period, particularly if oral intake is allowed before the return of adequate upper airway protective reflexes. Complete recovery of the swallowing reflex occurs approximately 15 minutes after the return of consciousness following propofol anesthesia. Thus, patients who are deemed to be at risk from aspiration of gastric contents should be maintained at the lightest level of sedation possible. Ideally, the patient should be awake enough to recognize the regurgitation of gastric contents and be able to protect his or her own airway. If the ability of the patient to protect his or her own airway cannot be reliably guaranteed and regurgitation/aspiration is thought to be a significant risk, placement of a cuffed endotracheal tube under general anesthesia should be seriously considered. Propofol has a particularly potent suppressive effect upon upper airway protective reflexes.
Detailed crystallographic findings show that local anesthetics bind to a hydrophobic pocket within the sodium channels and suggest that ligand binding may be mediated primarily by hydrophobic and van der Waals interactions (Fig 75 mg indocin for sale arthritis pain neck. Compared with experimental setups using isolated nerves purchase indocin 50mg with visa rheumatoid arthritis vagus nerve stimulation, many other factors may influence the potency of local anesthetics on nerves in situ cheap indocin 25mg amex arthritis pain relief uk. Highly36 1444 lipid-soluble agents may be sequestered into surrounding adipose cells and myelin sheaths. Local anesthetics cause vasodilation, which in turn could alter regional drug redistribution. Hence,31 relative potency of local anesthetics has been determined clinically for different applications, and these values are listed in Table 22-4. Finally, anesthetic activity and potency are affected by the stereochemistry of the local anesthetic molecules. Many older drug preparations exist as racemic mixtures; that is, enantiomeric stereoisomers are in equal proportion. Newer agents, namely, ropivacaine and levobupivacaine, are available as specific enantiomers. Although the desired improvement in the safety index has been generally supported in clinical studies, this is at the expense of a slight decrease in potency overall and shorter duration of action compared with racemic mixtures. Topographic features at the channel-binding site are likely to play a key role in stereoselectivity of local anesthetics. Table 22-3 Physicochemical Properties of Clinically Used Local Anesthetics Table 22-4 Relative Potency of Local Anesthetics for Different Clinical Applications Additives to Increase Local Anesthetic Activity 1445 Epinephrine Reported benefits of epinephrine include prolongation of local anesthetic block, increased intensity of block, and decreased systemic absorption of local anesthetic. Epinephrine’s vasoconstrictive effects augment local anesthetics41 by antagonizing inherent vasodilating effects of local anesthetics, decreasing systemic absorption and intraneural clearance, and perhaps by redistributing intraneural local anesthetic. The smallest dose is suggested because epinephrine combined with local anesthetics may have toxic effects on tissue, the cardiovascular system, peripheral nerves, and45 46 the spinal cord. As previously discussed, the neutral form is believed to be important for penetration into the neural cytoplasm, whereas the charged form primarily interacts with the local anesthetic receptor within the sodium channel. Therefore, the rationale for alkalinization was to increase the ratio of local anesthetic existing as the lipid-soluble neutral form. However, clinically used local anesthetics cannot be alkalinized beyond a pH of 6. Together, alkalinization of local anesthetics appears limited as50 a clinically useful adjuvant to improving anesthesia. Opioids Opioids have multiple central and peripheral mechanisms of analgesic action (see Chapter 20). Spinal administration of opioids provides analgesia primarily by attenuating C-fiber nociception and is independent of51 supraspinal mechanisms. Coadministration of opioids with central neuraxial52 local anesthetics results in synergistic analgesia. An exception to this53 analgesic synergy is chloroprocaine, which appears to decrease the effectiveness of opioids coadministered epidurally. The reason is unclear,54 but the mechanism does not seem to involve direct antagonism of opioid receptors. Nonetheless, clinical studies support the practice of central55 neuraxial coadministration of local anesthetics and opioids for prolongation and intensification of analgesia and anesthesia. However, although some studies have reported favorable56 outcomes for such coadministration, others have failed to demonstrate any 1447 increased efficacy. A problem that has plagued many studies is the lack of57 adequate controls for differentiating the analgesic effects of opioids acting peripherally versus a more central mechanism resulting from systemically absorbed opioids. Nonetheless, recent carefully designed trials have shown that some opioids, namely, buprenorphine, may enhance and prolong postoperative analgesia better than either local anesthetics alone or local anesthetics administered with intramuscular buprenorphine. Clonidine also has direct inhibitory effects on61 peripheral nerve conduction (A and C nerve fibers). Thus, addition of62 clonidine may have multiple mechanisms of action depending on the type of application. Preliminary evidence suggests that coadministration of an α -2 agonist and local anesthetic results in central neuraxial and peripheral nerve analgesic synergy, whereas systemic (supraspinal) effects are additive. On63 64 average, clonidine improves the duration of analgesia by about 2 hours, regardless of whether an intermediate- or long-acting local anesthetic is used. Overall, results from clinical trials indicate that clonidine can enhance65 local anesthetic effects when used for intrathecal and epidural anesthesia and peripheral nerve blocks. Experiments in animals using extended-release preparations of local anesthetics have found that addition of dexamethasone to the mixture prolongs the conduction block after peripheral nerve application. Clinical reports of the use of69 dexamethasone as an adjuvant to local anesthetics have shown similar prolongation of anesthesia after brachial plexus blockades70,71 and intravenous regional anesthesia. Combined with intermediate- to long-acting72 local anesthetics, dexamethasone extends the duration of analgesia by approximately 50% after supraclavicular or interscalene approaches to the70 71 brachial plexus block (Fig. Although initial laboratory data show no evidence of increased neurotoxicity from use of dexamethasone as compared with other adjuvants, our current understanding of its mechanism of action 1448 and potential side effects remains incomplete. Currently, such preparations are approved for local infiltration of surgical wounds after bunionectomy and hemorrhoidectomy. Data are shown as the Kaplan–Meier survival density estimates, with the shaded region representing the 95% confidence interval. Effect of dexamethasone on the duration of interscalene nerve blocks with ropivacaine or bupivacaine. Clinically, most frequently reported untoward effects of liposomal79 bupivacaine were nausea and pyrexia. Having a thorough understanding of the factors involved would enable one to maximize the local anesthetic potential while avoiding possible complications arising from systemic local anesthetic toxicity. Systemic Absorption Decreasing systemic absorption of local anesthetics increases their safety margin in clinical uses. The rate and extent of systemic absorption depends on the site of injection, the dose, the drug’s intrinsic pharmacokinetic properties, and the addition of a vasoactive agent. The vascularity of the tissue markedly influences the rate of drug absorption, such that deposition of local anesthetics in vessel-rich tissues results in higher peak plasma levels in a shorter period of time. Accordingly, the rate of systemic absorption is greatest with intercostal nerve blocks, followed in decreasing order by caudal and epidural injections, brachial plexus block, and femoral and sciatic nerve blocks (Table 22-6). Thus, the same amount of local anesthetics injected would result in unequal peak plasma levels depending on the site of drug delivery. For a given site of injection, the rate of systemic absorption and the peak plasma level are directly proportional to the dose of local anesthetic deposited. In general, more potent lipid-soluble agents are associated with a slower rate of absorption than less lipid-soluble compounds (Fig. Local anesthetics exert direct effects on vascular smooth muscles in a concentration-dependent manner. At low concentrations, more potent agents appear to cause more vasoconstriction than less potent agents, thereby decreasing the rate of vascular absorption. At high concentrations, vasodilatory effects seem to38 predominate for most local anesthetics. The pattern of distribution is largely dependent on organ perfusion, the partition coefficient between compartments, and plasma protein binding.
Strategies for acute pain management should also consider the sex of the patient as sex differences appear to exist for pain perception as well as response to opioid analgesics buy indocin now arthritis medication samples. Evidence suggests that women experience more pain following surgery than men cheap indocin 75mg free shipping rheumatoid arthritis bursitis, and therefore require more morphine to achieve a similar level of pain relief generic 75 mg indocin arthritis for dogs treatment. This strategy, known as pharmacogenetics, takes advantage of polymorphic genes, which can impact the pharmacokinetics of a drug by altering drug- metabolizing enzymes, drug transport proteins, and drug receptors. The net effect will determine both the efficacy and side effects of individual drugs in each patient based on their personal genetic profile. Point-of-care phenotype-based dosing strategies would preclude prescribing hydrocodone to patients with the poor metabolizer phenotype. Whereas slow metabolizers of codeine display poor analgesia from the drug, rapid metabolizers can experience toxicity from the active metabolite, morphine (Fig. The frequency of poor metabolizers varies by ethnicity and is reported to be 8% in whites, 2% to 7% in African Americans and 0% to 0. Future strategies will likely incorporate pharmacogenetic approaches to design individualized gene-based pain therapy for each patient, to optimize pain control and minimize adverse effects. No one asked the patient about pain with movement, breathing, moving bowels, and so forth, all potentially important functional goals for the postoperative course that may be undermined by untreated pain. A variety of well-studied pain measurement scales exist that can be helpful yet are not definitive. Unidimensional instruments such as the familiar numerical pain scale already mentioned, the visual analogue scale, and the “faces” (Fig. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Multidimensional instruments, such as the Mcgill Pain Questionnaire or the Brief Pain Inventory, provide a broader picture of a patient’s experience, but are usually more cumbersome to administer and, in the end, suffer the same limitations as all other attempts to measure pain. A number of tools to assess cancer-related and noncancer chronic pain have been advanced and validated. Most of these focus on persistent background pain and do not15 help identify intermittent or breakthrough pain. The Breakthrough Pain Questionnaire was introduced by Portenoy and Hagen to assess breakthrough pain in cancer patients, and has also been studied in patients with acute noncancer pain, for which it can offer a picture of both breakthrough and background pain states. Attempts to reduce the experience to finite details may lead to failure to ask the right questions, distance us from our patients, focus us away from the whole person, and potentially miss golden diagnostic clues that could lead to effective interventions. Effective treatment of acute pain requires assessment as well as vigilant reassessment to determine if the primary goals are met, adversity has occurred, or changes are necessary. Acute pain may be viewed as breakthrough, intermittent, or background in nature (Table 55-5). The assessment process for each of these is relatively similar and will help to resolve the related condition into broad pathophysiologic groups such as cancer versus noncancer, and nociceptive versus neuropathic, or mixed pain states. Such an approach supports a rational process for developing a useful differential diagnosis and approaches. Table 55-6 lists the common features of pain that are usually reviewed during the assessment for acute pain. A thorough physical examination must also be performed with particular attention to the neurologic examination, which may offer clues to aberrant neural processing. Such neurologic findings may indicate nerve injury, alerting the astute clinician to a neuropathic rather than a nociceptive pain state that requires a different analgesic approach. A provocative physical17 examination may include examination of the affected areas with maneuvers that may provoke pain such as range of motion testing, walking, and cough. The benefits of provocative testing must outweigh the associated suffering incurred by the patient. Overemphasis on imaging data should, however, be avoided as this can potentially lead to misinterpretation of the patient’s underlying pain 3938 syndrome. Table 55-5 Three Classes of Acute Pain Table 55-6 Features of Pain Commonly Addressed during Assessment Opioid Analgesics Opioids are the mainstay for the treatment of acute postoperative pain, and morphine is the “gold standard. The opioid receptors are members of a G protein–coupled (guanosine triphosphate regulatory proteins) receptor family, which signals via a second messenger such as cyclic adenosine monophosphate or an ion channel. In the ascending pain pathway, opioid receptors are located in three areas that include (1) the periphery, following inflammation; (2) the spinal cord dorsal horn; and (3) supraspinally in the brainstem, thalamus, and cortex. Peripheral opioid receptors, which mediate analgesia, are located on primary afferent neurons. Activation of these receptors inhibits the release of pronociceptive and proinflammatory substances like substance P, which accounts for the analgesic and anti-inflammatory effects. There is great diversity in the available routes of administration of opioid analgesics. The reader is referred to Perioperative Pain Management of the Opioid-Dependent Patient for a detailed discussion of incomplete cross-tolerance between the different opioids and dosing considerations. Common adverse side effects associated with opioid therapy include nausea, vomiting, constipation, urinary retention, delirium, hallucinations, myoclonus, falls, hypotension, aspiration pneumonia, dizziness, sedation, and respiratory depression. Opioid-related adverse effects have the potential to increase the utilization of health-care resources, which can have profound economic consequences. It is well known that the sine qua non of opioid intoxication is a terminal lethal apnea. Patient characteristics, which increase the risk of21 3940 sedation and respiratory depression, are listed in Table 55-9. Recommendations, which can decrease the risk of opioid-related respiratory depression, include the liberal use of opioid-sparing multimodal pharmacotherapy, regional anesthesia techniques, and the continuous monitoring of patient ventilation with pulse oximetry and capnography, particularly in the high-risk individual. See Table 55-4 for recommendations for multimodal therapy for some commonly performed surgeries. A more comprehensive discussion of this topic is beyond the scope of this chapter and the reader is referred to the excellent review by Javaheri and Randerath. Finally, opioid analgesics22 have profound immunomodulatory effects, which include inhibition of cellular and humoral immune functions, depressed natural killer cell activity, promotion of angiogenesis, and inhibition of apoptosis. Such effects can be beneficial or deleterious depending upon the clinical situation. Although the plasma half-life of the drug is approximately 2 hours its analgesic duration of action is closer to 4 to 5 3942 hours. Morphine undergoes hepatic glucuronidation to morphine-6- glucuronide and morphine-3-glucuronide, both of which are cleared by the kidney. Morphine-6-glucuronide is an active metabolite of morphine and is thought to be responsible for most of the analgesia associated with chronic dosing of the drug. Morphine-3-glucuronide, on the other hand, is considered to be devoid of analgesic activity. With chronic dosing these metabolites can accumulate and can be particularly problematic in patients with renal failure. Dosing adjustment is therefore necessary and monitoring of side effects is important.