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By T. Giores. Columbia College of Missouri.

However order propranolol 80mg fast delivery cardiovascular system pictures, there take inhibitors (SNRIs) purchase propranolol 80 mg without a prescription cardiovascular system vs lymphatic system, 5-HT2A blockers buy 40mg propranolol visa cardiovascular disease gene therapy, and other novel is evidence that newer anticonvulsant medications order 80mg propranolol overnight delivery cardiovascular system lab practical, includ­ antidepressants in the last 15 years has radically changed ing lamotrigine, may be more effective in the depressed the medication histories of the patients referred for ECT. The mechanism by which the These newer agents are remarkably well tolerated, and a anticonvulsants exert their antidepressant effects is poorly majority of patients receiving ECT have had at least one understood and is hypothesized to occur through a number complete trial of an antidepressant without improvement. The ECT response hancing the effect of inhibitory neurotransmitters and neu­ rate in antidepressant medication-refractory patients is ropeptides. The problem of decreased acute response for the antidepressant properties of ECT. Examining the to ECT in this growing population of medication-refractory relationship of the anticonvulsant effects of ECT to the patients has led to new interest in the technical factors that efficacy of the treatments by blocking or augmenting control the response to acute ECT. Among these factors are the anticonvulsant properties of ECT can test this hypothe­ electrode placement, stimulus dose, and possibly concurrent sis. For example, CSF neuropeptides associated with the medications. These neuropep­ has only recently come to appreciate the relative contribu­ tides could be given in conjunction with ECS to determine tions of stimulus electrode placement and stimulus intensity if the coadministration of these neuropeptides would block to the therapeutic and adverse effects of ECT. As previously discussed, clinical wisdom prior to 1987 taught that as long the therapeutic efficacy of ECS (50). Although ethical con­ as the EEG seizure during ECT was �25 seconds, then the siderations may limit this type of research in humans, stud­ treatment was maximally effective. Further veloping algorithms to determine the relationship of ECT work by this group clarified that the efficacy of right unilat­ treatment variables (e. ANTIDEPRESSANT RESPONSE RATE BY ELECTRODE PLACEMENT AND STIMULUS DOSE OPTIMIZATION OF ACUTE EC Barely 2. More recently, RUL 17% 43% tients achieving remission after an acute BL 65% 63% conservatively estimated at between 50% Chapter 76: Electroconvulsive Therapy 1101 This work demonstrated that, within the stimulus dose patients even a suprathreshold stimulus set at 400 mC may studied, the efficacy for RUL was sensitive to dose, whereas be too low to achieve antidepressant efficacy. Continued support for the efficacy of suprathreshold Also, RUL ECT appeared inferior to BL ECT at any dose. RUL ECT has raised some concern about the fact that ECT Subsequent work confirmed that the efficacy of RUL ECT machines in the United States are restricted in the amount is dose dependent and that RUL ECT administered at six of energy they can deliver per treatment (504 to 576 mC times the initial seizure threshold is as effective as BL ECT maximal output). Abrams argues that the FDA mandated with fewer cognitive side effects than BL ECT (54). McCall maximum output for ECT machines used in this country and colleagues found a dose–response relationship in pa­ often does not allow for the administration of effective su­ tients receiving RUL ECT that extended to 12 times the prathreshold treatments and has called for a reexamination seizure threshold and, as predicted, cognitive side effects of these guidelines (59). The response rate for RUL ECT at or initiate antidepressant medication during a course of eight to 12 times threshold was about 70%, approximately acute ECT is also pertinent to the issue of improving the the rates typically quoted for BL ECT. Clinically, physicians are divided recommend that ECT be delivered with either BL electrode in their practice regarding antidepressant medications dur­ placement at a stimulus dose just above threshold, or with ing ECT, and there are no good data to support any posi­ RUL placement at a stimulus dose markedly above thresh- tion. One of the developments in ECT practice in the 1990s old. Although the virtual lack of TCA trials in these same patients before it is clear that the lower intensity RUL strategies have less coming to ECT. This is especially important because there acute amnesia side effects, this advantage is probably offset are some data to suggest that TCAs (i. Possibly, the addition of an antide­ dictors of QOL in severely depressed patients (56,57). There is a potential risk to stimulating the vagus nerve with subconvul­ PREVENTION OF RELAPSE AFTER ECT sive stimuli without adequate compensatory adrenergic dis­ charge from a seizure and the possibility of prolonged asys­ In general, patients who receive an acute course of ECT are tole. However, a controlled operative setting with cardiac either subsequently resistant or intolerant of antidepressant monitoring decreases the possibility of brief periods of medications. Patients diagnosed with psychotic depression bradycardia causing any significant risk for a majority of are particularly susceptible to relapse after an acute course patients. Two studies found a relapse rare of approximately Second, some would argue that the initial treatment in 70% in 1 year for a total of 53 patients with a diagnosis of a series of titrated seizures is a 'wasted' seizure, adding psychotic depression (61,62). These studies were retrospec­ to costs and potential cognitive side effects without any significant therapeutic benefit to the patient. The unilateral tive and could not examine compliance rates or the ade­ seizure at or near the seizure threshold used during the initial quacy of either the initial (pre-ECT) or continuation medi­ treatment setting to determine seizure threshold probably cation trial. However, the potential advantages of In a prospective study, Sackeim and co-workers (63) fol­ determining the seizure threshold and adjusting the subse­ lowed 58 patients for 1 year after ECT. They examined a quent seizures to the threshold has advantages in maximiz­ number of clinical variables including a retrospective review ing benefit and decreasing the potential for future ineffective of the adequacy of the pre-ECT medication trial. The most treatments (if the energy delivered is too low) and cognitive important factor in determining relapse on maintenance side effects (if the energy is too high). Patients (with and without ment for depression (55,58) and this data could obviate the psychotic features) who were rated as receiving a therapeutic need to determine seizure threshold. Because the majority medication trial(s) prior to their acute course of ECT re- of patients treated with ECT are older and older patients lapsed at a rate that was twice the rate found in patients have very high seizure thresholds, dose titrations at eight to who did not receive an adequate pre-ECT medication trial ten times threshold are generally at or above the 400-mC (64% versus 32%). The maintenance medication was not range used by McCall and associates. In fact, in some older standardized but the results indicated that the adequacy of 1102 Neuropsychopharmacology: The Fifth Generation of Progress the post-ECT medication trial was only marginally related senting for ECT after multiple failed medication trials and to the relapse rate and then primarily in patients who did there may be little benefit from yet another trial of an SSRI. The pa­ In fact the one medication regimen that has been shown tients who were not determined to be medication resistant to be effective in maintenance therapy is a combination of prior to ECT had a lower relapse rate when they received lithium and nortriptyline (discussed in the following). Sackeim and as­ benefit of this combination therapy may be owing to the sociates argue that many of these patients may have re­ fact that few patients had been given lithium augmentation sponded to antidepressant medication prior to ECT if they prior to their acute course of ECT. The overall relapse rate re­ Finally, maintenance ECT is similar to depot haloperidol mained very high (approximately 50%) and most of the in the treatment of schizophrenia and may provide prophy­ patients who relapsed did so in the first 4 months of this lactic benefit from improved compliance in patients who 1-year follow-up study. This finding indicates that the effi­ might otherwise not comply with their maintenance medi­ cacy of ECT may be relatively transient. Most studies of maintenance ECT only report pa­ ing medication resistance found in most ECT patient popu­ tients who complied with the treatment regimen. The expe­ lations, the clinical challenge is increasingly to determine rience at the Emory University Outpatient ECT program the most effective maintenance treatments and increasingly is similar to the data reported by Clarke and colleagues (67). There is ance with antidepressant medications; (c) can comply with clear evidence that these treatments are being used increas­ the overall treatment plan including behavioral restrictions ingly in clinical practice, yet there is a lack of guidelines to (i. The NIMH is presently funding three studies The guidelines for the use of C-ECT have been actively that will add significantly to our understanding of mainte­ discussed but there are little prospective data on which to nance ECT. Two multicenter trials are examining the effi­ base recommendations on frequency of treatments and how cacy of different maintenance strategies after an acute re­ long they should be continued or the nature of the potential sponse to ECT. Sackeim and colleagues are comparing cognitive side effects. A majority of the studies are case re- maintenance placebo, nortriptyline versus nortriptyline and ports and many predate antidepressant medication (66). Preliminary results More recent reports in patients with depression (66–74), from this line of investigation show that nortriptyline pro­ mania (75,76), and schizophrenia (77) describe a marked vides only marginally greater protection against relapse dur­ decrease in the number of hospitalizations, hospital days, ing the post-ECT period than does placebo, with relapse depressive symptoms, increased functional status, and stable rates of approximately 70% during the first year. The addi­ cognitive functioning for the period of continuation ECT. Charles Kellner is the principal investigator on a nance medication. First, maintenance ECT may be effective trial comparing maintenance medication and maintenance because the ECT treatments are gradually tapered rather ECT. The authors are currently examining the cost effec­ than abruptly discontinued. During this taper, most clinical tiveness of maintenance medication compared to mainte­ protocols decrease the interval between the maintenance nance ECT in elderly patients with recurrent major depres­ treatments if the patient shows signs of relapse. These last two trials do not yet have preliminary data schedule over this period may be critical because most pa­ available, but together they will provide prospective data on tients relapse within 3 months of stopping the treatments. ECT The second potential therapeutic benefit may be the fact that ECT has a different mechanism of action than the The one significant remaining ECT-related morbidity is the antidepressant medications. Increasingly patients are pre­ potential for cognitive side effects. Although there is little Chapter 76: Electroconvulsive Therapy 1103 scientific literature supporting permanent brain damage frequency in which it is administered. In general, rTMS after ECT (80–82), memory disturbances continue to be acts by inducing action potentials in neuronal elements, but a serious side effect after an acute course of ECT. Clearly, at high frequency (�5 Hz) the net effect of a stimulus train there have been significant advances over the last 50 years. This technique pro­ frequencies (1 Hz) the net effect of a stimulus train is usually vided no advantage over more conservative forms of ECT inhibitory (99,100). In animal studies, rTMS has been dem­ and has been abandoned. Replacement of sine wave stimuli onstrated to cause down-regulation of B-adrenoreceptors with machines that provide a brief pulse stimuli, and the (101) and, as has been shown in ECS, rTMS up-regulates elucidation of the appropriate stimulus parameters that in- astroglial gene expression in the CNS (102). Preliminary crease the efficacy of safer treatments (suprathreshold right data support rTMS in the treatment of a number of psychi­ unilateral versus threshold bilateral ECT) have both been atric disorders including depression, schizophrenia, obses­ important contributions to the decrease in the ECT associ­ sive-compulsive disorder, and posttraumatic stress disorder ated memory loss over the past few decades. From the outset it should oxone (84), and thyrotropin releasing hormone (TRH) (85) be stressed that the efficacy of rTMS in the treatment of all hold promise for further decreasing ECT-associated depression is modest and much of the research has been memory loss. Double-blind placebo controlled trials using focused narrowly on a relatively restricted group of treat­ with intranasal vasopressin (86,87), ACTH (88,89), dexa­ ment parameters. The majority of rTMS studies use set methasone (90), and nimodipine (91) have not shown the parameters: high frequency or fast stimulations (�10 Hz) active drug to be more effective than placebo. Twice-weekly These parameters are based on PET data (104) and ECT ECT is associated with an antidepressant response as good data (34) demonstrating hypofunctioning of the left pre- as thrice-weekly ECT, but with less adverse memory effects frontal cortex in depression as well as two pivotal early stud­ (and a slower rate of antidepressant response) (92,93). Re­ ies demonstrating an antidepressant effect of fast left cently, the issue of optimal electrode placement has been DLPFC rTMS (105,106).

Double-blind studies propranolol 40mg low price heart disease world statistics, at most cheap propranolol 40 mg with amex cardiovascular collapse icd 9, report marginal ment produces lasting benefit buy propranolol 80 mg fast delivery cardiovascular system quizlet. A new generation of studies success in treatment of specific problems such as improving has begun to focus on whether medication can prevent re- the rate of weight gain during refeeding discount 80mg propranolol overnight delivery cardiovascular games, and disturbed atti- lapse after patients leave to a structured treatment setting. Use of Antidepressants in AN One problem with determining the efficacy of pharma- cotherapy in AN is that often medications have been given There has been controversy as to whether AN and major in association with other therapies. Thus, it may be unclear depressive disorders share a common diathesis; however, whether it was the medication or therapy that resulted in critical examination of clinical phenomenology, family his- improvement. Furthermore, the primary criterion for im- tory, antidepressant response, biological correlates, course provement has often been weight gain, not a normalization and outcome, and epidemiology yield limited support for of thinking and reduction in fears of being fat. Still, the high frequency of mood tant to emphasize that treatment in structured settings, such disturbances associated with this disorder resulted in trials as inpatient units, even without medication, succeeds in of drugs such as amitriptyline (41–43), and lithium (44). Thus, it may be difficult to prove that an active medi- compared with the effects of placebo. However, relapse within For more that 50 years (45), investigators have suggested 1 year after successful inpatient weight restoration is very that AN shares similarities with obsessive-compulsive disor- common (25). In fact, patients with AN have a high prevalence ported that only 23% of the patients had a good outcome of obsessive-compulsive symptoms or disorders (46–48), as at 1 year after discharge despite intensive outpatient individ- well other anxiety disorders (49). Controlled trials of the neuroleptics pimozide (27) and Individuals with a past history of AN display evidence of sulpiride (28) have suggested limited effects in accelerating increased serotonin (51) activity that persists after long-term weight gain or altering anorectic attitudes for some patients weight recovery. In addition, women who recover from AN for part of the study, but overall drug effect was marginal. Similarly (10), personality characteris- a good outcome on placebo (P. Aside tics associated with AN, such as introversion, self-denial, from improved outcome, fluoxetine administration was as- limited spontaneity, and a stereotyped thinking style, may sociated with a significant reduction in obsessions and com- also persist after weight recovery. Studies in humans and pulsions and a trend toward a reduction in depression. Together, these data raise the possibility in some patients with AN. Women plicated in OCD (52) and only serotonin-specific medica- with AN, when malnourished and underweight, have re- tion has been found to be useful in treating OCD. In addition, low estrogen values during the malnour- patients with AN. Initial reports on cyproheptadine, a drug ished state may reduce serotonin activity by effects on gene that is thought to act on the serotonergic and histaminergic expression for serotonin receptors (64) or the serotonin system (53), indicated that it might have beneficial effects transporter (65). SSRIs are dependent on neuronal release on weight gain, mood, and attitude in some patients (54, of serotonin for their action. Cyproheptadine data from comparison trials with ami- compromised release of serotonin from presynaptic neu- triptyline and placebo found cyproheptadine to significantly ronal storage sites and reduced synaptic serotonin concen- improve weight gain in the restricting subtype of AN, trations, then a clinically meaningful response to an SSRI whereas amitriptyline was more effective in those patients might not occur (66). The possibility that fluoxetine is only with bulimic behavior (56). For example, CSF 5-HIAA levels are low might help patients with AN gain and/or maintain a healthy in underweight anorexics, normal in short-term weight-re- body weight. Recently, the Pittsburgh group reported a dou- stored anorexics, and elevated in long-term weight-restored ble-blind placebo-controlled trial of fluoxetine in 35 pa- anorexics (67). If CSF 5-HIAA levels accurately reflect CNS tients with restrictor-type AN (59). Subjects were started serotonin activity, then these data imply that a substantial on fluoxetine after they achieved weight restoration (approx- increase in serotonin activity occurs after weight gain. The use of serotonin-specific medications in the treat- Patients were randomly assigned to fluoxetine (N 16) ment of AN is promising but many questions remain. First, or placebo (N 19) after inpatient weight-restoration and only one double-blind placebo-controlled study has been then were followed as outpatients for 1 year. After 1 year completed in a relatively small number of restrictor-type of outpatient follow-up, 10 of 16 (63%) subjects had a good patients. Thus, it will be important to replicate this work FIGURE 116. Survival of subjects with anorexia ner- vosa treated with fluoxetine or placebo. Chapter 116: Psychopharmacology of Eating Disorders 1679 in a larger group of patients. Second, more data are needed to determine if there are differential effects in the restricting of binge eating/purging subtypes of AN. Third, it needs to be determined whether certain features are especially re- sponsive to serotonin-specific medications: core anorexic symptoms, depression, anxiety, obsessionality, or eating be- havior. Guidelines for Clinical Treatment The first line of treatment for underweight patients with AN should be refeeding and weight restoration. As noted, although difficult, most patients will gain weight in a struc- tured eating disorders treatment program without the use of medication. Weight gain alone tends to reduce exaggerated obsessionality and dysphoric mood in many patients (68). Median percentage change in the number of binge-eating episodes among patients with bulimia nervosa re- There is limited evidence that fluoxetine and possibly other ceiving fluoxetine or placebo. It is important to emphasize that some physio- logic and cognitive alterations persist for months after achieving goal weight, including increased energy needs, menstrual disturbances, several neurotransmitter distur- of benefit from antidepressant treatment typically is quite bances, urges to engage in disordered eating patterns, and rapid (Fig. Thus, treatment should continue No trials have been published in which the efficacy of for at least 3 to 6 months after achieving goal weight, prefer- one antidepressant is compared directly to that of another. We strongly support use of the recent American oxetine, only fluvoxamine has been formally examined in Psychiatric Association (APA) guidelines for eating disor- BN. Fichter and colleagues reported a study of novel design ders (69), which describe comprehensive treatment of AN. Although fluvoxamine was associated with PHARMACOLOGIC TREATMENT OF BN a dropout rate of 38% over 19 weeks compared to 14% on placebo, the active drug was superior to placebo in reducing As summarized in Neuropsychopharmacology, the Fourth the re-emergence of bulimic behaviors and attitudes. In light Generation of Progress, a substantial body of work was pub- of these results, it is surprising that a large European trial lished during the 1980s and early 1990s demonstrating that has been reported to find no difference between the response antidepressants are more effective than placebo in the treat- to fluvoxamine and placebo in the initial treatment of out- ment of BN (70). In 1996, the FDA approved the use of patients with bulimia (Freeman, personal communication, fluoxetine (71,72) for this disorder, the only medication to 1999). Thus, although most clinicians expect sertraline, pa- receive such an official indication to date. Although the roxetine, citalopram, and venlafaxine to be useful, the effi- notion of using antidepressants for BN emerged because of cacy and ideal dose of SSRIs other than fluoxetine for the the high frequency of symptoms of depression and anxiety, treatment of BN have not been established. CBT is generally believed to be more effec- of appetite. The notion that antidepressants may be useful tive than a single course of an antidepressant medication in BN via mechanisms other than those that are responsible (69). This fact, coupled with reasonable evidence of sus- for their antidepressant activity is also suggested by the ob- tained benefit following CBT and the reluctance of many servations that a higher daily dose of fluoxetine (60 mg per patients to take psychotropic medications, has led to CBTs day) appears superior to the standard antidepressant dose being generally considered the treatment of first choice for (20 mg per day) in the treatment of BN and that the onset BN. Several studies have examined whether it is beneficial 1680 Neuropsychopharmacology: The Fifth Generation of Progress to combine psychological treatment with antidepressant from one treatment approach or another would be ex- medication. Unfortunately, attempts to identify such The earliest studies of the combination of medication predictors of treatment response have been impressively un- and psychotherapy utilized tricyclic antidepressants. Because those patients who derive the greatest ell and associates (74) found that imipramine was associated benefit from treatment typically exhibit an early response with a greater reduction in measures of anxiety and depres- (80), it may useful to initiate treatment with CBT, for exam- sion than was placebo when combined with an intensive ple, and to add another intervention such as medication if group psychotherapy program; however, imipramine did the initial response is not satisfactory. Recent data demon- not augment the impact of the psychological treatment on strate that medication can be useful for patients who do the salient behavioral symptom, binge eating. Agras and not respond adequately to psychological treatment or who colleagues (75) compared five treatments for BN: individual relapse following the end of treatment (18). CBT alone, desipramine alone for 16 or 24 weeks, and CBT Despite the progress in developing treatment approaches plus desipramine for either 16 or 24 weeks. As was also for bulimia in the last 20 years, a major current problem is true of the study of Mitchell and colleagues, Agras and co- the absence of treatments of established efficacy other than workers reported that the outcome of psychological treat- CBT and antidepressant medication. Even in the best ment alone was clearly superior to that of a course of tricyclic hands, only about 50% of patients achieve remission with antidepressant. There were a few hints of a small advantage these treatments, and a significant number relapse following for the combination of medication and CBT, but these were the conclusion of the initial intervention. Leitenberg and co-workers (76) attempted investigators have considered the use of other psychotropic to compare CBT to a course of desipramine and to a combi- medications that are believed to reduce appetite, such as nation, but terminated the study prematurely because of topiramate, but no controlled data are available to date about its utility in BN. Recently, Faris and associates (82) a high dropout rate, primarily caused by medication side have reported that the antiemetic medication ondansetron, effects. The Columbia group has reported the results of data regarding the side effects of ondansetron and its impact a study that compared two forms of individual psychological on psychological features of the disorder are required to treatment (CBT and supportive psychotherapy) combined assess the clinical utility of this agent, but the exploration either with placebo or a two-stage medication intervention of novel medication interventions for BN is overdue. Patients assigned to receive active medication received desipramine; if desipramine was either ineffective or intoler- able, the medication was changed to fluoxetine under dou- ble-blind conditions. In this study, CBT was clearly superior PHARMACOLOGIC TREATMENT OF BINGE to supportive psychotherapy in reducing the key behavioral EATING DISORDER symptoms of BN. In addition, compared to placebo, active medication added modestly but significantly to improve- During the development of DSM-IV, interest grew in defin- ment in binge eating and depression. Unfor- pensatory behavior required for the diagnosis of BN. Out tunately, interpretation of the results is limited by a high of these discussions, criteria for binge eating disorder (BED) dropout rate, which resulted in few significant differences evolved, and were included in an appendix of DSM-IV as among the three treatments. Beumont and colleagues (79) a criteria set for further study. Significant interest in the reported a comparison of fluoxetine versus placebo when characteristics and treatment of BED has since developed, combined with nutritional counseling, which presumably and the results of several psychopharmacologic interven- included many elements of CBT. Although obesity is not required ing program was impressively effective, and at the conclu- by the criteria for BED suggested in DSM-IV, the studies sion of treatment, there were no significant differences be- to date have generally focused on overweight or obese indi- tween the fluoxetine and placebo groups in binge frequency; viduals. Clinically, guidelines neither desipramine nor placebo was associated with signifi- to identify patients who are particularly likely to benefit cant weight loss in this short-term study.

All citations were ® imported into an electronic database (EndNote X4; Thomson Reuters purchase propranolol 40 mg without a prescription coronary artery location and function, Philadelphia purchase propranolol 40mg otc cardiovascular system chapter 21, PA) buy propranolol 80mg on-line cardiovascular disease pathophysiology. We used several approaches to identify relevant grey literature including requests to drug and device manufacturers for scientific information packets and searches of study registries and conference abstracts for relevant articles from completed studies purchase propranolol online pills cardiovascular system blood youtube. Grey literature databases searched included ClinicalTrials. Search terms used for all of the above sources are provided in Appendix A. Inclusion and Exclusion Criteria The PICOTS (Populations, Interventions, Comparators, Outcomes, Timings, and Settings of interest) criteria used to screen articles for inclusion/exclusion at both the title-and-abstract and full-text screening stages are detailed in Table 1. Inclusion and exclusion criteria PICOTS Element Inclusion Criteria Exclusion Criteria Populations • Humans • Patients who have known • Adults (age ≥ 18 years of age) reversible causes of AF (including • Patients with AF (includes atrial flutter) but not limited to postoperative, o Paroxysmal AF (recurrent episodes that self- postmyocardial infarction, terminate in less than 7 days) hyperthyroidism) o Persistent AF (recurrent episodes that last more • All subjects are <18 years of age, than 7 days) or some subjects are under <18 o Permanent AF (an ongoing, long-term episode) years of age but results are not • Subgroups of potential interest include: broken down by age o Patients stratified by age (≤ 40, 41–64, 65–74, 75–84, 85+) o Patients with different types of AF (paroxysmal, persistent, permanent) o Patients with specific comorbidities (heart failure, coronary artery disease, kidney disease, hypertrophic cardiomyopathy, thyroid disease, pulmonary disease) o Patients for whom a prior rate- (KQ 3) or rhythm- control (KQ 5) pharmacological strategy was ineffective o Women o Patients with an enlarged left atrium o Patients at high risk for stroke and bleeding events (patients with diabetes, heart failure, and hypertension) 8 Table 1. Inclusion and exclusion criteria (continued) PICOTS Element Inclusion Criteria Exclusion Criteria Interventions • Pharmacological agents for rate control (KQ 1, KQ 2, • Studies comparing different KQ 3, KQ 6): imaging or mapping techniques o Beta blockers (e. Inclusion and exclusion criteria (continued) PICOTS Element Inclusion Criteria Exclusion Criteria Outcomes Study assesses a patient-centered outcome of interest: Study does not include any outcomes • Intermediate outcomes: of interest o Restoration of sinus rhythm (conversion) o Maintenance of sinus rhythm o Recurrence of AF at 12 months o Ventricular rate control o Development of cardiomyopathy a • Final outcomes: o Mortality (all-cause, cardiovascular) o Myocardial infarction o Cardiovascular hospitalizations (including AF hospitalizations) o Heart failure symptoms o Control of AF symptoms (e. Abbreviations: AF=atrial fibrillation; AVN=atrioventricular node; CRT=cardiac resynchronization therapy; KQ=Key Question; ICD=implantable cardioverter defibrillator; PICOTS=Populations, Interventions, Comparators, Outcomes, Timing, Settings; RCTs=randomized controlled trials 10 Study Selection Using the prespecified inclusion and exclusion criteria described in Table 1, two investigators independently reviewed titles and abstracts for potential relevance to the KQs. Articles included by either reviewer underwent full-text screening. At the full-text review stage, paired researchers independently reviewed the articles and indicated a decision to “include” or “exclude” the article for data abstraction. When the two reviewers arrived at different decisions about whether to include or exclude an article, they reconciled the difference through review and discussion, or through a third-party arbitrator if needed. Full-text articles meeting our eligibility criteria were included for data abstraction. Relevant systematic review articles, meta-analyses, and methods articles were flagged for manual searching of references and cross-referencing against the library of citations identified through electronic database searching. For citations retrieved by searching the grey literature, the above-described procedures were modified such that a single screener initially reviewed all search results; final eligibility of citations for data abstraction was determined by duplicate screening review. All screening decisions were made and tracked in a Distiller SR database (Evidence Partners Inc. Data Extraction The research team created data abstraction forms and evidence table templates for abstracting data for each KQ. Based on clinical and methodological expertise, a pair of investigators was assigned to abstract data from each eligible article. One investigator abstracted the data, and the second reviewed the completed abstraction form alongside the original article to check for accuracy and completeness. To aid in both reproducibility and standardization of data collection, researchers received data abstraction instructions directly on each form created specifically for this project within the DistillerSR database. We designed the data abstraction forms to collect the data required to evaluate the specified eligibility criteria for inclusion in this review, as well as demographic and other data needed for determining outcomes (intermediate, final, and adverse events outcomes). We paid particular attention to describing the details of treatment (e. In addition, we described comparators carefully, as treatment standards may have changed during the period covered by this review. The safety outcomes were framed to help identify adverse events, including those from drug therapies (e. Data necessary for assessing quality and applicability, as described in the 22 Methods Guide, were abstracted. Before the data abstraction form templates were used, they were pilot-tested with a sample of included articles to ensure that all relevant data elements were captured and that there was consistency/reproducibility between abstractors. Forms were revised as necessary before full abstraction of all included articles. In these instances, we used the web-based software, EnGauge Digitizer (http://digitizer. Appendix B provides a detailed listing of the elements included in the data abstraction forms. We applied criteria for each study type derived from core elements described in the Methods Guide. Criteria of interest for all studies included similarity of groups at baseline, extent to which outcomes were described, blinding of subjects and providers, blinded assessment of the outcome(s), intention-to-treat analysis, and differential loss to followup between the compared groups or overall high loss to followup. Criteria specific to RCTs included methods of randomization and allocation concealment. For observational studies, additional elements such as methods for selection of participants, measurement of interventions/exposures, addressing any design-specific issues, and controlling for confounding were considered. To indicate the summary judgment of the quality of individual studies, we used the summary ratings of good, fair, or poor based on the classification scheme presented in Table 2. Definitions of overall quality ratings Quality Rating Description Good A study with the least bias; results are considered valid. A good study has a clear description of the population, setting, interventions, and comparison groups; uses a valid approach to allocate patients to alternative treatments; has a low dropout rate; and uses appropriate means to prevent bias, measure outcomes, and analyze and report results. Fair A study that is susceptible to some bias but probably not enough to invalidate the results. The study may be missing information, making it difficult to assess limitations and potential problems. As the fair-quality category is broad, studies with this rating vary in their strengths and weaknesses. The results of some fair-quality studies are possibly valid, while others are probably valid. Poor A study with significant bias that may invalidate the results. These studies have serious errors in design, analysis, or reporting; have large amounts of missing information; or have discrepancies in reporting. The results of a poor-quality study are at least as likely to reflect flaws in the study design as to indicate true differences between the compared interventions. Studies of different designs were graded within the context of their respective designs. Thus, RCTs were graded good, fair, or poor, and observational studies were separately graded good, fair, or poor. Data Synthesis We began our data synthesis by summarizing key features of the included studies for each KQ: patient characteristics; clinical settings; interventions; and intermediate, final, and adverse event outcomes. We grouped interventions by drug class; in this context, we considered all nondihydropyridine calcium channel blocker drugs to be similar enough to be grouped together and all beta blocker drugs to be similar enough to be grouped together. Similarly, we categorized procedures into electrical cardioversion, atrioventricular node (AVN) ablation, AF ablation by pulmonary vein isolation (either open surgical, minimally invasive, or transcatheter procedures), and surgical Maze procedures, and explored comparisons among these categories. For the KQs focusing on pharmacological agents versus procedures (KQ 3 and KQ 5), we also explored grouping all pharmacological agents together and comparing them to all procedures. Finally for 12 our evaluation of rate- versus rhythm-control strategies (KQ 6), we grouped all rate-control strategies together and all rhythm-control strategies together regardless of the specific agent or procedure. We determined the appropriateness of a quantitative synthesis (i. Where at least three comparable studies reported the same outcome, we used random-effects models to synthesize the available evidence quantitatively using Comprehensive Meta-Analysis software (Version 2; Biostat, Englewood, NJ). We tested for heterogeneity using graphical displays and test statistics 2 (Q and I statistics), while recognizing that the ability of statistical methods to detect heterogeneity may be limited. For comparison, we also performed fixed-effect meta-analyses. We present summary estimates, standard errors, and confidence intervals in our data synthesis. Unless noted otherwise, when we were able to calculate odds ratios (ORs), we assumed that an OR between 0. We anticipated that intervention effects might be heterogeneous. Where there were sufficient studies, we performed subgroup analyses and/or meta-regression analyses to examine these hypotheses. Strength of the Body of Evidence We rated the strength of evidence for each KQ and outcome using the approach described in 22,136 the Methods Guide. In brief, the approach requires assessment of four domains: risk of bias, consistency, directness, and precision (Table 3). Strength of evidence—required domains Domain Rating How Assessed Risk of bias Low Assessed primarily through study design (RCT versus Medium observational study) and aggregate study quality High Consistency Consistent Assessed primarily through whether effect sizes are generally on Inconsistent the same side of “no effect” and the overall range of effect sizes Unknown/not applicable Directness Direct Assessed by whether the evidence involves direct comparisons or Indirect indirect comparisons through use of surrogate outcomes or use of separate bodies of evidence Precision Precise Based primarily on the size of the confidence intervals of effect Imprecise estimates Abbreviation: RCT=randomized controlled trial Additional domains were used when appropriate: strength of association (magnitude of effect) and publication bias (as assessed through a search of ClinicalTrials. These domains were considered qualitatively, and a summary rating of “high,” “moderate,” or “low” strength of 13 evidence was assigned after discussion by two reviewers. In some cases, high, moderate, or low ratings were impossible or imprudent to make; for example, when no evidence was available or when evidence on the outcome was too weak, sparse, or inconsistent to permit any conclusion to be drawn. In these situations, a grade of “insufficient” was assigned. This four-level rating scale consists of the following definitions: • High—High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect. Further research may change our confidence in the estimate of effect and may change the estimate. Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.

The main elements of ventilation are the res- piratory pump buy propranolol 40 mg capillaries for dummies, which generates a pressure gradient responsible for air flow buy 80 mg propranolol overnight delivery arteries definition biology, and the loads that oppose such action 40mg propranolol free shipping capillaries fenestrated. The machinery of the respiratory pump includes the cerebrum 40 mg propranolol overnight delivery capillaries leaving alveoli, brain stem, spinal cord, phrenic and intercostal nerves, and the muscles of respiration. Inspiratory muscle con- traction lowers pleural pressure (Ppl) thereby inflating the lungs ( V). The diaphragm, the most important inspiratory muscle, moves downward as a piston at the floor of the thorax, raising abdominal pressure (Pabd). The inspiratory decrease in Ppl by the respiratory pump must be suffi- cient to counterbalance the opposing effect of the combined loads, including the airway flow resis- tance, and the elastic recoil of the lungs and chest wall. The ventilatory requirement influences the load by altering the frequency and depth of the ventilatory cycle. The strength of the respiratory pump is evaluated by the pressure generated ( P = Ppl - Pabd). A higher load can be caused by increased venti- piratory pum p is unable to balance the opposing load, respiratory latory dem and, augm ented airway flow resistance, and stiffness of acidosis develops. Decreases in respiratory pum p strength, increases the lungs or chest wall. In m ost cases, causes of the various determ i- in load, or a com bination of the two, can result in carbon dioxide nants of carbon dioxide retention, and thus respiratory acidosis, are retention. Respiratory pum p failure can occur because of depressed categorized into acute and chronic subgroups, taking into consider- central drive, abnorm al neurom uscular transm ission, or respiratory ation their usual m ode of onset and duration. Developm ent of posthypercap- nic m etabolic alkalosis is shown after abrupt norm alization of the arterial carbon dioxide tension (PaCO 2) by way of m echanical ven- 80 tilation in a 70-year-old m an with respiratory decom pensation who has chronic obstructive pulm onary disease and chronic hypercapnia. W hen a diet rich in chloride (Cl-) is provided, the excess bicarbon- 40 ate is excreted by the kidneys over the next 2 to 3 days, and acid- base equilibrium is norm alized. In contrast, a low-chloride diet sus- tains the hyperbicarbonatem ia and perpetuates the posthypercapnic 40 m etabolic alkalosis. Abrupt correction of severe hypercapnia by Low-Cl–diet way of m echanical ventilation generally is not recom m ended. Subsequent m easures m ust • Administer O2 via nasal mask or prongs to maintain PaO > 60 mm Hg. Mental status and blood gases evaluated • If PaO2 does not increase to > 60 mm Hg or PaCO2 rises to > 60 mm Hg proceed to steps described in the box below. In contrast, a m ore conserva- tive approach is advisable in patients with chronic hypercapnia because of the great Yes difficulty often encountered in weaning these patients from ventilators. As a rule, the lowest possible inspired fraction of oxygen that achieves adequate oxygenation (PaO 2 on the order of 60 m m H g) is used. Contrary to acute respiratory acidosis, the underlying cause of chronic respiratory aci- • Consider intubation and use of • Consider use of noninvasive nasal mask ventilation dosis only rarely can be resolved [1,9]. Respiratory Alkalosis FIGURE 6-9 Arterial blood [H+], nEq/L Adaptation to respiratory alkalosis. Respiratory alkalosis, or 150 125 100 80 70 60 50 40 30 20 prim ary hypocapnia, is the acid-base disturbance initiated by a decrease in arterial carbon dioxide tension (PaCO 2) and entails PaCO2 120 100 90 80 70 60 50 alkalinization of body fluids. H ypocapnia elicits adaptive decre- mm Hg 40 m ents in plasm a bicarbonate concentration that should be viewed 50 as an integral part of respiratory alkalosis. An im m ediate decre- m ent in plasm a bicarbonate occurs in response to hypocapnia. This acute adaptation is com plete within 5 to 10 m inutes from the onset 40 30 of hypocapnia and is accounted for principally by alkaline titration of the nonbicarbonate buffers of the body. To a lesser extent, this acute adaptation reflects increased production of organic acids, 30 notably lactic acid. W hen hypocapnia is sustained, renal adjust- Normal 20 m ents cause an additional decrease in plasm a bicarbonate, further am eliorating the resulting alkalem ia. This chronic adaptation 20 requires 2 to 3 days for com pletion and reflects retention of hydro- 10 gen ions by the kidneys as a result of downregulation of renal acid- ification [2,10]. Shown are the average decreases in plasm a bicar- 10 bonate and hydrogen ion concentrations per m m H g decrease in PaCO 2after com pletion of the acute or chronic adaptation to respi- ratory alkalosis. Em piric observations on these adaptations have been used for constructing 95% confidence intervals for graded 6. The black ellipse near the center of the figure indicates the norm al range for Steady-state relationships in respiratory alkalosis: the acid-base param eters. N ote that for the sam e level of PaCO 2, average decrease per mm Hg fall in PaCO2 the degree of alkalem ia is considerably lower in chronic than it is [HCO–] mEq/L [H+] nEq/L in acute respiratory alkalosis. Assum ing that a steady state is pre- 3 Acute adaptation 0. A, Sustained hypocapnia entails a persistent decrease in the renal tubular secretory rate of hydrogen ions and a persistent increase in the chloride reab- sorption rate. As a result, transient suppression of net acid excretion occurs. This suppression is largely manifested by a decrease in ammonium excretion and, early on, by an increase in bicarbonate excretion. The transient discrepancy between net acid excretion and endogenous acid production, in turn, leads to positive hydrogen ion balance and a reduction in the bicarbonate stores of the body. M aintenance of the resulting hypobicarbonatemia is ensured by the gradual suppression in the rate of renal bicarbonate reabsorption. This suppression itself is a reflection of the hypocapnia-induced decrease in the hydrogen ion secretory rate. A new steady state emerges when two things occur: the reduced filtered load of bicar- bonate is precisely balanced by the dampened rate of bicarbonate reabsorption and net acid excretion returns to the level required to offset daily endogenous acid production. The transient retention of acid during sustained hypocapnia is normally accompanied by a loss of sodium in the urine (and not by a retention of chloride as analogy with chronic respiratory acidosis would dictate). The resulting extra- cellular fluid loss is responsible for the hyperchloremia that typically 0 1 2 3 accompanies chronic respiratory alkalosis. Hyperchloremia is sus- Days tained by the persistently enhanced chloride reabsorption rate. If dietary sodium is restricted, acid retention is achieved in the compa- Km Vmax ny of increased potassium excretion. Available evidence indicates a parallel decrease in the rates of the luminal sodium ion–hydrogen ion (Na+-H+) exchanger and the basolateral sodium ion–3 bicarbonate + - ion (Na -3HCO3) cotransporter in the proximal tubule. This parallel decrease reflects a decrease in the maximum velocity (Vmax) of each transporter but no change in the substrate concentration at half- 5 500 maximal velocity (K ) for sodium (as shown in B for the Na+-H+ m exchanger in rabbit renal cortical brush-border membrane vesicles). M oreover, hypocapnia induces endocytotic retrieval of H+- adenosine triphosphatase (ATPase) pumps from the luminal mem- brane of the proximal tubule cells as well as type A intercalated cells of the cortical and medullary collecting ducts. It remains unknown whether chronic hypocapnia alters the quantity of the H+-ATPase Control Chronic Control Chronic hypocapnia hypocapnia pumps as well as the kinetics or quantity of other acidification trans- (9% O2) (9% O2) porters in the renal cortex or medulla. The m anifestations of prim ary hypocap- nia frequently occur in the acute phase, but Central Nervous System Cardiovascular System Neuromuscular System seldom are evident in chronic respiratory alkalosis. Several m echanism s m ediate these Cerebral vasoconstriction Chest oppression Numbness and paresthesias clinical m anifestations, including cerebral Reduction in intracranial pressure Angina pectoris of the extremities hypoperfusion, alkalem ia, hypocalcem ia, Light-headedness Ischemic electrocardiographic changes Circumoral numbness hypokalem ia, and decreased release of oxy- Confusion Normal or decreased blood pressure Laryngeal spasm gen to the tissues by hem oglobin. Consequently, no encountered because it occurs in norm al pregnancy and high- attem pt has been m ade to separate these conditions into acute altitude residence. Pathologic causes of respiratory alkalosis and chronic categories. Som e of the m ajor causes of respiratory include various hypoxem ic conditions, pulm onary disorders, cen- alkalosis are benign, whereas others are life-threatening. Prim ary tral nervous system diseases, pharm acologic or horm onal stim u- hypocapnia is particularly com m on am ong the critically ill, lation of ventilation, hepatic failure, sepsis, the anxiety-hyper- occurring either as the sim ple disorder or as a com ponent of ventilation syndrom e, and other entities. Its presence constitutes an om inous prog- are associated with the abrupt occurrence of hypocapnia; howev- nostic sign, with m ortality increasing in direct proportion to the er, in m any instances, the process m ight be sufficiently prolonged severity of the hypocapnia. FIGURE 6-13 Respiratory alkalosis Respiratory alkalosis management. Because chronic respiratory alka- losis poses a low risk to health and produces few or no symptoms, measures for treating the acid-base disorder itself are not required. In Acute Chronic contrast, severe alkalemia caused by acute primary hypocapnia requires corrective measures that depend on whether serious clinical No manifestations are present. Such measures can be directed at reducing Blood pH ≥ 7. Even if the baseline plasma Yes bicarbonate is moderately decreased, reducing it further can be partic- ularly rewarding in this setting. In addition, this maneuver combines Hemodynamic instability, No • Consider having patient rebreathe effectiveness with relatively little risk [1,2]. This entity develops in patients with profound depres- sion of cardiac function and pulm onary perfusion but relative preservation of alveo- Normal lar ventilation. Patients include those with advanced circulatory failure and those undergoing cardiopulm onary resuscitation. The severely reduced pulm onary blood flow lim its the am ount of carbon dioxide deliv- pH 7. In contrast, the increased ven- PO2 95 PO2 40 FiO 0. N ote a progressive Arterial Venous widening of the arteriovenous difference in compartment compartment pH and PCO 2 in the two settings of cardiac dysfunction. The hypobicarbonatem ia in the setting of cardiac arrest represents a Circulatory Failure com plicating elem ent of lactic acidosis. Despite the presence of arterial hypocapnia, pseudorespiratory alkalosis represents a special case of respiratory acidosis, as pH 7.

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