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Com partm ent syndrom e cheap seroquel generic, with vein or when it accidentally becom es dislodged into the subcuta- loss of distal m otor function or sensation in the arm cheap seroquel 100 mg, is another neous tissue buy seroquel 100mg on-line. The venous return needle presents the biggest prob- concern in this setting seroquel 100mg without prescription, and drainage m ust be perform ed to treat lem. In the face of typical pum p speeds of 400 to 500 m L/m in a this surgical em ergency. A, Radiograph depicting an angioplasty balloon inflated across an outflow vein with a stenotic lesion. The “waist” in the balloon (arrow) indicates the location of the stenosis. W ith increasing inflation pressure the waist disappears, an indication of successful angioplasty. Failure to elim inate the waist in the balloon indicates incom plete dilata- tion of the lesion. O ccasionally, outflow vein stenoses are very resistant to dilatation and require high inflation pressures. This is not surprising given the am ount of scarring and intim al hyper- plasia that can develop in a dialysis access site. B, Resected graft-venous anastom osis from a one-year-old PTFE graft. Angioplasty of lesions such as these is often unsuccessful, as this rigid m aterial is likely to rebound to its stenotic state with any m anipulation. Failure to remove this meniscus invariably leads to rethrom- bosis. B, This type of clot is demonstrated in an arteriogram per- formed through the brachial artery following thrombolytic therapy. The arterial end of this polytetrafluoroethylene (PTFE) graft demon- strates a residual intraluminal thrombus (arrow), which is typical of the platelet-rich plug or arterial type thrombus. A third type of clot (not shown) consists of a white laminar material that lines the graft over time, especially in sites of repeated puncture. This material can create a stenosis along the body of the graft and may be removed by curettage at the time of thrombectomy using an atherectomy catheter. Failure to remove this material decreases blood flow through the graft and may lead to rethrombosis. E Eighty percent of thrombosed accesses have an associated stenotic lesion. C, An eccentric focal stenosis is demonstrated at the anasto- FIGURE 5-11 mosis of a PTFE forearm graft and its outflow vein (arrow), which Graft thrombosis due to outflow vein stenosis requiring use of an did not respond to percutaneous transluminal angioplasty. Thrombectomy of a dialysis access site involves was subsequently resected using a Simpson atherectomy catheter, removal of three types of clot. A, The body of a thrombosed access which consists of a concealed cutting chamber that is deflected into contains a red or purplish thrombus that is often gelatinous. It is eas- contact with the stenotic lesion of the vessel wall by inflating the ily removed with a balloon-tipped thrombectomy/embolectomy associated balloon. W ith the lesion projecting into the cutting cham- catheter. This photograph also demonstrates the small meniscus of ber, a high-speed cylindrical cutting blade resects tissue into a collect- firm, laminar, platelet-rich clot that usually obstructs arterial inflow. This chamber is rotated sequentially until the circum- On occasion, it is also found at the venous end. This type of clot can ference of the lesion has been treated. D, The Simpson atherectomy be tenacious and may not be removed with thrombolytic therapy or catheter is placed across the stenotic lesion. A cutdown at the arterial end of the graft may venogram shows that the lesion was successfully resected. To increase the efficiency of drug throm bolysis, pulse spray catheters are often used. The technique involves em bed- ding the catheter within the clot and intentionally obstructing the catheter end hole with a guidewire. W hen the fibrinolytic agent is injected, it is forced out through the catheter sideholes in jets and perm eates the clot. W ith this m ethod, a larger surface area of clot is exposed to the fibrinolytic agent. Several types of m echanical throm bectom y devices have been developed as alternatives to pharm aceutical fibrinolysis. All m echanically m acerate or disrupt clot into sm all fragm ents that em bolize into the central veins and, eventually, the pulm onary vascular bed. This photograph dem onstrates a brush attached to a m otor drive that im parts high-speed rotary m otion to disrupt the throm bus. The danger of m ost m echanical devices is the risk of vascular injury. A B C D FIGURE 5-14 O utflow vein stenosis with stenting. A, Arteriography in this develop vigorous fibrosis at the venous site of a stent. D, This patient with a Brescia-Cim ino fistula dem onstrates stenosis of the photograph dem onstrates what had occurred only 1 m onth after outflow vein approxim ately 15 cm central to the fistula (arrow). Stents can be a problem when dealing with sub- B, Percutaneous translum inal angioplasty was perform ed in this sequent vascular access dysfunction. During throm bectom y, the patient; however, because of im m ediate elastic recoil, the lesion tiny wires of a stent can puncture balloon catheters. C, Following stent placem ent ed segm ents restenose, it is im possible to perform open patch (arrow), there is no residual stenosis, and good flow through the angioplasty over such segm ents, and it becom es necessary to stent is apparent. It is not clear whether Although they m ay im prove patency in central vein stenoses (vide stents in or adjacent to dialysis grafts are cost effective in m ain- infra), in the periphery they m ay be a hindrance. A, This arteriogram demonstrates a forearm atherectomy or surgical revision. Since this region of the access is loop polytetrafluoroethylene (PTFE) graft with an intragraft stenosis subject to needle cannulation, the placement of a stent would be (arrow). Stenotic lesions in this site are less com m on than those inadvisable. Intragraft stenoses may be located between the sites of involving either the venous anastom osis or the outflow vein. If so, the B, These lesions can be treated successfully with percutaneous trans- most common screening studies, namely venous pressure measure- luminal angioplasty (arrow). In cases where angioplasty is unsuccess- ments and recirculation, do not have abnormal findings and the ful, intragraft stenoses can also be treated using percutaneous lesion may remain undetected until access thrombosis develops. Severe aneurysm al degeneration poses a significant surgical prob- lem for both patient and surgeon. A, Photograph dem onstrating an anastom otic aneurysm in a loop forearm polytetrafluoroethylene (PTFE) graft. This aneurysm is an exam ple of the type of degenerative changes that occasionally occur in both arteries and veins subjected to turbulence and high tangential wall stress. This is com m on in the native circulation in areas of poststenotic dilatation. The PTFE graft with high flow volum es m anifested the enlarge- m ent of the venous outflow. This bulge, which constitutes a segm ent of flow stagnation, is associated with increased risk of throm bosis over tim e. Since this would jeopardize the long-term function of the access, the area was revised by interposing a short segm ent of PTFE to a new venous outflow adjacent to the aneurysm al segm ent. B, Radiograph dem on- strating a pseudoaneurysm in the m idportion of a forearm loop PTFE graft (arrow). This lesion represents a com m unication between the graft and a confined space in the tissue sur- rounding the graft and is a com m on finding in dialysis patients. C, A pseudoaneurysm in a patient with a 3-year-old left groin PTFE graft. The lateral area of the loop was initially replaced, and when this was healed C and functioning well the m edial segm ent was replaced. Vascular steal is a com m on problem of dialysis access sites.

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In recent nucleus accumbens has been postulated to relate to the anti- years purchase seroquel online, concerted research and development efforts have been psychotic activity of both conventional and atypical drugs made to produce a second generation of 'atypical' antipsy- (26 purchase 50 mg seroquel otc,27) cheap 300 mg seroquel free shipping. The Fos expression in the dorsolateral striatum purchase discount seroquel, chotic drugs, including risperidone, olanzapine, quetiapine, which is not induced by clozapine, has been proposed to and ziprasidone, with the therapeutic advantages of clozap- be predictive of a liability to induce EPS (23,27). More ine, without the properties contributing to its serious side recently, it has been reported that haloperidol, but not clo- effects (13). Ongoing clinical evaluation of the new 'atypi- zapine, increased the immediate-early gene, arc (activity- cal' antipsychotic drugs will eventually allow comprehen- regulated cytoskeleton-associated gene) mRNA levels in the sive assessment of their efficacy and safety. After chronic treatment, haloperidol also induces an increase in D2 receptor density and D2L receptor mRNA in the striatum (29–31). Interestingly, several inves- tigators have reported striatal enlargement after chronic REVIEW AND CRITIQUE OF CURRENT treatment with conventional antipsychotics, but not atypi- SCHIZOPHRENIA PHARMACOTHERAPY cal drugs, in both schizophrenic patients (32,33) and rats ConventionalAntipsychotic Drugs (34). Thus, available data suggest that conventional antipsy- chotic drugs may induce long-term plastic changes that lead Pharmacology to morphologic alterations in the striatum, and that the Conventional or typical antipsychotic drugs can be classified efficacy and side-effect profile of typical antipsychotics relate as high, intermediate, or low potency based on their affinity to antagonistic actions at D2 dopamine receptors. Efficacy Haloperidol, the prototypical high-potency typical antipsy- chotic, has relatively high affinity for D2 receptors and a Although typical neuroleptics vary in side-effect profile and dose of 2 to 4 mg of haloperidol is equivalent to approxi- hence tolerability, there is little evidence for differences in mately 100 mg of chlorpromazine. However, in rare cases, thioridazine) have a chlorpromazine equivalent dose of patients failing a trial of one class may respond to the other. There is a good correlation between anti- Although conventional neuroleptic drugs are effective for psychotic potency and D2 affinity for conventional antipsy- alleviating positive symptoms of schizophrenia, and pre- chotics of several chemical classes (4). Conventional drugs venting their recurrence in many patients, they have serious have various interactions with serotonin receptors, ranging limitations. Approximately 30% of patients with acutely from slight (e. Negative emission computed tomography (SPECT) studies have fur- symptoms, mood symptoms, and cognitive deficits are mar- ther elucidated the importance of dopamine receptor occu- ginally responsive to conventional neuroleptics. In particu- pancy as a predictor of antipsychotic response and adverse lar, primary negative symptoms are very resistant to the Chapter 56: Therapeutics of Schizophrenia 777 typical drugs (7,35). The presence of negative symptoms unfortunate trade-off is inevitable with conventional anti- and cognitive impairment often leads to poor social and psychotic treatment (46). Thus, in the absence of a clini- cal response at acute phase of the illness, clinicians often AtypicalAntipsychotic Drugs switch to a newer atypical agent (38). A series of atypical compounds has been developed since the introduction of clozapine. These include risperidone, Safety olanzapine, quetiapine, and ziprasidone, which were ap- proved by the FDA in 2000, and aripiprazole and iloperi- Most conventional antipsychotics are associated with a wide done, which are in late Phase III development. Up to 70% of patients given recom- understood despite intensive research efforts. Defining the mended therapeutic dosages of conventional antipsychotics role of the individual complex actions of clozapine responsi- develop acute EPS (40). The most troublesome neurologic ble for its unique therapeutic profile (Table 56. Further, the anticholinergic drugs that are often used A distinguishing feature of clozapine in comparison to to reduce EPS, can also produce serious side effects (e. All these adverse effects can contribute to treatment (47) provided evidence that combined 5-HT2A/D2 antago- noncompliance, and hence increase rates of relapse and re- nistic actions, with greater relative potency at the 5-HT2A hospitalization during the course of the chronic illness (7, receptor, may be critical to atypicality, in terms of enhanced 39). Based on this theoretic model, risperidone was developed to mimic the relative 5- HT2A/D2 affinities of clozapine, although risperidone has Effectiveness substantially higher affinity for both receptors than cloza- Treatment with typical antipsychotics may result in poorer pine (Table 56. The reduced EPS side effects associated clinical and quality of life outcomes than with atypical anti- with low-dose risperidone treatment (4 to 6 mg per day), psychotics (6). The mean first-year relapse rate during con- even at high levels of D2 receptor occupancy, may be owing tinuing maintenance treatment with conventional antipsy- to the 5-HT2A antagonistic properties of the drug (47,48). Even under the best condi- cating that 5-HT2A receptor antagonism alone cannot com- tions, when patients are maintained on therapeutic doses pletely eliminate EPS associated with high D2 receptor of depot conventional antipsychotics, approximately 30% blockade. The potential role of 5-HT2A receptor antago- of discharged patients with schizophrenia will be rehospital- nism in therapeutic responses to atypical antipsychotic ized within 1 year (44). Hospital readmission rates are drugs may become more apparent when data from clinical higher for conventional antipsychotics than for atypical trials are available for the selective 5-HT2A antagonist M- antipsychotics (45). However, the results to date support the hypothesis patients taking optimal doses of a depot neuroleptic is esti- that some degree of D2 antagonism is still required to mated to be 3. Moreover, at this point it is have discontinued their medication is 11. Often, when considering the best dose of a conven- potential therapeutic significance of the adrenergic receptor tional antipsychotic, there is a trade-off between maximizing blocking properties of clozapine and risperidone is uncer- relapse prevention and optimizing comfort (46). Addition of the 2-antagonist idazoxan to the regime there has been substantial progress in understanding main- of patients treated with the typical neuroleptic fluphenazine tenance dosing, for most patients with schizophrenia, this resulted in improved treatment responses in patients refrac- 778 Neuropsychopharmacology: The Fifth Generation of Progress TABLE 56. AFFINITY OF ANTIPSYCHOTIC DRUGS FOR HUMAN NEUROTRANSMITTER RECEPTORS (Ki, nM)a Receptor Clozapine Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Iloperidone Haloperidol D 290 580 52 1,300 130 410c 320 120 1 D 130 2. Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia. Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Iloperidone binding to human and rat dopamine and 5-HT receptors. However, as well as H1 and 1-adrenergic receptors (55) (Table 56. Aripiprazole is distinct from the other atypical useful for treating cognitive deficits of the disease (50). Olanzapine is more potent at 5-HT2A than D2 drugs (56,57). Clozapine, however, does not exhibit high receptors (Table 56. The low occupancy of striatal D2 receptors by but there are also some notable distinctions between the clozapine could account for its low EPS liability (20,58, two drugs. For example, clozapine has substantially higher 59). Although 5-HT2A receptor an- for 5-HT2A than for D2 receptors, but also some affinity tagonism is likely to be associated with the low EPS liability for 1-adrenergic and H1 receptors (53) (Table 56. Inter- of risperidone and olanzapine, the role of this molecular estingly, quetiapine produces only transiently high striatal action in the superior therapeutic responses to clozapine is D2 occupancy in schizophrenic patients, although the study unclear (13). Ziprasidone has potent 5-HT2A and D2 affinities, and like clozapine, it Efficacy shows 5-HT1A agonist properties that could potentially act as protective effects on the development of EPS. Ziprasi- Although the proportion of patients who improve and the done also has significant affinity for 5-HT1D and 5-HT2C, magnitude of therapeutic effects vary greatly, atypical anti- Chapter 56: Therapeutics of Schizophrenia 779 psychotics are at least as effective for psychotic symptoms and clozapine in treatment-resistant patients. Well-controlled double-blind was found to be more effective than haloperidol (74,76), studies of atypical antipsychotics suggest that clozapine, but not chlorpromazine (77), in treatment-refractory pa- risperidone, and olanzapine may be superior to haloperidol tients. In a recent randomized double-blind study of treat- for controlling psychotic symptoms (61). At selected doses, ment-resistant schizophrenia, olanzapine and clozapine had risperidone appears to be more effective than haloperidol similar antipsychotic efficacy (74). Additional studies are in treating positive and negative symptoms (53). Olanza- needed to reach definitive conclusions regarding efficacy pine has been demonstrated to be effective for positive, neg- of the newer atypical antipsychotics in treatment-resistant ative, and depressive symptoms (62), and in some studies schizophrenia. Results of studies investigating the effects the drug was superior to haloperidol and risperidone in of atypical antipsychotics in treatment-resistant patients are terms of negative symptoms and long-term efficacy (63,64). However, in a recent large double-blind study (that has The efficacy of atypical antipsychotics in treating primary only been preliminarily reported), risperidone demonstrated negative symptoms has not been clearly demonstrated (61). Quetiapine inantly negative symptoms is less clear (8). In addition, the appears to be comparable to chlorpromazine and haloperi- effects of atypical antipsychotics on cognitive impairment dol in treating both positive and secondary negative symp- have not yet been clearly proved. Similarly, ziprasidone appears to be as effective ies (only three of which were double-blind) of atypical anti- as haloperidol in alleviating positive and negative signs in psychotics and cognitive impairment in patients with schiz- an acute treatment study (66), whereas a 52-week placebo- ophrenia suggests that they may improve attention and controlled maintenance study found primary and secondary executive function (37). Available results, however, are rela- negative symptom efficacy for ziprasidone (67). Furthermore, To date, clozapine is the only drug that has proven effi- there are statistical limitations and a lack of standard con- cacy in treatment-refractory schizophrenia (68,69). It appears that ficacy rates for clozapine in treatment-refractory patients there could be significant differences among the atypical vary from 20% to more than 70% (11,70,71). In some drugs in terms of what types of cognition they improve.

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If a well-nourished patient W ITH ACUTE RENAL FAILURE can resum e a norm al diet within 5 days best order for seroquel, no specific nutritional sup- port is necessary purchase online seroquel. The degree of accom panying catabolism is also a factor purchase seroquel cheap. For patients with underlying diseases associated with excess Decisions dependent on protein catabolism order seroquel 200mg fast delivery, nutritional support should be initiated early. Patients ability to resume oral diet (within 5 days? M odern nutritional strategies should be aimed at 1. W hat patient with acute renal failure needs nutritional support? At what degree of impairment in renal function should the nutritional regimen 24 hours after trauma or surgery) nutritional support should be be adapted for renal failure? In a patient with multiple organ dysfunction, which organ determines the type of utilized, could increase oxygen requirements, and aggravate tissue nutritional support? Is enteral or parenteral nutrition the most appropriate method for providing The nutritional regim en should be adapted for renal failure when nutritional support? The m ultiple m etabolic alterations char- acteristic of ARF occur when kidney function is below 30% of norm al. Thus, when creatinine clearance falls below 50 to 30 m L per m inute/1. N utrition in patients with acute renal failure (ARF): decision m ak- W ith the exception of severe hepatic failure and massively deranged ing. N ot every patient with ARF requires nutritional support. It is amino acid metabolism (hyperammonemia) or protein synthesis (deple- im portant to identify those who will benefit and to define the opti- tion of coagulation factors) renal failure is the major determinant of the m al tim e to initiate therapy. The decision to initiate nutritional support is influenced by the Enteral feeding is preferred for all patients, including those with ARF. Nutrition and M etabolism in Acute Renal Failure 18. FIGURE 18-29 Patient classification: substrate requirem ents. Ideally, a nutritional program should be designed for each individual acute renal failure (ARF) patient. In clinical practice, it has proved useful to distinguish three groups of patients based on the extent of protein catabo- lism associated with the underlying disease and resulting levels of dietary requirem ents. G roup I includes patients without excess catabolism and a UN A of less than 6 g of nitrogen above nitrogen intake per day. ARF is usually caused by nephrotoxins (am inogly- cosides, contrast m edia, m ism atched blood transfusion). In m ost cases, these patients are fed orally and the prognosis for recovery of renal function and survival is excellent. G roup II consists of patients with m oderate hypercatabolism and a UN A exceeding nitrogen intake 6 to 12 g of nitrogen per day. Affected patients frequently suffer from com plicating infections, peritonitis, or m oderate injury in association with ARF. Tube feed- ing or intravenous nutritional support is generally required, and dialysis or hem ofiltration often becom es necessary to lim it waste product accum ulation. G roup III are patients who develop ARF in association with severe traum a, burns, or overwhelm ing infection. UN A is m arkedly elevated (m ore than 12 g of nitrogen above nitrogen intake). Treatm ent strategies are usually com plex and include parenteral nutri- tion, hem odialysis or continuous hem ofiltration plus blood pressure and ventilatory sup- port. To reduce catabolism and avoid protein depletion nutrient requirem ents are high and dialysis is used to m aintain fluid balance and blood urea nitrogen below 100 m g/dL. M ortality in this group of patients exceeds 60% to 80% , but it is not the loss of renal function that accounts for the poor prognosis. It is superim posed hypercatabolism and the severity of the underlying illness. The gastrointestinal tract should be used whenever possible because enteral nutrients m ay help to m aintain gastrointestinal function and the m ucosal barrier and thus prevent translocation of bacteria and system ic infection. Even sm all am ounts of enteral diets exert a protective effect on the intestinal m ucosa. Recent anim al experim ents suggest that enteral feeds m ay exert additional advantages in acute renal failure (ARF) patients: in glycerol-induced ARF in rats enteral feeding im proved renal perfusion, A, and preserved renal function, B. For patients with ARF who are unable to eat because of cerebral im pairm ent, anorexia, or nausea, enteral nutrition should be provided through sm all, soft feeding tubes with the tip positioned in the stom - ach or jejunum. Feeding solutions can be adm inistered by pum p interm ittently or con- tinuously. If given continuously, the stom ach should be aspirated every 2 to 4 hours until adequate gastric em ptying and intestinal peristalsis are established. To avoid diarrhea, the am ount and concentration of the solution should be increased gradually over several days until nutritional requirem ents are m et. Undesired, but potentially treatable side effects include nausea, vom iting, abdom inal distension and cram ping and diarrhea. The protein content is lower and is confined to high- m ulas designed for subjects with norm al renal function that can quality proteins (in part as oligopeptides and free am ino acids), the also be given to patients with acute renal failure (ARF). M ost form ulations contain Unfortunately, the fixed com position of nutrients, including pro- recom m ended allowances of vitam ins and m inerals. The diets can be supplemented with addi- therapy of patients with chronic renal failure (CRF) can be used. Recently, ready-to- The preparations listed here m ay have advantages also for patients use liquid diets have also become available for renal failure patients. Standard solutions are available with am ino acids, glucose, and lipids plus added vitam ins, trace elem ents, and electrolytes contained in a single bag (“total adm ixture” solutions, “all-in-one” solutions). The stability of fat em ulsions in such m ixtures should be tested. If hyperglycem ia is present, insulin can be added to the solution or adm inistered separately. To ensure m axim al nutrient utilization and avoid m etabolic derangem ents as m ineral im balance, hyperglycem ia or blood urea nitrogen rise, the infusion should be started at a slow rate (providing about 50% of requirem ents) and gradually increased over several days. O ptim ally, the solution should be infused continuously over 24 hours to avoid m arked derangem ents in substrate concentrations in the presence of im paired utilization for several nutritional substrates in patients with acute renal failure. EAA, N EAA— essential and nonessential am ino acids; TPN — total parenteral nutrition. Nutrition and M etabolism in Acute Renal Failure 18. FIGURE 18-33 Am ino acid (AA) solutions for parenteral nutrition in acute renal tions or in special proportions designed to counteract the failure (ARF). The m ost controversial choice regards the type of m etabolic changes of renal failure (“nephro” solutions), includ- am ino acid solution to be used: either essential am ino acids (EAAs) ing the am ino acids that m ight becom e conditionally essential exclusively, solutions of EAA plus nonessential am ino acids in ARF. O ne Use of solutions of EAA alone is based on principles established for should be aware of the fact that the am ino acid analogue N -acetyl treating chronic renal failure (CRF) with a low-protein diet and an tyrosine, which previously was used frequently as a tyrosine EAA supplement. This may be inappropriate as the metabolic adapta- source, cannot be converted into tyrosine in hum ans and m ight tions to low-protein diets in response to CRF may not have occurred even stim ulate protein catabolism. Plus, there are fundamental differences in the Despite considerable investigation, there is no persuasive evi- goals of nutritional therapy in the two groups of patients, and conse- dence that am ino acid solutions enriched in branched-chain am ino quently, infusion solutions of EAA may be sub-optimal. System atic Thus, a solution should be chosen that includes both essential studies using glutam ine supplem entation for patients with ARF are and nonessential am ino acids (EAA, N EAA) in standard propor- lacking (see Fig. Because of the well-docu- m ented effects of overfeeding, energy intake of patients with ARF m ust not exceed their actual energy expenditure (ie, in m ost cases 100% to 130% of resting energy expenditure [REE]; see Figs. Glucose should be the principal energy substrate because it can be utilized by all organs, even under hypoxic conditions, and has the potential for nitrogen sparing. Since ARF im pairs glucose tolerance, insulin is frequently necessary to m aintain norm oglycem ia. Any hyperglycem ia m ust be avoided because of the untoward associated side effects— such as aggravation of tissue injury, glycation of pro- teins, activation of protein catabolism , am ong others.

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