Desyrel

By J. Bradley. University of Houston, Victoria.

Strength of evidence domains for antiarrhythmic drugs versus electrical cardioversion Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) Comparison of Various Methods for External Electrical Cardioversion (Biphasic vs discount 100mg desyrel overnight delivery. Monophasic Waveforms) Restoration of 4 (411) RCT/Low Consistent Direct Precise SOE=High Sinus Rhythm OR 4 generic desyrel 100mg. Anteroposterior Cardioversions) Restoration of 4 (393) RCT/Low Inconsistent Direct Imprecise SOE=Low Sinus Rhythm OR 0. Strength of evidence domains for antiarrhythmic drugs versus electrical cardioversion (continued) Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) Comparison of Various Methods for External Electrical Cardioversion (Energy Protocols) Restoration of 3 (432) RCT/Low Consistent Direct Precise SOE=High Sinus Rhythm OR 0. No Drug Enhancement) Restoration of 2 (218) RCT/Low Consistent Direct Imprecise SOE=Moderate Sinus Rhythm No significant benefit for patients given ibutilide or metoprolol pretreatment (p values NR) Maintenance of 2 (195) RCT/Low Consistent Direct Imprecise SOE=Moderate Sinus Rhytm Significant benefit for patients given verapamil or metoprolol pretreatment (p values of 0. Sotalol) Restoration of 4 (736) RCT/Low Inconsistent Direct Imprecise SOE=Low Sinus Rhythm OR 1. Rate-Control Drugs) Restoration of 7 (613) RCT/Low Consistent Direct Precise SOE=High Sinus Rhythm OR 2. Rhythm-Control Procedures and Drugs for Maintenance of Sinus Rhythm KQ 5: What are the comparative safety and effectiveness of newer procedural rhythm-control therapies, other nonpharmacological rhythm- control therapies, and pharmacological agents (either separately or in combination with each other) for maintenance of sinus rhythm in atrial fibrillation patients? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest? Key Points Procedural therapies: • Transcatheter pulmonary vein isolation (PVI) versus antiarrhythmic drugs o Based on 8 RCTs (5 good, 3 fair quality) involving 921 patients, transcatheter PVI is superior to antiarrhythmic drugs for maintenance of sinus rhythm over 12 months of followup in patients with paroxysmal AF (high strength of evidence). This evidence is strongest in younger patients with little to no structural heart disease, and with no or mild enlargement of the left atrium. Overall Description of Included Studies A total of 83 studies met our inclusion criteria and assessed the comparative safety and effectiveness of new procedural rhythm-control therapies, other nonpharmacological rhythm- control therapies, and pharmacological agents for the maintenance of sinus rhythm in patients with AF (Appendix Table F-5). Studies began enrollment from 1994 to 2007 and enrolled between 22 and 665 patients per study, resulting in a total of 11,014 patients. All were RCTs, 178,180,181,207-239 144,145,240-280 with 36 rated as being of good quality, 43 fair quality, and 4 poor 205,281-283 quality. A majority of studies (54 [65%] included 144,145,178,181,205,207-215,219-228,232-237,242,244,245,247,249-251,253-256,258-261,265,269,270,273-275,280- sites in Europe, 282 180,215-218,220,223-225,228-230,236,241,253,256,266,267,271,276,277,279 22 included sites in North America, 10 224,231,238,246,257,262-264,278,283 224,240,243,248,268 included sites in Asia, 5 included sites in South America, 224,252 239,272 2 included sites in Australia; and 2 studies did not report a location. A majority of 144,181,205,207,208,210,211,213- studies (51 [61%]), did not report their source of funding. Three of these six studies were multicenter trials; the other three were single-center trials. Linked/secondary papers used in the analyses below were: 284 285 286 180 • Atwood, 2007; Batcher, 2007; and Singh, 2009 – all linked to Singh, 2005 (SAFE-T) 59 287 288 289 230 • Dorian, 2003; Dorian, 2002; and Lumer, 2002 – all linked to Roy, 2000 (Canadian Trial of Atrial Fibrillation) 290 214 • Khargi, 2001 – linked to Deneke, 2002 291 229 • Leong-Sit, 2011 – linked to Roux, 2009 (5A) 292 226 • Pappone, 2011 – linked to Pappone, 2006 (APAF) 293 228 • Reynolds, 2010 – linked to Wilber, 2010 (ThermoCool AF)] Below we provide an overview and then detailed syntheses stratified by the comparisons evaluated in the 83 studies. Procedural Therapies for Rhythm Control Description of Studies We identified 65 studies of procedural therapies for rhythm control. They enrolled 6,739 patients across 5 continents, with the 207- majority (36 studies) including sites in Europe. Thirty-one studies were rated as good quality, 223,225-229,231-239 240,242-244,246-248,250-255,257,262-268,270-280 282,283 32 as fair quality, and 2 as poor quality. The majority of studies (39 [59%]) did 207,208,210,211,213-216,220,222,223,226,229,231,234,238-240,242,244,248,250- not report their funding source. Eight studies were exclusively industry 217,218,228,232,236,237,265,273 funded, and one study reported both industry and nongovernment 209 207,209,211,213- funding. The majority of studies (38 [58%]) did not report the clinical setting. Thirty-six studies 207-215,220-223,225-228,232-236,242,244,247,250,251,253,255,265,270,273-275,280,282 included patients from Europe. Eleven included only patients with long- 208,214,219,220,231,238,243,248,268,276,277 standing persistent AF, 17 included only patients with 210,213,215,217,218,221,226,242,246,251,253,255,257,278-280,283 paroxysmal AF, and 4 included only patients with 212,216,225,240 persistent AF. Finally, two studies enrolled only patients with comorbid heart 240,264 failure. Figure 11 represents the treatment comparisons evaluated for this KQ.

The right coronary artery (RCA) supplies the right ventricle cheap 100 mg desyrel otc, as well as the inferior (diaphragmatic) and posterior-lateral walls of the left ventricle discount desyrel 100mg without a prescription, and the posterior third of the septum. The RCA also gives off the AV nodal coronary artery in 85- 90% of individuals; in the remaining 10-15%, this artery is a branch of the LCX. Not all of the 6 patterns are seen in every patient; the time from onset of MI to the final pattern is quite variable and is related to the size of MI, the rapidity of reperfusion (if any), and the location of the MI. Normal ECG waveform prior to the onset of plaque rupture B. Hyperacute T wave changes - increased T wave amplitude and width; QT may prolong; may also see early ST segment elevation C. Marked ST elevation with hyperacute T waves (“tombstone” pattern) D. Pathologic Q waves appear (cell necrosis), ST elevation decreases, T waves begin to invert (this is also called the "fully evolved" phase) E. Pathologic Q waves, T wave inversion (necrosis and fibrosis) F. Q waves may get smaller or disappear with time 67 I. Note tall hyperacute T waves with ST elevation in II, III, aVF (ST↑ in III > ST↑ in II suggests RCA occlusion); reciprocal ST depression is seen in I, and aVL. Example #2: Old inferior MI (note largest Q in lead III, next largest in aVF, and smallest in lead II). QRS Axis is -50° (LAD); T wave inversion is also present in leads II, III, and aVF. This is a 15-lead ECG with the addition of right precordial V4R (to rule out RV MI), and posterior leads V8 and V9 placed on the back horizontal to leads V4-6. In this ECG one can see ST elevation in V8-9, and slightly elevated ST segments in leads I and aVL. The absence of ST elevation in V4R rules out a right ventricular MI (see Example #6 below). The 15-lead ECG is useful in the differential diagnosis of ST depression in the right precordial leads. Example #6: Acute inferior MI also involving the right ventricle; 15-lead ECG (adding V4r, V8, V9). Note ST segment elevation in V4r indicative of proximal RCA occlusion causing right ventricular infarction in addition to the acute inferior left ventricular MI. Note: ST elevation in lead III > ST elevation in lead II, also indicative of RCA occlusion. Note also right atrial enlargement (tall P waves, inferior leads). This really big infarct occurred in a young man who dissected his LAD artery following a fall; although not a plaque rupture, his LAD was completely occluded! Fortunately, he was successfully treated with a stent to his LAD. Comment: The precise identification (and terminology) of MI locations on the ECG is evolving as new heart imaging (e. New terminology has been suggested (see Circulation 2006;114:1755). While not universally accepted, the following “new” Q-wave MI patterns (scar) have been defined for left ventricular segments seen on MRI imaging:  Septal MI: Q (or QS) waves in V1-2  Mid-Anterior MI: Q waves in aVL, sometimes in lead I, V2, V3, but not in V5-6. No Q waves in I, aVL  Extensive Anterior MI: Combination of above 3 locations. It was inappropriately diagnosed as a non-STEMI because of the absence of typical ST segment elevation in 2 or more contiguous ECG leads. Instead of proceeding to emergent coronary intervention, the patient was treated with the non-STEMI protocol in a CCU for 12 hrs. The ECG findings of left main sub-total coronary occlusion seen in the next ECG include:  ST segment elevation in aVR > any ST elevation in V1 and  ST segment depression in 7 or more leads of the 12-lead ECG  These ECG findings indicate circumferential subendocardial ischemia due to left main coronary artery occlusion or due to severe triple vessel CAD. MI with Bundle Branch Block  MI + Right Bundle Branch Block  Usually easy to recognize because the appearance of Q waves and ST-T changes in the appropriate leads are not altered by the presence of RBBB.

A tween CSF HVA and anxiety severity or panic attack fre- SPECT-iomazenil study that quantitated BZD-receptor quency (288) discount desyrel 100 mg on-line. In addition discount 100mg desyrel fast delivery, genetic studies examining associ- binding by derivation of distribution volumes found re- ations between PD and gene polymorphisms for the DA duced binding in the left hippocampus and precuneus in D4 receptor and the DA transporter have produced negative unmedicated PD relative to healthy control samples and results (289). Another ies involving small subject samples reported abnormal re- SPECT-iomazenil study reported lower distribution vol- ductions in DA-receptor binding. These findings appeared social phobic relative to healthy control samples (290), pre- consistent with the evidence cited earlier that stress down- sumably reflecting a reduction in DA-transporter binding. Central BZD-receptor binding has also been assessed in relative to healthy control subjects (291). Conversely, 5-HT2A–receptor expres- nucleus accumbens, amygdala, and lateral hypothalamus in sion is up-regulated during chronic stress and CORT ad- experimental animals (285). During exposure to fear-condi- ministration, and it is down-regulated in response to adre- tioned stimuli, the 5-HT turnover in the mPFC appears nalectomy (298,300). In view of evidence that 5-HT1A and particularly sensitive to the severity of stress, increasing as 5-HT2A receptors may play reciprocal roles in mediating the aversiveness of the US and the magnitude of the condi- anxiety, it is conceivable that these corticosteroid mediated tioned fear behavioral response increases (285). However, effects on 5-HT1A and 5-HT2A expression may be relevant exposure to repeated electric shocks sufficient to produce to the pathophysiology of anxiety. Preadministration of BZD-receptor agonists or tri- The literature regarding serotonergic function in anxiety cyclic antidepressant drugs prevents stress-induced reduc- disorders is in disagreement (see Table 63. In PD, platelet tions in 5-HT release and interferes with the acquisition 5-HT uptake has been reported to be abnormally elevated of learned helplessness, whereas infusion of 5-HT into the (301), normal (302), or abnormally reduced (303). Platelet frontal cortex after stress exposure reverses learned-help- imipramine binding (to a site related to the 5-HT trans- lessness behavior (292,293). Finally, administration of porter site), did not differ in PD relative to control samples 5-HT–receptor antagonists produces behavioral deficits (304,305). Another study reported reduced concentrations resembling those of the learned helplessness seen after ines- of circulating 5-HT in PD relative to control samples (306), capable shock during animal stress models that do not ordi- although this finding has not been replicated. Pharmacologic challenge studies involving 5-HT have The effect of stress in activating 5-HT turnover may been similarly unable to establish a primary role for 5-HT stimulate both anxiogenic and anxiolytic pathways within in the pathophysiology in PD. Neuroendocrine responses the forebrain, depending on the region involved and the to challenge with the 5-HT precursors, L-tryptophan and 5-HT–receptor subtype that is predominantly stimulated. Moreover, appears to enhance conditioned fear, whereas 5-HT injec- tryptophan depletion did not prove anxiogenic in unmedi- tion into the PAG inhibits unconditioned fear (260). Fenfluramine gic innervation of hippocampal 5-HT1A receptors sup- challenge also resulted in reduced CBF in the left posterior presses formation of new CS-US associations and provides parietal-superior temporal cortex in PD study subjects rela- resilience to aversive events. Potentially compatible with this tive to healthy controls (131), although it was unclear hypothesis, 5-HT1A–receptor knockout mice exhibit behav- whether this abnormality reflected an abnormality of seroto- iors consistent with increased anxiety and fear, and long- nergic function or a physiologic correlate of fenfluramine- term administration of 5-HT1A–receptor partial agonists induced anxiety, because more PD study subjects (56%) exerts anxiolytic effects in generalized anxiety disorder developed panic attacks than did control subjects (11%). Preliminary data regarding the sensitivity of specific 5- Notably, stress and glucocorticoids exert major effects HT–receptor subtypes appear more promising, particularly on the genetic expression of 5-HT1A and 5-HT2A receptors. Finally, increases in anxiety and plasma expressed (reviewed in ref. Thus, 5-HT1A–receptor cortisol in PD relative to control samples have been reported density and mRNA levels decrease in response to chronic after oral (312), but not intravenous, administration of stress or CORT administration and increase after adrenalec- the 5-HT2–receptor agonist, m-chloromethylpiperazine tomy (296–299). Although both controls, a finding suggesting alterations in the 5-HT trans- Chapter 63: Neurobiological Basis of Anxiety Disorders 919 porter (314). Thus, a subgroup between PD and a single nucleotide polymorphism found of patients with PTSD may have abnormal sensitivity to in the coding region of the CCK-B–receptor gene (321). If confirmed by replication, these Cholecystokinin data would suggest that a CCK-B–receptor gene variation CCK is an anxiogenic neuropeptide present in both the may be involved in the pathogenesis of PD. Iontophoretic administration of CCK has depolariz- were seen between the active drug and placebo treatment ing effects on pyramidal neurons and stimulates action po- groups. Nevertheless, because of the limited bioavailability tential formation in the dentate gyrus of the hippocampus of oral CI-988, studies involving this drug may not have (reviewed in ref. CCK has important functional interactions with other Other Neuropeptides systems implicated in anxiety and fear (noradrenergic, do- paminergic, BZD). For example, the panicogenic effect of Opioid Peptides CCK-4 in PD is attenuated by administration of the - Acute, uncontrollable shock increases secretion of opiate adrenoreceptor antagonist, propranolol, and by long-term peptides and decreases -opiate–receptor density (323, imipramine treatment, which down-regulates -adrenore- 324). The elevation of opioid peptide secretion may con- ceptors (316).