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By U. Kerth. Cabrini College.

In unstressed subjects purchase clomiphene 50 mg mastercard, severe anemia (Hb of 5 g/dL or less) is amazingly well tolerated due to physiologic compensations that maintain oxygen delivery and extraction generic 50mg clomiphene otc. However buy clomiphene 50 mg lowest price, it has long been assumed that critically ill patients have less efficient compensatory mechanisms and reduced physiologic reserve cheap 25 mg clomiphene amex, and thereby require a higher Hb concentration than unstressed individuals. A similar trial in pediatric patients found no mortality difference between restrictive and liberal transfusion strategies, suggesting that a restrictive strategy is safe in critically ill children. Prevention of anemia in critical illness is an appealing alternative to transfusion. As noted earlier, iatrogenic blood loss is a major factor in the development of anemia of critical illness. Another potential approach is the administration of recombinant erythropoietin and iron. Poor nutritional status is associated with increased mortality and morbidity among critically ill patients. Therefore, appropriate nutrition is an important aspect of critical care and adequate nutritional support should be considered a standard of care. Feeding intolerance due to high gastric residual volume can be improved by the administration of gastric prokinetic agents and positioning an enteric tube postpyloric. This effect appears more likely in surgical patients, such as those with burns and those who are in trauma. Specific enteral formulations, particularly those with high concentrations of glutamine, have the strongest data to support their use. Although individual medications frequently provide multiple pharmacodynamic effects, including sedation, analgesia, and anxiolysis, it is helpful to think about these effects separately when selecting medications for an individual patient. For instance, painful procedures such as the insertion of indwelling catheters, endotracheal tubes, and thoracostomy tubes require analgesia, but often do not require anxiolysis or sedation. Conversely, agitated delirium or acute alcohol withdrawal do not require analgesia and are more appropriately treated with sedatives. The patient with an ideal level of sedation and analgesia is at reduced risk for dislodging catheters, removing monitoring devices, or falling out of bed. They are more likely to be synchronous with the mechanical ventilator, which improves oxygenation and reduces the risk of lung injury. They are also better able to participate with care, early mobilization, and physical and occupational therapy. Therefore, it is important to titrate medications according to established therapeutic goals and reevaluate sedation requirements frequently. Features common to all of these scales are the ability to grade sedation over different depths and allow for indicators of agitation. The important point regarding assessment scales for pain, sedation, and delirium is that an assessment utilizing a validated scoring system should be made before and after every intervention to assess progress in achieving treatment goals. However, propofol, midazolam, and dexmedetomidine are the most commonly used hypnotic-anxiolytics. Each of these drugs has its own particular advantages and disadvantages, and detailed discussions of their properties can be found in Chapters 19 and 20. Dexmedetomidine is unique in that its mechanism of action is profoundly different from that of propofol and benzodiazepines. It provides sedation without inducing unresponsiveness or coma, may have some analgesic effects,200,201 and has little affect on respiratory drive. Generally speaking, however, dexmedetomidine is effective for patients who do not require deep sedation (e. Because it does not reliably produce amnesia, it is not appropriate as a solo hypnotic-anxiolytic in patients requiring paralysis. Propofol is generally more effective in these settings, but can cause hypertriglyceridemia and lead to the potentially lethal “propofol infusion syndrome. Neither randomized nor retrospective data 4127 support dexmedetomidine use in patients with alcohol withdrawal, in terms of meaningful clinical outcome. Although the aforementioned physiologic rationale for the choice of a certain regimen exists, certain regimens may be superior in terms of patient outcomes of untoward neurocognitive effects, time on the ventilator, and length of stay. A large, well-conducted study204 (two separate arms, no institutional cross-over) comparing dexmedetomidine with either propofol or midazolam demonstrated noninferiority for dexmedetomidine, although patients receiving propofol required less rescue sedation than those receiving dexmedetomidine. When compared to midazolam, dexmedetomidine may also be associated with a small reduction in the duration of mechanical ventilation, and it appears to provide significantly better patient responsiveness and cooperation compared to both drugs. Conversely, patients receiving dexmedetomidine were twice as likely as patients receiving propofol to have had cardiovascular instability. A trend toward higher mortality was observed in the dexmedetomidine group, but disappeared when all dexmedetomidine patients were compared to all propofol and midazolam patients. Interestingly, there was no difference between dexmedetomidine and midazolam on measures of agitation and delirium, whereas the difference between dexmedetomidine and propofol was statistically significant. A meta-analysis including 27 randomized trials comparing propofol versus midazolam suggested that tracheal extubation occurred earlier with the use of propofol for patients who were ventilated for a duration shorter than 36 hours. Greater levels of hypotension and elevated triglyceride levels were observed with the use of propofol. Like dexmedetomidine, opiates do not reliably produce amnesia, and are not appropriate as single agents in patients who require paralysis. Morphine should be avoided in patients with renal failure due to active metabolites that accumulate in the presence of impaired 4128 renal function. A single trial has demonstrated a benefit in mortality and ventilator-free days, but routine use is discouraged until these results are validated. Delirium and Neurocognitive Complications Neurocognitive complications including delirium and prolonged cognitive dysfunction are associated with a number of sedative medications, and may be more common in patients treated with deeper levels of sedation. The distinguishing characteristics of delirium include an acute onset and fluctuating course, inattention, disorganized thinking, and altered level of consciousness. Although some literature supports the notion that benzodiazepine use may be associated with an increased frequency of delirium, two well-conducted trials failed to show a reduction in delirium in patients randomized to dexmedetomidine compared to benzodiazepine. The 4129 only randomized, controlled trial of such use did show a reduction in periods of delirium with regular quetiapine administration, but the study was small. A systematic review of a number of pharmacologic prevention or treatment strategies (e. Approximately one-third will have signs and symptoms of cognitive dysfunction 12 months after discharge. Further, long-term follow-up of patients enrolled in sedation trials has not found sedation regimens promoting light sedation or daily awakening to be associated with increased long-term cognitive, psychological, or functional problems. At some level, nosocomial infections are unavoidable and occur because of the nature of intensive care—patients are critically ill with altered host defenses, they require invasive devices (endotracheal tubes, intravascular catheters, etc. On the other hand, many nosocomial infections are preventable with relatively simple interventions. Sinusitis Radiographic sinusitis is common in critically ill patients with indwelling oral and nasal tubes. Nasotracheal intubation confers a greater risk than does orotracheal intubation of radiographic sinusitis, occurring in approximately 95% and 25% of patients with nasal and oral tubes after 1 week of intubation, respectively. Prevention of sinusitis should focus on efforts to improve sinus drainage, including semirecumbent positioning and avoidance of nasal tubes. If radiographic sinusitis is documented, any nasal tubes should be removed, and nasal irrigation and short-term administration of nasal decongestants should be considered. If the patient is severely ill, broad-spectrum antibiotic coverage should be considered. If these maneuvers do not result in resolution of signs and symptoms of sinusitis in 2 to 3 days, otolaryngologic consultation and consideration of sinus drainage procedures may be undertaken. In general, early-onset organisms are associated with zero or low attributable mortality, whereas late-onset organisms, particularly Pseudomonas and Acinetobacter species, are associated with higher mortality. The simplest and least expensive interventions are strict handwashing between patients, and semirecumbent 4132 positioning of the patient (head-of-bed angle at 30 degrees or greater from horizontal). The use of acid suppression therapy to prevent gastrointestinal bleeding is more controversial. Thus, gastrointestinal acid suppression therapy may be reserved for high-risk patients, and sucralfate may be considered as an alternative agent to acid-suppressive regimens despite its potentially reduced effectiveness. Invasive strategies typically involve collection of either tracheal aspirate specimens or bronchial–alveolar specimens using lavage or protected brushes, and then quantitating bacterial growth in the laboratory. Antibiotics can then be narrowed in spectrum or discontinued altogether depending on the results from quantitative cultures after 48 to 72 hours (Table 57-6). This approach is known as “de-escalating therapy” and is designed to ensure adequate antibiotic treatment up front, but avoid overuse of antibiotics in the long term. It is unclear whether intermediate courses of therapy would have avoided infection recurrence. However, the incidence of bacteremia is affected by several factors, including the conditions and technique of insertion, type and location of catheter, and the duration of catheterization, and can vary widely from study to study. This includes pre-insertion handwashing, full gown and gloves, and the use of a large barrier drape. In addition, skin cleansing with22 chlorhexidine is more effective than other agents at reducing catheter-related infection. However, routine catheter replacement at 3 or 7 days does not reduce the incidence of infection, and results in increased mechanical complications. Catheters coated with either antiseptics (chlorhexidine and silver sulfadiazine) or antibiotics (rifampin and minocycline) reduce bacterial colonization of catheters as well as bacteremia. Routine flushing of catheter ports with heparin reduces both the incidence of thrombosis and infection. However, heparin solutions contain antimicrobial preservatives and it is unclear if the heparin or the preservative is responsible for the beneficial effect. Depending on the patient’s severity of illness, a strong suspicion of catheter-related bacteremia should trigger the institution of broad-spectrum antibiotic coverage, including coverage for methicillin-resistant staphylococcal species and nonlactose–fermenting gram- negative rods, until culture results return, with subsequent de-escalation of therapy. Positive cultures from sterile fluid remain the gold standard, but may take 72 to 96 hours to turn positive and may be positive in only 50% of autopsy-confirmed infections. Candida is frequently cultured from the urine and sputum, but treatment is usually not necessary, as Candida pneumonia is unlikely and candiduria often clears without treatment, mostly with discontinuation of the bladder catheter. In addition, candiduria often recurs after initially successful antifungal therapy. True Candida peritonitis is also difficult to separate from contamination of culture specimens, but given that the mortality associated with Candida peritonitis is approximately 50%, treatment is warranted if clinical signs suggest infection. Disseminated blood-borne Candida infection can result in endophthalmitis, endocarditis, and hepatic and pulmonary abscesses. It is likely to occur when initial treatment of candidemia is delayed, and is associated with a high mortality. Prophylactic therapy with fluconazole may be effective at reducing the risk of invasive Candida infection in high-risk patients, but this strategy has not been associated with improved mortality in the nonneutropenic population, and may increase the incidence of invasive infection with more resistant species, such as C. However, care should be taken to de-escalate therapy after several days in the absence of positive cultures or clinical response. Documented Candida bloodstream infection should be treated aggressively, with therapy started promptly and continued for at least 2 weeks after the last positive blood culture. An ophthalmologic examination is warranted in patients with documented or suspected bloodstream infection, as patients with endophthalmitis may require longer courses of therapy.

However generic 100mg clomiphene visa, the anticonvulsant properties of benzodiazepines and barbiturates may attenuate the seizures associated with neurotoxicity buy clomiphene 25 mg visa. In both of these circumstances purchase 50mg clomiphene overnight delivery, it is possible that the symptoms of cardiotoxicity will be the first evidence that an adverse reaction has occurred clomiphene 100mg amex. Thus, appropriate treatment is delayed or inadvertent intravascular injection is continued because of the absence of any clinical evidence of neurotoxicity. Cardiovascular toxicity usually occurs at a higher plasma concentration than neurotoxicity, but when it does occur, it is usually much more difficult to manage than neurotoxicity. Although cardiotoxicity is usually preceded by neurotoxicity, it may on occasion be the initial presenting feature. Deep sedation is occasionally delivered by trained specialists, including emergency department physicians and intensivists. The specific reasons for nonanesthesiologist involvement differ from institution to institution and from case to case and include convenience, availability, and scheduling issues; perceived lack of anesthesiologist availability; perceived increased cost; and a perceived lack of benefit concerning patient satisfaction and safety when sedation and analgesia are provided by anesthesiologists. Despite our frequent noninvolvement in these cases, anesthesiologists are indirectly involved in the care of these patients by being required to participate in the development of institutional policies and procedures for sedation and analgesia, as mandated by the Joint Commission. The practice guidelines emphasize that sedation and analgesia represent a continuum of sedation wherein patients can easily pass into a level of sedation deeper than intended. This statement contains a chart representing the clinical progression along this continuum (Table 30- 9). The importance of continuous patient monitoring is discussed—in particular, the response of the patient to commands as a guide to the level of sedation. The appropriate monitoring of ventilation, oxygenation, and hemodynamics is also discussed, and recommendations are made for the contemporaneous recording of these parameters. The task force strongly suggests that an individual other than the person performing the therapeutic or diagnostic procedure be available to monitor the patient’s comfort and physiologic status. Specific educational objectives include the potentiation of sedative-induced respiratory depression by concomitantly administered opioids, adequate time intervals between doses of sedative/analgesics to avoid cumulative over-dosage, and familiarity with sedative/analgesic antagonists. At least one person with Basic Life Support training should be available during moderate sedation, with immediate availability (1 to 5 minutes) of personnel trained in Advanced Life Support. This individual should have the ability to recognize airway obstruction, establish an airway, and maintain oxygenation and ventilation. The practice guidelines recommend that appropriate patient- size emergency equipment be readily available, specifically including equipment for establishing an airway and delivering positive pressure ventilation with supplemental oxygen, emergency resuscitation drugs, and a working defibrillator. Adequate postprocedure recovery care with appropriate monitoring must be provided until discharge. Controversy exists regarding the level of training required for nonanesthesiologists to be credentialed to provide moderate and deep sedation. These “anesthesia” services must be provided by: A qualified anesthesiologist; a doctor of medicine or osteopathy, a dentist, oral surgeon, or podiatrist who is qualified to administer anesthesia under state law; an appropriately supervised Certified Registered Nurse Anesthetist or Anesthesia Assistant, all who are separate from the practitioner performing the procedure. Failure to follow these recommendations could put patients at increased risk of significant injury or death. These devices integrate patient monitoring variables with the programmed delivery of propofol. The manufacturer of this system required that it should only be used in facilities where an anesthesia professional is immediately available to assist or consult as needed. However, the device worked in conjunction with a single administered dose of fentanyl given 3 minutes prior to the start of a propofol infusion in an attempt to yield some analgesic effect. After a maintenance infusion rate escalation, further increases were limited by a 3-minute lockout period. There were several safety mechanisms in place to ensure both adequate depth of sedation, and prevention of oversedation. An automated responsiveness monitor actuated by the patient assessed his/her responsiveness by requiring interaction with a hand-held device when prompted by vibratory or auditory stimulation. Oxygen delivery was also automatically titrated as determined by oxygen saturation measurement. There were alarm systems to alert the provider to low respiratory rate, low oxygen saturation or apnea events. Monitored anesthesia care presents an opportunity for our patients to observe us at work. For the anesthesiologist, monitored anesthesia care presents an opportunity to provide a more prolonged and intimate level of care and reassurance to our patients that is in contrast to the more limited exposure that occurs during and after general anesthesia. Our airway management skills and our daily practice of applied pharmacology make us uniquely qualified to provide this service. Monitored anesthesia care presents us with an opportunity to display these skills and increase our recognition in areas outside the operating room. The availability of drugs with a more favorable pharmacologic profile allows us to tailor our techniques to provide the specific components of analgesia, sedation, anxiolysis, and amnesia with minimal morbidity and to facilitate a prompt recovery. As the population ages, increasing numbers of patients will become candidates for monitored anesthesia care. It is our responsibility to clearly demonstrate to our nonanesthesia colleagues that anesthesiologist-provided monitored anesthesia care contributes to the best outcome for our patients. If anesthesiologists are not willing or able to provide these services, others, who are less well qualified, are prepared to assume that role. The effect of the assignment of a pre-sedation target level on procedural sedation using propofol. Comparison of a computer-assisted infusion versus intermittent bolus administration of alfentanil as a supplement to nitrous oxide for lower abdominal surgery. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Context-sensitive half-times: What are they and how valuable are they in anaesthesiology? Use of alfentanil and propofol for outpatient monitored anesthesia care: Determining the optimal dosing regimen. Pharmacokinetic- pharmacodynamic modeling of the electroencephalographic effects of benzodiazepines. Comparison of propofol administration techniques for sedation during monitored anesthesia care. The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision. Reduction by fentanyl of the Cp50 values of propofol and hemodynamic responses to various noxious stimuli. The pharmacodynamic interaction between propofol and fentanyl with respect to the suppression of somatic or hemodynamic responses to skin incision, peritoneum incision, and abdominal wall retraction. Hypnotic and anaesthetic interactions between 2088 midazolam, propofol and alfentanil. Achieving control of anesthetic administration: The infusion pump versus the vaporizer. Fentanyl or alfentanil decreases the minimum alveolar anesthetic concentration of isoflurane in surgical patients. Anesthesia matters: Patients anesthetized with propofol have less postoperative pain than those anesthetized with isoflurane. A comparison of propofol and midazolam by infusion to provide sedation in patients who receive spinal anaesthesia. Sedative infusions during local and regional anesthesia: a comparison of midazolam and propofol. Propofol decreases early postoperative nausea and vomiting in patients undergoing thyroid and parathyroid operations. Day-surgery patients anesthetized with propofol have less postoperative pain than those anesthetized with sevoflurane. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. Propofol anaesthesia and postoperative nausea and vomiting: Quantitative systematic review of randomized controlled studies. Comparison of propofol, droperidol, and metoclopramide for prophylaxis of postoperative nausea and vomiting after breast cancer surgery: A prospective, randomized, double-blind, placebo-controlled study in Japanese patients. Prevention of postoperative nausea and vomiting with a small dose of propofol combined with dexamethasone 4 mg or dexamethasone 8 mg in patients undergoing middle ear surgery: a prospective, randomized, double- blind study. Fospropofol disodium injection for the sedation of patients undergoing colonoscopy. Erroneously published fospropofol pharmacokinetic-pharmacodynamic data and retraction of the affected publications. Fospropofol assay issues and impact on pharmacokinetic and pharmacodynamic evaluation. Fospropofol assay issues and impact on pharmacokinetic and pharmacodynamic evaluation. Clinical trial: A dose-response study of fospropofol disodium for moderate sedation during colonoscopy. A randomized, double-blind, phase 3 study of fospropofol disodium for sedation during colonoscopy. Propofol versus midazolam for monitored sedation: A comparison of intraoperative and recovery parameters. Propofol and alfentanil for sedation during placement of retrobulbar block for cataract surgery. Effects of fentanyl on pain and hemodynamic response after retrobulbar block in patients having phacoemulsification. A comparison of midazolam, alfentanil and propofol for sedation in outpatient intraocular surgery. Optimal target concentration of remifentanil during cataract surgery with monitored anesthesia care. Remifentanil versus alfentanil as analgesic adjuncts during placement of ophthalmologic nerve blocks. Impaired memory and behavioral performance with fentanyl at low plasma concentrations. Effect of single-dose fentanyl on the cardiorespiratory system in elderly patients undergoing cataract surgery. Can remifentanil be a better choice than propofol for colonoscopy during monitored anesthesia care? Propofol/remifentanil versus propofol alone for bone marrow aspiration in paediatric haemato-oncological patients. Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid. Remifentanil as an analgesic adjunct in local/regional anesthesia and in monitored anesthesia care. Remifentanil-propofol versus fentanyl-propofol for monitored anesthesia care during hysteroscopy.

An additional difficulty in defining anesthesia is that our understanding of the mechanisms of consciousness is rather amorphous at present cheap clomiphene 50mg on line. One cannot easily define anesthesia when the neurobiologic phenomena ablated by anesthesia are not well understood generic clomiphene 100 mg on line. As discussed later in this chapter proven clomiphene 25mg, the neural substrates for consciousness are beginning to be unraveled1 discount clomiphene 100mg,2 and new theories3,4 have incorporated this new anatomic knowledge leading to identification of surrogate physiologic markers of consciousness. These new5 insights into mechanisms of consciousness are discussed in the section Where in the Central Nervous System Do Anesthetics Work? Finally, it has long been assumed that anesthesia is a state that is achieved when an anesthetic agent reaches a specific concentration at its effect site in the brain and that if tolerance to the anesthetic develops, increasing concentrations of anesthetic might be required to maintain a constant level of anesthesia during prolonged anesthetic administration. The finding that it takes a higher anesthetic brain concentration to induce anesthesia than to maintain anesthesia (i. This6 phenomenon, referred to as neural inertia, adds a wrinkle to the definition of anesthesia, suggesting that the mechanisms of anesthetic induction and emergence may be different. This suggestion is supported by the recent finding that the sedative component of anesthesia can be reversed by stimulation of specific arousal pathways in the brain, even in the presence of “anesthetic” concentrations of inhalational agents. In order to study the pharmacology of anesthetic action, quantitative measurements of anesthetic potency are absolutely essential. First, it is an extremely reproducible measurement that is remarkably constant over a wide range of species. Second, the use of end-9 tidal gas concentration provides an index of the “free” concentration of drug required to produce anesthesia since the end-tidal gas concentration is in equilibrium with the free concentration in plasma. To date, these monitors have not been shown to be more effective at preventing awareness during anesthesia than simply maintaining an adequate end-tidal anesthetic concentration13,14 or giving a standard dose of intravenous anesthetic. The Meyer–Overton Rule More than 100 years ago, Meyer and Overton independently17 18 observed that the potency of gases as anesthetics was strongly correlated with their solubility in olive oil (Fig. Since a wide variety of structurally unrelated compounds obey the Meyer–Overton rule, it has been reasoned that all anesthetics are likely to act at the same molecular site. On the basis of this reasoning, the anesthetic target site was assumed to be hydrophobic in nature. Since olive oil/gas partition coefficients can be determined for gases and volatile liquids, but not for liquid anesthetics, attempts have been made to correlate anesthetic potency with solvent/water partition coefficients. To date, the octanol/water partition coefficient best correlates with anesthetic potency. This correlation holds for a variety of classes of anesthetics and spans a 10,000-fold range of anesthetic potencies. The properties of the19 solvent octanol suggest that the anesthetic site is likely to be amphipathic, having both polar and nonpolar characteristics. Some characteristics of an exceptionally potent inhaled anesthetic: thiomethoxyflurane. On the basis of olive oil/gas partition coefficients of the halogenated convulsant compounds, anesthesia should have been achieved within the range of concentrations studied. Halogenated compounds have23 also been identified that are neither anesthetic nor convulsant, despite oil/gas partition coefficients that would predict they should be anesthetics. In several homologous series of anesthetics, anesthetic potency increases with increasing chain length until a certain critical chain length is reached. Beyond this critical chain length, compounds are unable to produce anesthesia, even at the highest attainable concentrations. In the series of n- alkanols, for example, anesthetic potency increases from methanol through dodecanol; all longer alkanols are unable to produce anesthesia. Cutoff effects have been described for several homologous series of anesthetics including n-alkanes, n- alkanols, cycloalkanemethanols, and perfluoroalkanes. While the26 27 anesthetic potency in each of these homologous series of anesthetics shows a cutoff, a corresponding cutoff in octanol/water or oil/gas partition coefficients has not been demonstrated. Therefore, compounds above the cutoff represent a deviation from the Meyer–Overton rule. A final deviation from the Meyer–Overton rule is the observation that enantiomers of anesthetics differ in their potency as anesthetics. Enantiomers (mirror-image compounds) are a class of stereoisomers that have identical physical properties, including identical solubility in solvents such as octanol or olive oil. Animal studies of barbiturate anesthetics, ketamine,28 29 neurosteroids, etomidate, and isoflurane all show enantioselective30 31 32 differences in anesthetic potency. It is argued that a major difference in anesthetic potency between a pair of enantiomers can only be explained by a protein-binding site (see Protein Theories of Anesthesia); this appears to be the case for etomidate and the neurosteroids. The exceptions to the Meyer– Overton rule indicate that the properties of a solvent such as octanol describe some, but not all, of the properties of an anesthetic-binding site. Properties such as size and shape must also be important determinants of anesthetic sites 598 of action. Lipid versus Protein Targets Anesthetics might interact with several possible molecular targets to produce their effects on the function of ion channels and other proteins. Anesthetics might dissolve in the lipid bilayer, causing physicochemical changes in membrane structure that alter the ability of embedded membrane proteins to undergo conformational changes important for their function. Alternatively, anesthetics could bind directly to proteins (either ion channel proteins or modulatory proteins), thus either interfering with binding of a ligand (e. The following section summarizes the arguments for and against lipid theories and protein theories of anesthesia. Lipid Theories of Anesthesia In its simplest incarnation, the lipid theory of anesthesia postulates that anesthetics dissolve in the lipid bilayers of biologic membranes and produce anesthesia when they reach a critical concentration in the membrane. Consistent with this hypothesis, the membrane/gas partition coefficients of anesthetic gases in pure lipid bilayers correlate strongly with anesthetic potency. Also, consistent with the lipid theories, various membrane33 perturbations are produced by general anesthetics; however, the magnitude of these changes produced by clinical concentrations of anesthetics are quite small and are thought to be very unlikely to disrupt nervous system function. While some of the more sophisticated lipid theories can account34 for the cutoff effect and for the ineffectiveness of nonimmobilizers, no lipid theory can plausibly explain all anesthetic pharmacology. Thus, most investigators do not consider lipids as the most likely target of general anesthetics. Protein Theories of Anesthesia The Meyer–Overton rule could also be explained by the direct interaction of anesthetics with hydrophobic sites on proteins. Anesthetics could bind in hydrophobic pockets that are fortuitously present in the protein core. Hydrophobic amino acids also form the lining of binding sites for hydrophobic ligands. For example, there are hydrophobic pockets in which fatty acids tightly bind on proteins such as albumin and the low–molecular-weight fatty acid–binding proteins. Anesthetics could compete with endogenous ligands for binding to such sites on either water-soluble or membrane proteins. Hydrophobic amino acids are major constituents of the α-helices, which form the membrane-spanning regions of membrane proteins; hydrophobic amino acid side chains form the protein surface that faces the membrane lipid. Anesthetic molecules could interact with pockets formed between the α-helices or with the hydrophobic surface of these membrane proteins, disrupting normal lipid–protein interactions and possibly directly affecting protein conformation. Direct interaction of anesthetic molecules with proteins not only satisfies the Meyer–Overton rule, but would also provide the simplest explanation for compounds that deviate from this rule. Any protein-binding site is likely to be defined by properties such as size and shape in addition to its solvent properties. Limitations in size and shape could reduce the binding affinity of compounds beyond the cutoff, thus explaining their lack of anesthetic effect. Enantioselectivity is also most easily explained by a direct binding of anesthetic molecules to defined sites on proteins; a protein-binding site of defined dimensions could readily distinguish between enantiomers on the basis of their different shapes. Protein-binding sites for anesthetics could also explain the convulsant effects of some polyhalogenated alkanes. Different compounds binding (in slightly different ways) to the same binding pocket can produce different effects on protein conformation and hence on protein function. For example, polyhalogenated alkanes (nonimmobilizers) could be inverse agonists, binding at the same protein sites at which halogenated alkane anesthetics are agonists. The evidence for direct interactions between anesthetics and proteins is briefly reviewed in the following section. Evidence for Anesthetic Binding to Proteins A breakthrough in protein theories of anesthesia was the demonstration that a purified water-soluble protein, firefly luciferase, could be inhibited by general anesthetics. This provided the important proof of principle that anesthetics could bind to proteins in the absence of membranes. Numerous studies have extensively characterized the anesthetic inhibition of firefly luciferase activity and have shown that inhibition occurs at concentrations very similar to those required to produce clinical anesthesia, is consistent with the Meyer–Overton rule, is competitive with respect to the substrate D-luciferin, and exhibits a cutoff in anesthetic potency for both n-alkanes and n-alkanols. To address proteins more relevant to anesthetic effects on the nervous system, numerous studies have employed site-directed mutagenesis of anesthetic-sensitive ion channels to identify amino acid residues that are crucial to anesthetic action. While the residues identified in these studies may contribute to anesthetic-binding sites, they may alternatively be sites that are essential for anesthetic-induced conformational changes in the protein. The literature on site-directed mutagenesis studies to identify putative anesthetic- binding sites on ion channels is extensively reviewed in the section Anesthetic Actions on Ion Channels. These44 45 photoaffinity-labeling reagents can be used to identify putative anesthetic- binding sites, the functional significance of which can be validated using site- directed mutagenesis. These data suggest an etomidate-binding pocket in the3 transmembrane domain at the interface between the α and β subunits. Photoaffinity-labeling studies with other anesthetic agents including propofol43,47 and barbiturates have identified binding pockets for48 anesthetics, which are currently being tested and validated using site-directed 601 mutagenesis. Although photoaffinity-labeling techniques can provide extensive information about anesthetic-binding sites on proteins, they cannot reveal the details of the three-dimensional structure of these sites. X-ray diffraction crystallography can provide this kind of three-dimensional detail and has been used to study anesthetic interactions with a small number of proteins. Firefly luciferase has been crystallized in the presence and absence of the anesthetic bromoform, confirming that anesthetics bind in the D-luciferin–binding pocket. Human serum albumin has also been crystallized in the presence of49 either propofol or halothane, demonstrating binding of both anesthetics to preformed fatty acid–binding pockets. While these data provide insight into the structure of anesthetic-binding sites, x-ray crystallographic studies of anesthetic-binding sites on biologically relevant targets such as ion channels have been hampered by difficulties with crystallizing membrane proteins. These data reveal a preformed binding cavity in51 the interface between the transmembrane domains of each subunit of the ion channel. It is important to recognize that even the x-ray crystal structures of anesthetics bound to target ion channels may not fully elucidate how and where anesthetics act. Ion channels are allosteric proteins that fluctuate between multiple conformations, whereas x-ray structures are static “snapshots” of just one conformation. Anesthetics bind to and stabilize specific conformations of proteins, which may or may not be the same conformation in which the protein is crystallized. Summary Evidence from studies using water-soluble proteins demonstrates that anesthetics can bind to hydrophobic pockets on proteins and that anesthetic– protein interactions can account for the Meyer–Overton rule and deviations from it. While the long-standing controversy between lipid and protein theories of anesthesia may be behind us, numerous unanswered questions remain about the details of anesthetic–protein interactions, including: 1. Do anesthetics compete with endogenous ligands for binding to hydrophobic pockets on protein targets or do they bind to fortuitous cavities in the protein? Do all anesthetics bind to the same pocket on a protein or are there multiple hydrophobic pockets for different anesthetics? How many proteins have hydrophobic pockets in which anesthetics can bind at clinically relevant concentrations? How Do Anesthetics Interfere with the Electrophysiologic Function of the Nervous System?

It is important to note that severely preeclamptic women need to be adequately prepared prior to neuraxial anesthesia with judicious hydration and control of blood pressure cheap clomiphene 100 mg otc. Systemic and pulmonary blood pressure during cesarean section in parturients with gestational hypertension generic clomiphene 100 mg with amex. Rapid-sequence induction of anesthesia and intubation of the trachea are occasionally difficult because of a swollen tongue cheap 100 mg clomiphene free shipping, epiglottis discount clomiphene 100 mg online, or pharynx (see Chapter 28). In patients with impaired coagulation, laryngoscopy and intubation of the trachea may provoke profuse bleeding. Marked systemic and pulmonary hypertension occurring at intubation and extubation enhance the risk of cerebral hemorrhage and pulmonary edema (Fig. However, 2879 these hemodynamic changes can be minimized with appropriate antihypertensive therapy, such as administration of labetalol or nitroprusside infusion. Magnesium may prolong the effects of all muscle relaxants through its actions on the myoneural junction. Therefore, relaxants should be administered with caution (using a nerve stimulator) to avoid overdosage. General anesthesia may be necessary in acute emergencies, such as abruptio placentae, and in patients who do not meet the criteria for neuraxial anesthesia. Obstetric Hemorrhage Worldwide, hemorrhage remains the leading cause of maternal mortality, causing 25% of peripartum deaths. The vast majority of these deaths occur in the developing world; however, there is evidence that the rate and severity of hemorrhage are increasing in developed nations, including the United States. Antepartum hemorrhage occurs in association with placenta previa (abnormal placental implantation on the lower uterine segment and partial-to- total occlusion of the internal cervical os) and abruptio placentae. Risk factors for placenta previa include previous cesarean delivery, uterine surgery, or pregnancy termination. The risk for placenta previa increases in a “dose-dependent” manner with the number of previous cesarean deliveries and greater parity. If bleeding is not profuse and the fetus is immature, obstetric management is conservative to prolong pregnancy. Admission to a high-risk unit is advisable if contractions or acute bleeding are present. Intravenous access and typed and cross-matched blood should be available at all times. In severe cases, or if the fetus is mature at the onset of symptoms, prompt delivery is indicated, usually by cesarean section. Anesthesia for delivery of patients with placenta previa may be with neuraxial anesthesia, provided the mother is hemodynamically stable. Past 2880 recommendations for general anesthesia to provide “more control” are not supported by the literature, as there is no difference in complications between the two techniques, except that general anesthesia is associated with greater blood loss and greater need for transfusion. An emergency hysterectomy may be required if there is severe hemorrhage, even after delivery of the placenta, because of uterine atony. The risk of severe hemorrhage after attempted removal of the placenta is greatly increased in patients who have undergone prior uterine surgery, including cesarean delivery. This is related to a higher incidence of placenta accreta, which results from the penetration of myometrium by placental villi. The risk of placenta accreta in women with previa increases from 3% in primary cesarean section to 61% in quaternary section. When placenta accreta is suspected or known, delivery is usually scheduled at 36 to 37 weeks of gestation via cesarean hysterectomy. Some institutions may use occlusive balloon catheters placed in the internal iliac arteries prior to surgical delivery. In the face of bleeding with either placenta previa or accreta, when maintenance of fertility is desired, arterial embolization or ligation, uterine compression sutures, and/or methotrexate therapy may be attempted to avoid hysterectomy. Complications include Couvelaire uterus (when extravasated blood dissects between the myometrial fibers), renal failure, disseminated intravascular coagulation, and anterior pituitary necrosis (Sheehan syndrome). The diagnosis of abruptio placentae is based on the presence of uterine tenderness and hypertonus as well as vaginal bleeding of dark, clotted blood. Bleeding may be concealed if the placental margins have remained attached to the uterine wall. If the blood loss is severe (>2 L), there may be changes in the maternal blood pressure and pulse rate, indicative of hypovolemia. Fetal movement may increase during acute hypoxia or decrease if hypoxia is gradual. Management of abruption depends on presentation, gestational age, and the degree of compromise. Management of milder cases of abruption includes artificial rupture of 2881 amniotic membranes and oxytocin augmentation of labor, if required. In the presence of nonreassuring fetal status, an emergency cesarean delivery may be performed. If fetal death has occurred, usually with severe abruption, vaginal delivery is reasonable if the mother is stable. Postpartum hemorrhage is usually defined as blood loss greater than 500 mL after vaginal delivery or greater than 1,000 mL after cesarean section. The incidence of postpartum hemorrhage is increasing in the United States, mainly due to an increase in uterine atony. Treatment of postpartum hemorrhage may require aggressive uterotonic therapy for atony, intrauterine balloon tamponade or evacuation of the uterus for retained products of conception (Table 41-2). If there is a need for dilation and curettage, the anesthesiologist may be asked to provide uterine relaxation. This can be accomplished with volatile agents if the patient is under general anesthesia or with intravenous nitroglycerin if regional anesthesia or general anesthesia is used. The anesthesiologist’s role in management of obstetric hemorrhage includes both maternal resuscitation and provision of anesthesia for cesarean delivery, cesarean hysterectomy, or dilation and curettage. The choice of anesthetic technique depends on the anticipated duration of surgery, maternal condition and volume status, the potential for coagulopathy, and urgency of the procedure. General anesthesia is indicated in the presence of uncontrolled hemorrhage and/or severe coagulation abnormalities. Neuraxial anesthesia, usually continuous epidural anesthesia, has been successfully used for hysterectomy in planned, controlled situations. A saddle block is an option for anesthesia when dilation and curettage for treatment of postpartum hemorrhage is indicated and the patient is hemodynamically stable. All of these tasks may be challenging in the parturient and consideration should be given to performing them in advance of hemorrhage when hemorrhage is anticipated. Prompt transfusion of blood component therapy is crucial for replacement of blood loss, maintenance of tissue oxygenation, and correction of coagulopathy. In recent years, transfusion rates for postpartum hemorrhage have increased 92% in the United States. Early administration of platelets and cryoprecipitate has also become common in hemostatic resuscitation protocols for major traumatic hemorrhage, and crystalloid and colloid administration is minimized in favor of blood products (see Chapter 53). Hypothermia, metabolic acidosis, and coagulopathy commonly occur in traumatic and obstetric hemorrhage. Because of these commonalities, it has become common to extend these successful transfusion practices from the trauma literature to obstetric practice. Transfusion of cryoprecipitate or better, fibrinogen concentrate, should be incorporated early in obstetric hemorrhage because decreased fibrinogen levels strongly correlate with increased severity of postpartum hemorrhage. Other options are available to decrease transfusion requirements and reduce blood loss. Intraoperative cell salvage, formerly shunned because of concerns about the risk of amniotic fluid contamination of red cells, has been implemented safely during cesarean section in many centers. The antifibrinolytic drug tranexamic acid has been shown to decrease bleeding in both elective cesarean section and postpartum hemorrhage and is recommended for early use in resuscitation by a European task force131; however, further studies are needed to confirm its safety. Medical and surgical advancements have changed the types of cardiac problems seen in pregnancy. Patients with congenital heart disease are reaching childbearing age, and the number of patients with rheumatic heart disease has declined. Older parturients may present with aortic stenosis and insufficiency associated with a bicuspid aortic valve. The increase in maternal blood volume, which occurs at 20 to 24 weeks of gestation, may also precipitate cardiac decompensation. During labor, cardiac output increases progressively above antepartum levels; with each uterine contraction, approximately 200 mL of blood moves into the central circulation. Consequently, stroke volume, cardiac output, and left ventricular work increase, and each contraction consistently increases cardiac output by 10% to 25% above that of uterine diastole. The greatest change occurs immediately after delivery of the placenta, when cardiac output increases to an average of 80% above prepartum values; in some patients, it may increase 2884 by as much as 150%. Evaluation of pre-existing heart disease is crucial and a multidisciplinary approach is necessary when managing patients with complicated cardiac disease during pregnancy and parturition. Labored breathing and venous stasis from aortocaval compression may mimic pulmonary and peripheral edema associated with congestive heart failure. Finally, elevation of the diaphragm causes the heart to rotate, signs of which may be mistaken for cardiac hypertrophy. For the anesthesiologist, it is particularly important to understand how the hemodynamic consequences of different anesthetic techniques might adversely affect mothers with specific cardiac lesions. Exceptions are patients with pulmonary hypertension, right-to-left shunts, or coarctation of the aorta. Because hemodynamic changes observed during labor and delivery persist into the postpartum period, if used, invasive monitoring should continue for 24 to 48 hours postpartum. Congenital Heart Disease Many patients with successful surgical repair of congenital heart defects are asymptomatic with minimal cardiac findings. Patients with uncorrected or partially corrected lesions may have serious cardiac decompensation with pregnancy. This includes patients with corrected tetralogy of Fallot who may have recurrence of a small ventricular septal defect or develop outflow obstruction. Neuraxial labor analgesia is recommended to minimize hemodynamic changes associated with pain. Patients with corrected ventricular septal defects or atrial septal defects require no special care, nor do those with small asymptomatic atrial septal defects or ventricular septal defects. Large ventricular septal defects or atrial septal defects are associated with pulmonary hypertension. Eisenmenger syndrome occurs when uncorrected left-to-right shunt results in pulmonary hypertension, which, when severe, reverses flow to a right-to- 2885 left shunt. Pregnancy is not well tolerated and mortality can approach 30%, most commonly from embolic phenomena. Implementing labor analgesia that does not lead to deleterious hemodynamic changes is a challenge; opioid-based neuraxial techniques (e. Cesarean delivery is most often accomplished under general anesthesia in women with Eisenmenger syndrome. It should be recognized that arm-to- brain circulation times are rapid owing to right-to-left intracardiac shunts; drugs given intravenously have a rapid onset of action. In contrast to parenteral drugs, the rate of rise of arterial concentrations of inhaled drugs is slow because of decreased pulmonary blood flow. The myocardial depressant and vasodilating actions of volatile drugs may be hazardous in patients with Eisenmenger syndrome, and nitrous oxide, which may increase pulmonary vascular resistance, should be avoided.