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Is splanchnic perfusion pressure more predictive of outcome than intragastric pressure in neonates with gastroschisis? Splanchnic per- fusion pressure: a better predictor of safe primary closure than intraabdominal pressure in neonatal gastroschisis best 20 mcg ipratropium medications dispensed in original container. Dobutamine restores intestinal mucosal blood fow in a porcine model of intra-abdominal hyperpressure order ipratropium 20 mcg free shipping symptoms pink eye. What’s new in medical man- agement strategies for raised intra-abdominal pressure: evacuating intra-abdominal contents order ipratropium 20mcg otc medicine 6469, 184 T buy generic ipratropium 20 mcg online medical treatment 80ddb. Kaussen improving abdominal wall compliance, pharmacotherapy, and continuous negative extra- abdominal pressure. Perioperative crystalloid and colloid fuid management in children: where are we and how did we get here? Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Phosphodiesterase 5 inhibition protects against increased intra-abdominal pressure-induced renal dysfunction in experimental congestive heart failure. The pathophysiological hypothesis of kidney dam- age during intra-abdominal hypertension. Renal implications of increased intra-abdominal pressure: are the kidneys the canary for abdominal hypertension? Normotensive ischemic acute kidney injury as a manifesta- tion of intra-abdominal hypertension. Pathophysiology of renal hemodynamics and renal cortical microcirculation in a porcine model of elevated intra- abdominal pressure. Early Doppler changes in a renal transplant patient secondary to abdominal compartment syndrome. Renal circulation and microcirculation during intra- abdominal hypertension in a porcine model. Mechanisms of acute respiratory distress syndrome in children and adults: a review and suggestions for future research. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. What is normal intra-abdominal pressure and how is it affected by positioning, body mass and positive end-expiratory pres- sure? Experimental intra-abdominal hypertension infuences airway pressure limits for lung protective mechanical ventilation. Clinical signifcance of elevated intraabdominal pressure during common condi- tions and procedures. Intra-abdominal hypertension: defnitions, monitoring, interpretation and management. Matching positive end-expiratory pressure to intra- abdominal pressure improves oxygenation in a porcine sick lung model of intra-abdominal hypertension. Effects of intra-abdominal pressure on respiratory system mechanics in mechanically ventilated rats. Exogenous surfactant and alveolar recruitment in the treatment of the acute respiratory distress syndrome. Experience in the management of eighty-two newborns with congenital diaphragmatic hernia treated with high-frequency oscillatory ventilation and delayed surgery without the use of extracorporeal membrane oxy- genation. Observations on the effects of inhaled isofurane in long-term sedation of critically ill children using a modifed AnaConDa(c)-system. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012. Establishing early enteral nutrition with the use of self-advancing postpyloric feeding tube in critically ill children. Postinjury abdominal compartment syndrome does not preclude early enteral feeding after defnitive closure. Erythromycin for the prevention and treatment of feeding intolerance in preterm infants. The impact of multi-disciplinary intestinal rehabilitation programs on the outcome of pediatric patients with intestinal failure: a systematic review and meta-analysis. Nutritional Support in Patients 15 with an Open Abdomen Patricia Marie Byers and Andrew B. Peitzman nutrient deprivation coupled with a metabolic disturbance that causes increased protein turnover with a rapid loss of lean body mass. Host defenses are compro- mised with poor wound healing, increased infection rates, prolonged ileus, length- ened hospital stay, and increased mortality. It is important to understand the metabolic phases of injury of this catabolic response to customize the optimal nutritional support for each phase. The phases of damage control laparotomy coincide with the phases of the meta- bolic response as outlined by Cuthbertson in the early 1930s [10–12]. This immediate response to tissue injury is fueled by catecholamines with hemodynamic and reperfusion disturbances charac- terized by a pronounced acute phase reaction with vasoconstriction. Optimally, within 12–24 h, this phase is completed with normalization of perfusion, core tem- perature, and resolution of lactic acidosis. The flow phase follows, and the metabolic environment changes, now with increased levels of catecholamines and cortisol, usually persisting from 3 to 21 days . There is a state of increased energy expenditure and hypercatabo- lism with protein turnover and muscle protein breakdown for substrate, along with increased cardiac output and oxygen consumption. This “auto-cannibal- ism” can be viewed as an adaptive response that provides the brain and injured tissues with substrate to promote healing. Insulin resistance is responsible for the decreased peripheral use of glucose and the increased rates of lipolysis and proteolysis for the provision of amino acids and fatty acids as fuel substrates. The conversion of peripherally mobilized amino acids (primarily alanine), lac- tate, and pyruvate to glucose by gluconeogenesis is not suppressed by hyper- glycemia or the infusion of glucose solutions in this catabolic state. Branched-chain amino acids are used preferentially as fuel in the skeletal mus- cle. There are some amino acids that are taken up selectively by tissues for specific purposes. For example, glutamine, a conditionally essential amino acid, is taken up by the proximal nephron to sustain ammoniagenesis and to counteract acidosis, by fibroblasts and enterocytes to promote healing and by immune cells for replication . While adipose tissue is expendable and can be utilized as fat calories, protein is not, as all proteins have either structure or function. If the stress state is prolonged, the amino acid pool will become depleted of essential amino acids, and protein synthesis cannot match the increased rate of mus- cle protein breakdown. Over time, there will be functional deterioration in organ system function with poor wound healing, atelectasis, pneumonia, prolonged venti- lator dependence, and compromised host barrier function. This will prolong the stress state and result in poor outcomes, long-term functional disability, and increased mortality [14, 15]. Persistent infammation and immunosup- pression: a common syndrome and new horizon for surgical intensive care. However, it is important to identify patients with the highest risk early, as they have the worst outcomes and beneft the most from nutritional interventions [17–19]. Patients with an open abdomen may enter the illness malnourished, adequately nourished, or obese.
Secondary abdominal compartment syndrome is an elusive early complication of traumatic shock resuscitation cheap ipratropium 20mcg line medicine ads. Both primary and secondary abdominal compartment syndrome can be predicted early and are harbingers of multiple organ failure purchase ipratropium online now medicine over the counter. Patients with impending abdominal compartment syndrome do not respond to early volume loading generic 20mcg ipratropium fast delivery medications identification. Venous thromboembolism in patients with blunt trauma: Are comprehensive guidelines the answer? Limitations of compression ultrasound for the detection of syntomless postoperative deep vein thrombosis purchase ipratropium 20 mcg fast delivery treatment neuropathy. Strategies to improve compliance with evidence-based clinical management guidelines. A comparison of low-dose heparin with low-molecular- weight heparin as prophylaxis against venous thromboembolism after major trauma. A multimodal approach includes the appropriate use of nonsteroidal anti-inflammatory drugs, narcotics, adjuncts, regional and local anesthetics, as well as anxiety relief and appropriate emotional support. Good glycemic control may help with fighting infection and improve wound healing, which can result in better surgical outcomes. Hypoglycemia occurs because of nothing by mouth status, intraoperative administration of insulin, as well as the patient using programmable insulin pumps. The use of air warming blankets, warming mats, and intravenous fluid warmers all minimize hypothermia. Postanesthesia Recovery Each patient recovering from an anesthetic has circumstances that require an individualized problem-oriented approach. Postanesthesia recovery must continue to adapt to meet the needs of the changing perioperative landscape, advances in technology, and changing surgical techniques, and to respond to improved evidence-based research. Dissemination of anesthesia services beyond the perisurgical arena has brought changes and greater demands on recovery units. These five standards of28 care are used to determine who needs managed recovery, types of recovery, who is responsible, and how the patient is monitored prior to discharge. Value and Economics of Postanesthesia Care Unit The quality of postanesthesia care is composed of many variables such as tracking of complications, time per patient spent in recovery, overall clinical outcomes, and patient satisfaction. The value of postanesthesia care is a measure of the quality of care provided compared with the amount of resources spent per patient outcome. Triage and discharge policies affect both how many admissions occur and what resources each admission consumes. The level of monitoring provided affects the capital expenditure for equipment, and disposable items account for operating expenditures. The patient acuity mix also determines needs for staffing and equipment such as ventilators, additional monitors, intravenous pumps, and patient-controlled analgesia pumps. The type of physician coverage—such as dedicated coverage 3857 versus on-demand coverage—can affect response time, efficiency of care, costs, and patient outcomes. The use of routine postoperative diagnostic testing and therapies without evidence-based need can lead to unnecessary treatments, increasing cost per patient and possible worse patient outcomes. Cost comparisons between institutions are difficult because charges and cost factors vary widely across institutions, in different regions of the United States, and between countries. Regulatory requirements, standards of care, medical-legal climates, and institutional requirements vary greatly between regions and even between facilities in the same locale. This difference can be the result of levels of patient comorbidities, level of procedure complexity, surgeon, type of anesthetic, as well as patient perception and expectations. These are just some of the factors that can determine the type of care needed postoperatively. Medical professionals (physicians, nursing, and support staff) must work in concert to identify practices that are wasteful versus those that have proven yield/benefit. However, using a more expensive therapy may generate real savings by decreasing additional therapies, testing, admissions, or length of stay. Communication is perhaps the least expensive tool in medicine and the one most universally proven to be involved in human error events. Providers in the recovery unit must be 3858 aware of these protocols and manage patients accordingly. Observed change is frequently seen by reducing transportation delays, persistence of pain or nausea, waiting for space, or surgeon discharge delays. True savings are only realized when operational changes yield a decrease in expenditures for staff, supplies, or equipment. However, the areas of scheduling, clerical, or maintenance tasks must not consume excess staffing hours, without savings realized. Levels of Postoperative/Postanesthesia Care With continued demand to increase overall health-care efficiency, caution must be taken to provide the most appropriate care for each patient. As anesthesia services expand to cover a variety of patient types in ever- increasing areas outside the operating room, selecting the correct type of recovery is essential. For the many differing anesthesia areas ranging from inpatient surgery, ambulatory surgery, to off-site procedures, the level of postoperative care that a patient requires is determined by the degree of underlying illness, comorbidities, and the duration as well as the type of anesthesia and surgery. Less-invasive surgeries or procedures combined with shorter-duration anesthetic regimens facilitate high levels of arousal and minimal cardiovascular or respiratory depression at the end of surgery. Amenities such as recliners, reading material, television, music, and food improve perceptions (emotional satisfaction) without affecting quality or safety. Earlier reunion with family or visitors in the low-intensity setting is 3859 desirable assuming that postoperative care is safe and appropriate. Phase I recovery would be reserved for more intense recovery and would require more one-on-one care for staff. Triage should be based on clinical condition, length/type of procedure and anesthetic, and the potential for complications that require intervention. An individual patient undergoing a specific procedure or anesthetic should receive the same appropriate level of postoperative care whether the procedure is performed in a hospital operating room, an ambulatory surgical center, an endoscopy room, an invasive radiology suite, or an outpatient office. If doubt exists about a patient’s safety in a lower intensity setting, the patient should be admitted to a higher level of care for recovery. After superficial procedures using local infiltration, minor blocks, or sedation, patients can almost always recover with less intensive monitoring and coverage. Innovative anesthetic techniques, advanced surgical8 techniques, and use of bispectral index monitoring help facilitate fast-track postoperative care. This transfer still requires proper postoperative reporting to the accepting unit including how to communicate with the surgical service and anesthesiologist. Beyond usual safety policies, maintain staffing and training to ensure that an appropriate coverage and skill mix is available to deal with unforeseen crises. Less-skilled or training staff must be7 appropriately supervised, and a sufficient number of certified personnel must always be available to handle worst-case scenarios.
Table 33-5 Definition of General Anesthesia and Levels of Sedation/Analgesia18 2193 Figure 33-2 A radiology suite showing a C-arm and the high density of equipment that may separate the anesthesiologist from the patient buy discount ipratropium 20 mcg line medications used for fibromyalgia. Patient exposure to radiation during imaging and treatment varies depending on the type of procedure as well as patient- and operator-related factors cheap 20 mcg ipratropium visa medicine rocks state park. Standard procedures exist to minimize patient exposure to radiation and efforts to reduce occupational exposure for staff including anesthesiologists working in radiology suites are an important consideration order 20 mcg ipratropium otc nioxin scalp treatment. A number of terms are used to define exposure to radiation ; these are22 summarized in Table 33-6 discount ipratropium online american express medicine administration. Table 33-6 Common Terms Used in Radiation Exposure22 Staff, including the anesthesiologists, must be aware of the hazards of occupational exposure to ionizing radiation and take appropriate measures to protect themselves. Patients are subjected to direct exposure where the beam enters the skin, whereas staff members working in fluoroscopy suites are more at risk from scattered radiation. As a general rule the exposure to staff is 1/1,000th the entrance skin exposure at 1 m from the fluoroscopy 2194 tube. This finding was attributed to24 anesthesiologists being less likely to use the protective shielding during their patient care activities. Another recent study demonstrated that anesthesiologists working in the neurointerventional suite were are at equal risk of developing cataracts as neuroradiologists, and that the radiation may even be directed away from the neuroradiologists and toward the anesthesiologist. These studies highlight the need for anesthesiologists to be25 aware of the risks and the means to protect themselves from radiation, especially in areas where fluoroscopy is used. Using protective shielding (lead-lined garments and fixed and/or movable shields). Lead aprons, thyroid shields, and leaded eyeglasses are recommended despite being bulky and contributing to staff fatigue. Anesthesiology staff should consider using movable or fixed lead-lined glass shields so that they can gain easy access to their patients while protecting themselves from radiation. These data should be regularly reviewed by the facility’s radiation safety section or medical physics department. Radiologic contrast media are iodinated 2195 compounds classified according to their osmolarity (high, low, or iso- osmolar), their ionicity (ionic or nonionic), and the number of benzene rings (monomer or dimer). Nonionic contrast agents cause less discomfort on injection and have a lower incidence of adverse reactions. Adverse reactions to contrast agents may be divided into renal adverse reactions and hypersensitivity reactions. Nephrotoxic medications such as nonsteroidal anti-inflammatory drugs, aminoglycosides, and diuretics should be avoided for 24 to 48 hours before and after the use of intravenous contrast agents. Fatal hypersensitivity reactions may occur in about 1 per 100,000 contrast administrations. The clinical manifestations of various hypersensitivity reactions to contrast media are outlined in Table 33- 7. Although widely used, the effectiveness of corticosteroids and32 antihistamines in preventing hypersensitivity reactions to contrast agents in unselected patients is doubtful. Treatment of severe hypersensitivity33 reactions includes discontinuing the causative agent and supportive therapy, oxygen, intubating the trachea, cardiovascular support with fluids, 2196 vasopressors, and inotropes, and if required, bronchodilators. Severe reactions occur 1:10,000 to 1:40,000 and the mortality rate is 1 in a million injections. Patients are required to remain completely motionless during these procedures, which may be lengthy, particularly spinal angiography. Liberal use of local anesthetic at the puncture site precludes the need for intravenous analgesia. The injection of contrast media into the cerebral arteries may cause discomfort, burning, or pruritus around the face and eyes. During angiography and other interventional radiologic procedures, the patient is placed on a moving gantry and the radiologist positions the patient to track catheters as they pass from the groin into the vessels of interest. It is vital to have extensions on all anesthesia breathing circuits, infusion lines, and monitors to prevent these implements from being accidentally dislodged as the radiologist swings the x-ray table back and forth. The electrocardiogram electrodes and metallic coils in the cuffs of endotracheal tubes may cause interesting and annoying artifacts if they lie over the area being imaged. These procedures36 may be subdivided as “occlusive” and “opening” procedures (Table 33-2). A commonly employed technique is to insert37 detachable platinum coils into the abnormal vessel(s). Other occlusive agents include cyanoacrylates, “Onyx liquid embolic system” (Micro therapeutics Inc. These particles may also be used to produce temporary occlusion of blood vessels for preoperative embolization of vascular tumors, particularly meningiomas. In 2015, the American Heart Association and American Stroke Association jointly published guidelines for management of unruptured intracranial aneurysms. In the case of acute ischemic stroke, early (within 6 hours of symptoms) intervention to recanalize the occluded vessel by superselective intra-arterial thrombolytic therapy has been shown to improve outcome. Procedural and Anesthetic Technique Considerations in Interventional Neuroradiology For most interventional neuroradiologic procedures, arterial access is gained using a 6 or 7 French gauge sheath via the femoral or, rarely, the carotid or axillary artery. Anticoagulation is required during and up to 24 hours after interventional radiologic procedures to prevent thromboembolism. At the end of the procedure or in case of hemorrhage heparin may43 be reversed with protamine. General anesthesia and conscious sedation are both suitable techniques for interventional neuroradiology depending on the complexity of the procedure, the need for blood pressure manipulation, and the need for intraprocedural assessment of neurologic function. The anesthesiologist may facilitate the procedure by manipulating systemic blood pressure and controlling end-tidal carbon dioxide tension. The Wada test (injection of a small dose of a barbiturate or other anesthetic drug directly into one) is used to determine the dominant side for cognitive functions such as speech and memory. This procedure may be used prior to surgery for non–life-threatening conditions such as epilepsy. The50 worldwide unavailability of amobarbital has led to the use of other agents in these tests including propofol50,51 and etomidate. There is an absolute requirement for the patient to remain motionless while the study is being performed and children or adults with psychologic or neurologic disorders preventing immobility may require sedation or anesthesia (Table 33-1). Patients with acute thoracic, abdominal, and cerebral trauma often require urgent imaging to facilitate diagnosis. A high-frequency alternating current is used to generate a localized heat source directly into the tumor causing coagulative necrosis and tumor cell death while avoiding injury to the surrounding tissues. If an anesthesiologist does become involved in the care of these patients, careful evaluation is required; patients may be in the later stages of their disease, have often failed surgical treatment, and may have undergone extensive radiation therapy and/or chemotherapy. Beneficial effects include reduction in bleeding from varices and control of refractory cirrhotic ascites. The procedure causes minimal stimulation, lasts between 2 and 3 hours, and may be performed under sedation or general anesthesia.
Although radical nephrectomy is standard for central and large tumors purchase cheap ipratropium symptoms 3 days past ovulation, the value of nephron-sparing partial nephrectomy for early-stage and small renal cell cancers is being evaluated purchase ipratropium 20 mcg free shipping treatment alternatives. Although nonsurgical therapies are available buy ipratropium amex medications vitamins, renal cell cancers are resistant to radiation and chemotherapy cheap ipratropium 20 mcg overnight delivery medications safe during pregnancy. Blood loss during radical nephrectomy is highly dependent on the location and extent of the tumor. Laparoscopic innovations have reduced bleeding for all types of nephrectomy surgeries. Although often restricted to the vessel lumen, the thrombus may become adherent to the vessel wall,150 and right atrial involvement is present in 1% of cases. Radical nephrectomy procedures involving resection of tumor thrombus are particularly challenging owing to their risk of sudden major bleeding and potential for acute hemodynamic instability (e. In addition to sternotomy incision, such procedures require standard heparin anticoagulation and employ an added circuit venous line filter to trap tumor fragments (Fig. Other interventions used at some institutions in the treatment of renal tumor caval thrombus include venovenous bypass, inferior vena cava filter insertion, and even deep hypothermic circulatory arrest. Appropriate considerations when monitoring these complex procedures include radial arterial catheterization, central venous or pulmonary artery catheter placement, and intraoperative transesophageal echocardiography (Fig. In cases where supradiaphragmatic tumor thrombus is present, placement of a pulmonary artery catheter prior to thrombus resection is contraindicated owing to risk of embolization of tumor fragments. Preoperative therapeutic embolization of the tumor is sometimes also used in cases of arterial thrombus or extensive parasitic vessel formation or when there is anticipated difficulty in isolating the renal artery. Despite the potential for significant blood loss, cell saver technology use is discouraged owing to the potential for returning tumor cells to the circulation. Nephron-sparing Partial Nephrectomy Minimizing unnecessary loss of healthy tissue is a logical part of surgical planning for any kidney resection. Even when the contralateral kidney is normal, studies are now demonstrating comparable long-term results with nephron-sparing partial nephrectomy procedures as with radical nephrectomy for patients with a single, localized small tumor (<4 cm) or even medium- sized (<7 cm) peripherally located tumors. Limitations of partial nephrectomy include a higher perioperative risk of bleeding and urine leak, and a local tumor recurrence rate of 1% to 6%. Compared to open approaches, these minimally invasive strategies employ access through small airtight ports. Insufflation of carbon dioxide into the peritoneal cavity or retroperitoneal space is used to separate structures and enhance visibility. In recent years, laparoscopic techniques have surpassed open nephrectomies in popularity, particularly for simple and radical procedures. Laparoscopic approaches to radical nephrectomy are even being successfully employed in the treatment of locally invasive kidney cancer. Laparoscopic partial nephrectomy is technically more demanding than its open counterpart and currently involves temporary clamping of the renal hilum to optimize visibility during excision and minimize blood loss. B: Evidence of thrombus emboli in the venous filter 3555 following cardiopulmonary bypass highlights the friability of intravascular renal cell carcinoma thrombus. C: Intraoperative transesophageal echocardiography demonstrates right atrial extension of a renal cell tumor. Surgical management of renal cell carcinoma with inferior vena cava tumor thrombus. Laparoscopic radical nephrectomy for cancer involves smaller incisions, less blood loss, decreased postoperative analgesic requirement, shorter hospital stay and convalescent period, and similar long- term outcomes when compared with open radical nephrectomy. Traditional open nephrectomy is associated with a significant incidence of chronic pain ranging from 5% to 26%. The perceived differences between laparoscopic and open nephrectomy procedures have influenced clinical practice, including anesthesia planning for postoperative pain management. Compared to open nephrectomy, the reduced pain and shorter recovery times have meant that epidural anesthesia is less likely to be selected for laparoscopic approaches, with postoperative pain control for these procedures provided by a multimodal strategy involving opiates and appropriate nonopioid adjuncts. Recent small studies have reported good success with continuous local anesthetic infusions via catheters placed in the rectus and retroperitoneal sheaths intraoperatively (across the intercostal, ilioinguinal, and iliohypogastric nerves). Benefits include reduction of the following: pain levels, opioid requirements, nausea, time to recovery and discharge, and cost. Notably, robotic nephrectomy has specific positioning requirements owing to the robotic equipment, and care must be 3556 taken to assure that the robotic arms do not cause pressure injury to the patient. Depending on the experience of the surgical team, robotic procedures may also take more time. Notably, the role of robotic assistance is being similarly explored and developed for several other major urologic surgeries (e. Systemic vascular resistance and cardiac output usually return to near-normal values over the 10 minutes following institution of pneumoperitoneum. Preoperative fluid loading with additional preinduction colloid boluses before institution of pneumoperitoneum results in higher stroke volume and urine output compared to standard intraoperative fluid regimens, but studies are lacking regarding any evidence of improved outcome using this strategy. Following laparoscopic donor nephrectomy, some donors develop oliguria despite hemodynamic stability and liberal fluid management strategies. Cephalad2 displacement of the abdominal contents, particularly in obese patients, can also add atelectasis and ventilation–perfusion mismatch. Cardiac valvular dysfunction has been reported during laparoscopic nephrectomy,168 and cardiac ischemia can develop in at-risk patients with coronary artery disease. There is also an immediate increase in intracranial pressure with the institution of the pneumoperitoneum. Notably, adequate2 neuromuscular blockade plays a role in keeping insufflation pressures at the lowest level required to achieve optimal surgical exposure. Cystectomy and Other Major Bladder Surgeries Cystectomy involves removal of all or part of the urinary bladder. Although radical cystectomy is standard for most muscle-invasive malignant disease, simple cystectomy is primarily for benign bladder disease. Of the estimated 69,250 cases of bladder cancer in 2011 in the United States, approximately 90% were expected to undergo a surgical procedure for their disease. Radical cystectomy combines bladder removal with resection of other pelvic organs and lymph nodes. As a result of removal of the entire bladder, simple and radical cystectomy procedures require a companion surgery to allow for future urine collection. The so-called diversion procedures involve redirecting the ureters, most commonly to a pouch fashioned from ileum (ileal conduit) that passively drains urine into a bag through a stoma on the patient’s abdominal wall. Alternate options include the so-called continent diversion reconstructive procedures, which are becoming more popular. Because diversion surgeries can make future diagnosis of appendicitis difficult, some surgeons routinely also perform an appendectomy as part of urinary diversion procedures. Much like nephrectomy, both retroperitoneal and transperitoneal approaches are feasible for cystectomy, and laparoscopic and robotic-assisted techniques are becoming popular for both cystectomy and diversion procedures. Preoperative Considerations The most common patients presenting for cystectomy are those with bladder cancer. Approximately 90% have transitional cell tumors, and approximately 90% of these have already invaded muscle at diagnosis.
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