Marcelo Radisic, M.D.

• Attending Physician
• Transplant Infectious Diseases
• Instituto De Nefrolog?a
• Buenos Aires, Argentina

Patients with familial and malignant disease require a tailored approach that should include cardiology gastritis pronounce generic imodium 2mg overnight delivery, endocrinology gastritis vs gallbladder disease purchase imodium in india, and gastritis in pregnancy purchase imodium amex, if needed gastritis university of maryland buy 2mg imodium amex, medical oncology gastritis erosive symptoms imodium 2mg generic. Catecholamine release during intraoperative tumor manipulation can result in hazardous blood pressure elevation and cardiac arrhythmias diet when having gastritis cheap 2 mg imodium with mastercard. In the era before routine initiation of preoperative catecholamine blockade, some reported mortality rates as high as 50% (Pacak et al. In 2005, the First International Symposium on Pheochromocytoma recommended that all patients with pheochromocytoma and an abnormal metabolic evaluation undergo preoperative catecholamine blockade, including patients who do not exhibit evidence of blood pressure elevation and lack classic symptomatology (Pacak, 2007; Waingankar, et al 2015). Contemporary series demonstrate mortality rates of less than 3%, which has been attributed in part to optimized anesthetic care and routine preoperative blockade (Lenders et al. In the absence of appropriately conducted clinical studies comparing preoperative management strategies, no level 1 evidence exists regarding optimal preoperative or perioperative management (Pacak, 2007). Other permutations on approaches to preoperative catecholamine blockade exist but are less widely discussed in the literature (Pacak, 2007). Some authors have published reports that advocate the safety of forgoing catecholamine blockade in select patients (Shao et al. Thoughtful preoperative cardiac evaluation is paramount, because patients with pheochromocytoma are at risk for cardiomyopathy. We suggest that the patient undergo either a cardiology or anesthesia consultation before surgery. Phenoxybenzamine is the most common -blocker used for preoperative catecholamine blockade of pheochromocytoma. Accordingly, intraoperative catecholamine surges typically do not override its actions, because reversal of the blockade is possible only through synthesis of new receptor molecules (Pacak, 2007). Oral administration of 10 mg twice daily is initiated and titrated by increases of 10 to 20 mg to a blood pressure of 120 to 130/80 mm Hg in a seated position. Mild postural hypotension with systolic pressure greater than 80 mm Hg is acceptable (Kinney et al. Experience shows that a final dose of 1 mg/kg is usually sufficient to achieve adequate blockade (Pacak, 2007). Because of the irreversible nature of -blockade, patients may require transient blood pressure support after tumor resection (Pacak, 2007). Selective reversible 1-blockers, such as terazosin, doxazosin, or prazosin, are used at some centers in lieu of or in combination with phenoxybenzamine. Although these agents may have fewer side effects than phenoxybenzamine, data regarding their efficacy are contradictory (Lenders et al. Moreover, recent compelling data are emerging that preoperative -blockade may not be necessary in normotensive asymptomatic patients. In one report, a large cohort of asymptomatic normotensive patients with incidentaloma and a metabolic workup suggestive of pheochromocytoma was offered either -blockade with doxazosin (n = 38) or no preoperative blockade (n = 21) (Shao et al. No differences in blood pressure control or perioperative outcomes were seen between the two groups. The group that received doxazosin was more likely to require intraoperative administration of vasoactive agents (Shao et al. Although these data are provocative, they require validation from other centers, ideally in a prospective randomized fashion. It is important to understand that -blockade should never be started before appropriate -blockade. Indeed, in the absence of -blockade, antagonists cause potentiation of the action of epinephrine on 1 receptors resulting from blockade of the arteriolar dilation at the 2 receptor. For this reason, selective 1 adrenoreceptor blockers, such as atenolol and metoprolol, are usually preferred. Because blockade of catecholamine synthesis is incomplete, the use of metyrosine is usually coupled with -blockade by phenoxybenzamine. Some centers avoid routine use of this agent and reserve it for refractory or metastatic patients because of its central nervous system side effects, including sedation, mood depression, and galactorrhea. Extrapyramidal symptoms resembling parkinsonism can result and necessitate cessation of phenoxybenzamine use if present (Pacak et al. Calcium channel blockade in the context of catecholamine excess lowers blood pressure by generating smooth muscle relaxation (Ulchaker et al. Some have suggested the use of agents such as nicardipine as an adjunct to traditional -blockade therapy in refractory patients. Indeed, advocates of this strategy argue that this approach avoids the reflex tachycardia and postoperative hypotension that are seen with use of phenoxybenzamine (Ulchaker et al. Tumor volume reduction occurs in approximately 30% of patients, but complete responses are seen in less than 5% (Loh et al. Although toxicity was not trivial, 25% of patients (n = 3) exhibited a lasting complete response. Although response rates can be significant (over 50% radiographic tumor response and nearly 75% biochemical response), they are typically short-lived (2 years) (Huang et al. After surgical resection, patients with pheochromocytoma typically do exceedingly well. Hypertension usually resolves after resection, but not in all cases (Plouin et al. Despite an excellent prognosis, the disease can recur many years after resection in up to 16% of patients, necessitating vigilant lifelong follow-up (Amar et al. In some patients, metastatic disease progresses rapidly, whereas others exhibit nonaggressive disease and can live in excess of 20 years (Huang et al. Bone metastases appear to carry the most benign prognosis (Pacak, 2007; Scholz et al. For all-comers, 5-year survival statistics vary but are believed to be approximately 50% (John et al. Awareness of its potential presence and familiarity with its management are critical for every urologist. Pheochromocytoma must be considered in every adrenal mass and referral to a tertiary care facility made if the physician is unfamiliar with the care of these complex patients. Restoration of intravascular volume is perhaps the most important component of preoperative management of patients with pheochromocytoma. Intake of salt and fluid is encouraged once catecholamine blockade has been initiated (Lenders et al. Moreover, most centers admit patients the day before surgery and initiate aggressive intravenous fluid resuscitation. This approach minimizes potentially prolonged hypotension after tumor resection (Pacak, 2007). If phenoxybenzamine was used for preoperative -blockade, hypotension can occur, given the lasting effects of the agent (Pacak et al. Moreover, in a high catecholamine state, 2-adrenoreceptor stimulation inhibits insulin release. The withdrawal of this adrenergic stimulus after tumor resection may result in rebound hyperinsulinemia and subsequent hypoglycemia (Kinney et al. Hence, given the necessity for close monitoring, some experts advise overnight admission to the intensive care unit after pheochromocytoma resection (Lenders et al. Repeat metabolic testing should be performed after adrenalectomy to document normalization of chromaffin cell function (Pacak et al. Long-term vigilant postoperative follow-up of patients with pheochromocytoma is essential (Lenders et al. Lifelong screening for recurrence is recommended by some experts, because 10-year recurrence rates are as high as 16% in some series of fully resected lesions (Amar et al. Indeed, recurrent disease has been noted in patients more than 15 years after resection of the original tumor (Goldstein et al. Annual biochemical follow-up is mandatory for all patients with resected pheochromocytoma (Eisenhofer et al. No consensus on follow-up protocols exists; however, biochemical testing at 6 months after surgery, followed by annual testing, has been suggested (Pacak et al. Postoperative cross-sectional imaging is reasonable to document tumor resection and appropriate healing of the resection bed. Need for subsequent imaging should be guided by results of biochemical testing (Pacak et al. This strategy is used to avoid lifelong hormonal replacement, with its associated morbidity (Diner et al. Successful surgical outcomes require advanced surgical expertise and careful preoperative radiographic planning (Mitterberger et al. Nevertheless, the patient must be counseled that hormonal replacement may still be necessary despite a seemingly successful cortexsparing procedure. Life-threatening addisonian crisis can also occur despite close postoperative monitoring (Asari et al. Close long-term biochemical and radiographic follow-up is essential, whereas recurrence rates are poorly defined but appear to be significant (Asari et al. Surgical metastasectomy of resectable disease is the standard of care; however, little evidence exists to demonstrate that it prolongs patient survival or is more effective for symptomatic relief than medical treatment with /-blockade and -methyl-p-tyrosine (Eisenhofer et al. Local palliative tumor control using ablation techniques and embolization has also been described (Eisenhofer et al. Disorders of Decreased Adrenal Function Overview and Epidemiology Adrenal insufficiency, also known as Addison disease, is a condition whose management typically is beyond the scope of most urologic practices. Nonetheless, a working knowledge of the condition is essential for the urologic surgeon because the disease may result from either resection or pharmacologic inhibition of functioning adrenal tissues. Failure to consider and diagnose is potentially lethal and therefore warrants review. Indeed, if the condition is not anticipated and appropriate proactive therapies are not instituted, addisonian crises after simultaneous or staged bilateral adrenalectomy can result in death (Asari et al. Long-term follow-up is paramount, because recurrences are reported even 15 years after initial resection of a localized lesion. Adrenal insufficiency may be caused by primary adrenal failure or may occur secondary to extra-adrenal mechanisms. Pathophysiology In the Western world, the most frequent cause of primary adrenal insufficiency is autoimmune adrenalitis. Bilateral adrenal hemorrhage or infiltrative diseases, such as amyloidosis, sarcoidosis, and hemochromatosis may also affect the function of the glands (Oelkers, 1996). Bilateral metastatic disease involving the adrenal glands, although classically described as a potential cause of adrenal insufficiency, is a very rare cause of clinically significant Addison disease (Lutz et al. Nevertheless, a high index of suspicion for adrenal insufficiency must always remain in patients whose adrenal unit is removed. Secondary adrenal insufficiency is caused by abnormalities in the pituitary gland or, less frequently, the hypothalamus. Tumors, radiation, autoimmune conditions, pituitary apoplexy (also known as Sheehan syndrome when it occurs peripartally), and trauma are less common causes of the condition. Mineralocorticoid deficiency is therefore present only in patients with primary Addison disease (White, 1994). Although overt adrenal crises caused by this clinical scenario are exceedingly rare, the possibility exists in surgical patients on chronic steroids (Axelrod, 2003). Clinical Characteristics Clinical signs and symptoms of Addison disease are usually nonspecific and constitutional in most outpatients, who may complain of profound fatigue and anorexia for many months before definitive Adrenal insufficiency Primary Secondary Infectious adrenalitis. Acute adrenal insufficiency, or adrenal crisis, is a life-threatening condition often preceded by hypotension unresponsive to fluid resuscitation. Patients are easily and often misdiagnosed with an acute abdomen, whereas abdominal pain, nausea, vomiting, and fever frequently accompany hypovolemia in these individuals. Pediatric patients can exhibit hypoglycemic seizures (Arlt and Allolio, 2003; Bouillon, 2006). Adrenal insufficiency (an addisonian state) after adrenalectomy in the setting of a normally functioning contralateral adrenal gland is unlikely, but possible. This is especially true for patients who are undergoing adrenalectomy for a cortisol-secreting lesion, because functionality of the contralateral gland can be suppressed (Mitchell et al. Furthermore, patients with a history of contralateral partial or radical nephrectomy clearly represent a high-risk group. The integrity of the adrenal gland on the side of previous surgery may be compromised, or that gland may be altogether absent. Close examination of preoperative imaging and review of old operative and pathology reports for information regarding the status of the adrenal gland in the previous surgical field are paramount. Patients with primary Addison disease exhibit abnormal aldosterone and renin levels. To mimic physiologic circadian glucocorticoid cycling, the majority (one-half or two-thirds) of the daily dose is given in the morning, with the rest administered in one or two doses later in the day (Arlt and Allolio, 2003). Supplementation of adrenal androgens is advised by some experts but is often limited to those who experience constitutional complaints despite adequate glucocorticoid and mineralocorticoid supplementation (Arlt and Allolio, 2003). Careful monitoring of patients on hormone replacement for adrenal insufficiency is required and is often best left to experienced endocrine experts. The necessity of perioperative stress-dose steroid administration continues to be controversial. Again, because aldosterone physiology is not altered in these patients, mineralocorticoid replacement is unnecessary (White, 1994). There should be a low threshold to consult advanced endocrinologic expertise, given the complexity and the potentially grave consequences of the condition. Many patients complain of decreased energy, loss of libido, and psychological maleffects (Arlt and Allolio, 2003). Secondary adrenal insufficiency from hypopituitary disease is an established cause of premature death (Tomlinson et al.

Considerations in Obese Patients Although not a contraindication to laparoscopic or robotic surgery gastritis inflammation diet discount generic imodium canada, obesity frequently poses a challenge to the surgical team gastritis vs pud 2 mg imodium free shipping. Difficulties include the distorted or hidden anatomy resulting from the excess adipose tissue gastritis symptoms belching purchase imodium 2 mg fast delivery, limited range of trocar and instrument motion gastritis symptoms causes and treatment buy imodium 2mg cheap, need for longer instruments gastritis diet lunch order imodium 2mg visa, and higher pneumoperitoneum pressures gastritis in the antrum cheap imodium master card. These challenges may translate into higher complication rates and conversion to open surgery (Mendoza et al. Considerations in Elderly Patients the benefits of minimally invasive renal surgery have been demonstrated in all patient groups irrespective of age. Some of the minimally invasive renal surgery benefits are particularly advantageous in the elderly population, including reduced postoperative pain and Retroperitoneal Approach this approach resembles the open surgical technique in which the peritoneal cavity is not violated. Moreover, this may be preferred especially in instances of extensive intraperitoneal adhesions. In appropriately selected partial nephrectomy cases such as those with posterior tumors, the retroperitoneal approach may be faster and equally safe compared with the transperitoneal approach (Fan et al. The main limitations of the retroperitoneal approach include the following: limited working space leading to limited distance between trocars and decreased triangulation; less familiar anatomic landmarks; and surgical dissection being much closer to the lens, which may cause frequent smudging of the image. Anesthesia Monitor Surgeon Monitor Patient Positioning and Trocar Placement the patient is placed in a full flank position. Table flexion is used to increase the distance between the ribs and iliac crest to facilitate trocar placement. All pressure points should be carefully padded and the patient secured to the table to allow lateral tilting of the table. The patient is placed in a modified flank position with the operative side tilted up 30 to 45 degrees using a gel roll or a rolled blanket supporting the back. The lower arm is placed on a padded arm rest, and the other arm is flexed at the elbow and rested over the chest. Wide cloth or silk tape is used to secure the patient to the operating table to allow for table rotation during the surgery. The scrub technician (tech) is positioned to easily assist with instrument passage and exchange. A 12-mm trocar is placed lateral to the rectus at the level of the umbilicus, a second 10-mm trocar is placed at the umbilicus, and a 5-mm trocar is inserted in the midline between the umbilicus and the xiphoid process. Optional accessory subcostal, subxiphoid, and low midline trocar positions, which may be helpful for retraction, are also shown. An optional 10-mm lower midline trocar may also be placed for retraction, freeing the two other working hands for dissection. After the lumbodorsal fascia is divided and the retroperitoneum is entered, a working space is developed using blunt dissection with the laparoscope through a visual obturator or the finger. A simple balloon can be constructed using two fingers of a size 8 or 9 glove (Gaur, 1992). Care must be taken to place the balloon completely in the retroperitoneum to avoid dilating the muscle and causing postoperative flank hernia. The appearance of the characteristic yellow retroperitoneal fat confirms the correct trocar placement. Caution must be taken to avoid entering too anteriorly, which may cause inadvertent peritoneal violation or colon injury, or too posteriorly, which may result in bleeding from the quadratus lumborum or psoas muscles. Once the working space is fully established, the anatomic structures should be identified for orientation and additional trocar placement. In cases in which the retroperitoneal approach does not allow the safe completion of the procedure, an initial retroperitoneal access can be expanded to a transperitoneal approach by opening the peritoneum under direct vision. If the finger is in the correct position, the surgeon should feel the smooth surface of psoas muscle and the lower pole of the kidney covered by Gerota fascia. Because of its low profile, it will not obstruct the view or take up useful space in the retroperitoneum. The balloon and collar configuration eliminates the need for sutures and allows 360-degree rotation. In addition, the same incision, large enough for the hand, is also used to extract the surgical specimen. This approach is attractive for the novice laparoscopic surgeon particularly and in cases of significant scarring around the kidney, when difficult dissection is anticipated. Hand assistance may also be used in the event of an emergency, such as bleeding, by extending a trocar site and placing a hand port to assist in vascular control and repair. After the hand port is placed, the pneumoperitoneum is established, and additional trocars are placed under direct laparoscopic visualization. Care must be taken in the port placement to avoid the hand getting in the way of the laparoscope or other instruments. The surgeon should be aware of the increased pressure in the arm (from 30 to 100 mm Hg), which may cause tingling, numbness, and pain in the hand and forearm (Monga et al. Patient Positioning and Trocar Placement the patient is posited for a transperitoneal approach (see earlier). First, the hand port incision is made through the skin and fascia and into the peritoneal cavity. The incision should not be too large given this may cause leakage of gas and difficulty Robotic-Assisted Laparoscopy the robotic approach allows surgeons with limited laparoscopic skills to perform minimally invasive reconstructive renal surgery. It has the advantages of a three-dimensional view of the surgical field, greater degree of instrument motion, elimination of tremor, ergonomic position, and the ability to scale motions. The robotic kidney surgery can be done transperitoneally or retroperitoneally via multiple or single-site ports. On the right side, retraction of the liver is usually necessary to allow visualization and dissection of the renal hilum. A liver or bowel retractor can be placed through a subcostal trocar to assist with visualization or irrigation and aspiration. The camera is placed several centimeters lateral to the edge of the actual hand-assisted device (not the edge of the incision). The working port for the left hand is placed lateral to the rectus muscle, in line with or just inferior to the level of the umbilicus. Additional assistance with retraction of the liver can be accomplished through a subcostal trocar. The left hand works with the instrument passed through an umbilical trocar, and the camera is placed midway between the umbilicus and the xiphoid process. Additional assistance with retraction or aspiration can be accomplished through a fourth trocar placed at the subcostal margin. In most cases, the patient is positioned in the flank position with or without table flexion and secure to the table as previously described. In a three-arm configuration, the camera port is placed in the periumbilical area and two robotic trocars in the anterior axillary line, one above the iliac crest and a second one subcostal. A 12-mm assistant trocar is inserted in the low midline to allow passage of sutures, clamps, stapler devices, suction, or retraction. Attention must be paid to avoid robotic arm collision, especially in short patients. These approaches have evolved with the goal of further improving cosmesis and reducing postoperative pain. Operating room configured for left-sided robotic-assisted laparoscopic partial nephrectomy. Most approaches involve the placement of a multichannel access in the umbilicus or below the waistline to minimize visible scars. Laparoendoscopic single-site surgery performed using three low-profile trocars inserted through a single small extraction incision. The TriPort system (Advanced Surgical Concepts, Bray, Ireland) allows for passage of multiple instruments through a single incision. Conventional laparoscopic instrumentation can be used; however, flexible or articulated instruments provide extra degrees of motion. Moreover, a single-site surgical version of the daVinci device has been developed. Chronic refractory pyelonephritis, including xanthogranulomatous pyelonephritis, can be managed laparoscopically; however, these conditions are usually associated with dense perinephric adhesions, loss of tissue planes, and a higher risk for complication and conversion to open surgery (Gupta et al. In some cases, the use of hand assistance or subcapsular nephrectomy technique may be needed to safely complete the procedure. Anchored by inner (intra-abdominal) and outer rings drawn together with cylindric sleeve. Three-port (one 12-mm and two 5-mm) and four-port (two 12-mm and two 5-mm) configurations available. Various trocar sizes up to 27 mm, oval-shaped trocar accommodating multiple instruments. Single biconcave piece of foam with a valve for insufflation and three holes to accommodate trocars (three 5-mm low-profile trocars or two 5-mm trocars and one 10- to 12-mm trocar). Single-access device allowing for the use of flexible instruments passed through articulating instrument delivery tubes. Additional working channels allow for use of conventional laparoscopic instruments as well. Similar to GelPoint trocar using a wound retractor from the same company in addition to a sterile surgical glove. Surgical glove secured to the wound retractor using suture or sterile rubber bands. Trocars can be passed through each of the fingers of the surgical glove portion of the access device. Similar to other access devices in using a wound retractor base with an attachment cap. Integrates channels (two 5-mm instruments and a 10- to 12-mm instrument) with no trocar components protruding above the low-profile cap that can rotate. Placed through 2- to 4-cm fascial openings and able to traverse abdominal wall thickness up to 7 cm. The inferior limit is extended as needed to obtain adequate reflection of the colon. Dissection of the lateral attachments of the kidney should be avoided at this time given these will prevent the kidney from rolling over and obscuring the hilum. Identification of the plane between the mesenteric fat, which has brighter yellow hue, and the pale yellow retroperitoneal or Gerota fat is key for a proper dissection and to avoid making an incision in the mesocolon or Gerota fascia. If the mesocolon is accidentally opened, it should be repaired to prevent the development of an internal hernia (Regan et al. After the peritoneal incision as described earlier, medial traction on the colon reveals colorenal attachments that must be divided to complete the colon reflection. On the right side, the colon is reflected, and a Kocher maneuver may be performed to completely expose the kidney and the renal hilum. Incision of the white line of Toldt with endoshears, bipolar cautery, or ultrasonic energy allows reflection of the colon. Continuing superiorly allows incision of the lienocolic ligament, facilitating reflection of the spleen, pancreas, and colon. Medial traction on the colon helps identify additional colorenal attachments and assists in differentiating the undersurface of the large bowel mesentery. A curved dissector, in the left hand, is placed beneath the ureter and used to provide anterolateral elevation. On the right side the angle of insertion from the gonadal vein to the vena cava can be a source of significant bleeding if torn during elevation. Dissection of the Ureter Once the colon is medially reflected, the psoas muscle and tendon should be identified inferior to the lower pole of the kidney. Following the psoas medially, the gonadal vessels are usually encountered first, and the ureter is usually located just posterior to these vessels. Ureteral peristalsis can help differentiate the ureter from adjacent vascular structures. Once identified, the ureter is elevated, the gonadal vessels are swept medially, and the dissection is carried up proximally to the lower pole of the kidney. The tissue posterior to the ureter and lower pole of the kidney is swept anteriorly to further expose the anterior surface of the psoas muscle. Care should be taken to stay above the psoas fascia to minimize injury to cutaneous nerves, which would result in postoperative thigh numbness. The lower pole of the kidney and ureter are firmly retracted anterolaterally, placing the hilum on stretch. This can be accomplished by gently placing the lateral grasper under the ureter and kidney until it abuts the abdominal sidewall. With the ureter and lower pole of the kidney elevated, vessels entering the renal hilum can be identified and bluntly dissected. A gentle, layer-by-layer dissection is performed until the renal vein is identified. Gonadal, lumbar, and accessory venous branches can be clipped and divided as needed. Clips should not be placed in the anticipated staple line to prevent stapler misfire. If clips are used on the gonadal or adrenal vessels, the surgeon must be careful to exclude them from the jaws of the stapler. Securing the Renal Blood Vessels Once the hilum is exposed and kept under traction, the renal artery should be identified typically posterior to the vein. Preoperative imaging is usually helpful to identify the location and number of renal vessels. Meticulous dissection of the vein and artery can be accomplished with a combination of blunt and sharp dissection using irrigator-aspirator tip, hook electrode, scissors, or laparoscopic forceps. En bloc renal hilar vascular staple ligation appears to be a safe alternative to individual vessel ligation (Lai and Rais-Bahrami, 2017). Plastic clips alone are contraindicated for the ligation of the renal artery because of reports of fatal cases of clip failure (Hsi et al.

Improvements in nocturia-related quality of life were most strongly associated with treatment-associated declines in nocturia severity (van Dijk et al gastritis weight gain generic 2 mg imodium amex. Hours of uninterrupted sleep increased in both groups but were not statistically different (Simaioforidis et al gastritis diet plan uk buy imodium 2 mg free shipping. The optimal patients to treat with medications that target the bladder and the prostate appear to be those who have a large number of nocturia episodes (mostly resulting from severe urgency) gastritis clear liquid diet discount imodium 2mg with mastercard. There have also been various alternative treatments for nocturia gastroenteritis flu order line imodium, including cyclooxygenase-2 inhibitors combined with -blockers (Gorgel et al diet for gastritis and diverticulitis order imodium 2 mg with visa. Another phytotherapeutic gastritis ulcer disease imodium 2 mg line, Cernilton, is prepared from the rye-grass pollen Secale cereale. Cernilton reduced nocturia compared with placebo and another neutraceutical, Paraprost. The limitations of these trials were short duration, limited number of enrollees, gaps in reported outcomes, quality control of preparations, and lack of a proved active control (Wilt et al. For a complete list of medications used to treat diminished global or nocturnal bladder capacity, see Table 119. Mean reduction of nocturia episodes from treatment with terazosin alone was significantly different from that with treatment with combination therapy (P =. All subjects had eight or more micturitions per 24 hours with or without urge incontinence and nocturia (mean of 2. The suggestion here was that antimuscarinic therapy would benefit nocturic voids that are characterized by severe urgency. In a randomized, controlled trial of 658 patients at 52 sites, patients were given either placebo or trospium chloride 20 mg twice daily. After 12 weeks, a significant decrease was found in the mean number of nocturic episodes per night: 0. Fesoterodine significantly improved all diary end points compared with placebo except for nocturnal voids and nocturnal urgency episodes (Dmochowski et al. However, in a study powered to determine the effect of fesoterodine on nocturnal urgency as a primary end point, fesoterodine did decrease the number of nocturnal urgency episodes and the number of nocturnal voids when compared with placebo. This particular study looked at change from baseline to week 12 in the number of nocturnal urgency episodes per 24 hours. The mean reduction from baseline to week 12 in nocturnal urgency episodes per 24 hours was statistically significantly greater with fesoterodine than placebo (-1. Mean reduction from baseline to week 12 in nocturnal micturitions per 24 hours was significantly greater with fesoterodine than placebo (-1. A prospective randomized trial was conducted with 2583 men with one or more episodes of nocturia at baseline who were treated with doxazosin, finasteride, combination therapy (doxazosin + finasteride), or placebo. Treatment effectiveness was measured by a self-reported number of nocturia episodes at 1 and 4 years after treatment. After 4 years, the number of nocturia episodes was also significantly reduced in patients treated with doxazosin and combination therapy versus placebo (P <. In a subgroup of men older than 70 years of age (n = 495), all of the drugs significantly reduced nocturia at 1 year (finasteride 0. Nocturnal polyuria was a significant component of nocturia in 43% of the patients. Thus the cause of nocturia was found to be multifactorial and often unrelated to an underlying urologic condition (Weiss et al. Additional interventions included early evening leg elevation and compression stockings if patients had bilateral lower extremity edema. This proved to be a structured, multimodal approach with little risk (one trip to an emergency room for hypotension after taking terazosin) (Vaughan et al. Multicomponent treatment was further found to be an effective strategy to treat nocturia in a study by Johnson et al. Dipsogenic polydipsia is associated with a history of a central neurologic abnormality such as a history of brain trauma or radiation. For example, if a patient with polyuria has diabetes mellitus, controlling glycosuria may improve the polyuria. Patients without diabetes insipidus who are found to have polydipsia and are compulsive water drinkers may benefit from psychotherapy (Weiss, 2012). Nocturia as a manifesting complaint is expected to benefit from appropriate therapy for polyuria. Polyuria Etiology Polyuria is defined as 24-hour urine output greater than 40 mL/ kg. Once a steady state is reached, polyuria is associated with excessive oral intake of fluids (polydipsia). This results in urinary frequency both day and night because of the global overproduction of urine in excess of bladder capacity. Hence, it behooves the urologist to understand both its cause and diagnostic measures to sort out its various causes. Common underpinnings of polyuria include uncontrolled diabetes mellitus, diabetes insipidus, and primary polydipsia (dipsogenic, caused by an abnormality of the thirst mechanism, and psychogenic). Diabetes insipidus is a disorder of water balance in which inappropriate excretion of water leads to polydipsia in an effort to prevent circulatory collapse. This can be caused by loss of neurosecretory neurons in the hypothalamus or the posterior pituitary gland as a result of trauma, primary pituitary tumors. It is normal if the first-morning urine osmolality is greater than 800 mOsm/kg H2O. Management Patients who have a 24-hour urine production greater than 30 mL/ kg may benefit from water restriction during the day and night. This illustrates that guidance on water intake may be a safe and effective conservative lifestyle management strategy. Because primary thirst disorders are distinctly rare, a safety mechanism in recommending fluid intake restriction is to have patients drink only just enough to satisfy their thirst. Everaert K, Herve F, Bower W, et al: How can we develop a more clinically useful and robust algorithm for diagnosing and treating nocturia Hashim H, Coyne K, Chapple C, et al: Nocturia: risk factors and associated comorbid conditions-findings from an international cross-sectional study. Kaynak H, Kaynak D, Oztura I: Does frequency of nocturnal urination reflect the severity of sleep-disordered breathing The structures involved include the smooth musculature of the bladder and the bladder outlet, and striated muscle, both intrinsic (to the bladder outlet) and extrinsic (the striated musculature surrounding the bladder outlet and the striated musculature of the pelvic floor). These component structures are controlled by a complex interplay among the central and peripheral nervous systems and local regulatory factors. This article considers the pharmacologic management of bladder filling and storage and bladder emptying and voiding dysfunction. The conceptual basis of the organization is that of the expanded functional classification shown in Boxes 70. Although the principles expressed are generally applicable to patients of all ages, specifics concerning usage in the pediatric age groups and in the elderly are considered in detail in Chapters 141 and 142. As an apology in explanation to significant contributors to the field whose works have not been specifically referenced by name as frequently as they could have been, please note that the citations have been chosen primarily because of their comprehensive review or specific informational content and not because of originality or initial publication on a particular subject, except where noted. Regarding the subject of bladder tone during filling, Andersson (1999a, 1999b, 2004, 2011b) and Andersson and Yoshida (2003) have pointed out that although it is widely accepted that there is normally no sacral parasympathetic outflow to the bladder during filling, antimuscarinic drugs increase, and anticholinesterase inhibitors decrease, bladder capacity. Outlet resistance, at least as reflected by urethral pressure measurements, does not seem to be clinically affected. In many animal models, atropine only partially antagonizes the response of the whole bladder to pelvic nerve stimulation and of bladder strips to field stimulation, although it does completely inhibit the response of bladder smooth muscle to exogenous cholinergic stimulation. The facilitation in these preparations is primarily mediated by M3 muscarinic receptors (Somogyi and de Groat, 1999). The relative roles of the different presynaptic and postsynaptic receptor subtypes in normal and abnormal bladder function still require clarification, and thus speculation regarding optimal drug therapy based only on in vitro receptor selectivity profiles represents, at the very least, a gross oversimplification of assumptions regarding the muscarinic regulation of bladder function. However, it is not always clear what the changes mean in terms of changes in detrusor function. Receptor selectivity, however, is not the only basis on which a drug may be uroselective. This seems to be the case also in the animal species investigated (Andersson and Arner, 2004; Chess-Williams, 2002; Hegde and Eglen, 1999). Both M2 and M3 receptors can be found on detrusor muscle cells, where M2 receptors predominate at least 3: 1 over M3 receptors, but also in other bladder structures, which may be of importance for detrusor activation. Thus, muscarinic receptors can be found on urothelial cells, on suburothelial nerves, and on other suburothelial structures, such as interstitial cells (Andersson, 2011a; Bschleipfer et al. In human and animal detrusor, the M3 receptors are believed to be the most important for contraction (Abrams et al. No differences between genders could be demonstrated in rat and human bladders (Kories et al. However, based on animal experiments, M2 receptors have been suggested to directly contribute to contraction of the bladder in certain disease states (denervation, outflow obstruction). They concluded that normal detrusor contraction is mediated by the M3 receptor subtype, whereas contractions can be mediated by the M2 receptors in patients with neurogenic bladder dysfunction. Muscarinic receptors are coupled to G proteins, but the signal transduction systems may vary. In general, M1, M3, and M5 receptors are considered to couple preferentially to Gq/11, activating phosphoinositide hydrolysis, in turn leading to mobilization of intracellular calcium. They concluded that carbachol-induced contraction of human urinary bladder is mediated via M3 receptors and largely depends on Ca2+ entry through nifedipine-sensitive channels and activation of the Rho-kinase pathway. Thus, it may be that the main pathways for muscarinic-receptor activation of the detrusor via M3 receptors are calcium influx via L-type calcium channels, and increased sensitivity to calcium of the contractile machinery via inhibition of myosin light chain phosphatase through activation of Rho-kinase. The signaling mechanisms for the M2 receptors are less clear than those for M3 receptors. Muscarinic receptors may also be located on the presynaptic nerve terminals and participate in the regulation of transmitter release. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Chapter 120 Pharmacologic Management of Lower Urinary Tract Storage and Emptying Failure 2681 and the dose that produces side effects. A differential effect could be based not only on receptor selectivity but also on other known and as yet undefined physiologic, pharmacologic, or metabolic characteristics. The 6th International Consultation on Incontinence assessed drugs used for treatment of incontinence (Andersson et al. Still, the ways by which they exert their beneficial effect have not yet been established. There is also good experimental evidence that antimuscarinics act during the storage phase by decreasing the activity in afferent nerves (both C and A fibers) from the bladder (De Laet et al. Muscarinic receptors are found on bladder urothelial cells, where their density can be even higher than in detrusor muscle. The role of the urothelium in bladder activation has attracted much interest (Andersson, 2002a, 2011b; Birder and Andersson, 2013; Birder and de Groat, 2007; Birder et al. In general, antimuscarinics can be divided into tertiary and quaternary amines (Abrams and Andersson, 2007; Guay, 2003).

Urodynamic stress incontinence: the involuntary leakage of urine during increased abdominal pressure in the absence of a detrusor contraction gastritis diet of the stars order imodium 2 mg without prescription. Phasic detrusor overactivity: a characteristic waveform that may or may not lead to urinary incontinence gastritis cronica generic imodium 2 mg on-line. Terminal detrusor overactivity: A single involuntary detrusor contraction occurring at cystometric capacity that cannot be suppressed gastritis diet ������ order imodium paypal, resulting in incontinence with bladder emptying gastritis problems discount imodium 2mg without prescription. Detrusor overactivity incontinence: Incontinence related to involuntary detrusor contractions gastritis symptoms last buy generic imodium 2mg online. Neurogenic detrusor overactivity: Overactivity accompanied by a neurologic condition gastritis diet 02 purchase imodium amex. Idiopathic detrusor overactivity: Detrusor overactivity without concurrent neurologic etiology. Provocative maneuvers: Techniques used during urodynamic border to provoke detrusor overactivity. Cough-associated detrusor overactivity*: When the onset of the detrusor overactivity (with or without leakage) occurs immediately after the cough pressure peak. Normal voiding function*: Flow rate (and pressure-rise) are within normal limits; begin more or less directly after permission to void, and end with an empty bladder. Situational inability to void and situational inability to void as usual*: When, in the opinion of the person performing the test, in communication with the patient, the attempted voiding has not been representative. Detrusor contractility*: Any method that aims to quantify "intrinsic" detrusor muscle properties. Dropped pabd at void*: A drop in pabd during voiding is reported during the voiding time, pabd decreases below the previous resting pressure (as a consequence of pelvic and abdominal muscle relaxation). Straining*: Straining is observable as a temporary increase in both pves and pabd pressure. Straining may be associated with (patient-active) position change (such as repositioning from leaning backward to upright). After-contraction*: A continued or new detrusor pressure rise immediately after flow ended. Urethral pressure profile: A graph indicating the intraluminal pressure along the length of the urethra. Urethral closure pressure profile: the subtraction of intravesical pressure from urethral pressure. Functional profile length: the length of the urethra along which the urethral pressure exceeds intravesical pressure in women. Pressure transmission ratio: the increment in urethral pressure on stress as a percentage of the simultaneously recorded increment in intravesical pressure. Abdominal leak point pressure: the intravesical pressure at which urine leakage occurs because of increased abdominal pressure in the absence of a detrusor contraction. Pressure-flow studies: the method by which the relationship between pressure in the bladder and urine flow rate is measured during bladder emptying. Premicturition pressure: the pressure recorded immediately before the initial isovolumetric contraction. Opening time: the elapsed time from original rise in detrusor pressure to onset of flow. Pressure at maximum flow: the lowest pressure recorded at maximum measured flow rate. Flow delay: the time delay between a change in bladder pressure and the corresponding change in measured flow rate. Pressure drift*: Continuous slow fall or rise in pressure that is physiologically inexplicable. Poor pressure transmission*: When the cough/effort pressure peak signals on pves and pabd are not nearly equal. Expelled catheter*: When a catheter is expelled, this is observed as a sudden drop in either pves or pabd, usually below zero. Catheter flush*: When one of the catheters is flushed during the test, a steep pressure rise is observed in that pressure line for one or two seconds followed by an immediate fall to resting pressure. Tube knock*: Observable as high-frequency, short-duration spikes visible in pves, pabd, or both and with spikes also usually visible in pdet. Pump vibrations*: Pump vibrations are visible as stable frequency oscillations of small but constant amplitude if the filling tube touches the pressure connecting tube (when a two-catheter system is used) and the pump is switched on (switching of the pump can ascertain the situation). The standardization of terminology of lower urinary tract function: report from the Standardization Subcommittee of the International Continence Society. Good urodynamic practices: uroflowmetry, filling, cystometry, and pressure-flow studies. International Continence Society Good Urodynamic Practices and Terms 2016: Urodynamics, uroflowmetry, cystometry, and pressure-flow study. These tests within the study can be used individually or in combination, depending on the information desired. It can be performed by ultrasonography (bladder scan) or catheterization (method should be specified). There are multiple data points that can be reported from noninvasive uroflowmetry. In addition to these objective measurements, it is also important to observe the pattern or shape of the uroflow curve. Uroflow curve interpretation is somewhat subjective because of difficulty in qualitatively judging a pattern (Boone and Kim, 1998). When done as a standalone test, it may be easiest to optimize patient comfort and reduce anxiety by allowing the patient to perform the voiding in his or her preferred position. The patient should also be queried if the urine flow was representative of what occurs during a voiding during nontesting conditions (daily living). Also, the urodynamic voided volume can be compared with frequency volume charts or bladder diary when available. The filling phase starts when filling commences and ends when the patient and urodynamicist decide that "permission to void" has been given (maximum cystometric capacity). Cystometry can be performed by the single measurement of bladder pressure via a bladder catheter (urethral or suprapubic); however, changes in bladder pressure can represent a change in detrusor pressure (pdet) or a change in abdominal pressure (pabd) (see later). Therefore, it is recommended that cystometry be performed by measuring both the total vesical pressure (pves) and pabd (measured by a catheter placed in the rectum or vagina). Adding intra-abdominal pressure monitoring gives a better representation of the true detrusor pressure. Without having simultaneous monitoring of intraabdominal pressure, it is impossible if these pressure spikes are caused by a rise in detrusor or abdominal pressure. Now it can be clearly seen that changes in pves were caused by the changes in pabd. Urethral pressure is defined as the fluid pressure needed to just open a closed urethra. Detrusor pressure is measured as noted earlier with the simultaneous measurement of flow rate by a uroflowmeter. The voiding phase starts when "permission to void" is given, or when uncontrollable voiding begins, and ends when the patient considers voiding has finished. Another study concluded that they cannot be used interchangeably as air-charged catheters showed systematically higher readings (Zehnder et al. Air-charged catheters acted as an overdamped system and attenuated signals at frequencies higher than 3. They demonstrated significantly less motion and hydrostatic artifacts than water-filled catheters. The authors point out that most urodynamic signals occur below 3 Hz, and, as such, air-charged systems could be beneficial because most of the higher-frequency noise is dampened. However, urodynamic signals can have frequency components greater than 3 Hz, particularly when utilizing rapidly changing signals, such as coughs. The authors concluded that "knowledge of the characteristics of the pressure-measuring system is essential to finding the best match for a specific application. The studies reported that the systems are not interchangeable because values obtained from each were significantly different. Pattern analysis was not affected, however, when absolute (subtracted) pressures become relevant (as in pressureflow analysis or urethral pressure profiles), the possibility of clinically relevant differences exists. Some experts suggest that further validation of measurement techniques with air-filled systems be done before clinical similarity can be established (Abrams et al. The conclusions of the 6th International Consultation on Incontinence are that air-charged catheters may provide an acceptable alternative for measuring the closure pressure of the female urethra, however, reference values have not been established (Rosier et al. Thus, it is recommended that investigators planning to use air-charged catheters for intravesical and intraabdominal pressure monitoring check for themselves that they have an equivalent performance to their current system for measuring pressure (Rosier et al. Finally, a microtip or fiberoptic system can be used to process pressure transmission. These catheters are quite expensive; they are reusable and thus must be sterilized before each use. However, when choosing a system, one must consider the patient population and spectrum of diseases frequently encountered; available space; convenience of operation (if a factor); and the need for data storage and processing and possible electronic medical record integration. In addition, it is recommended that a multichannel system be used where channels are available to measure vesical pressure, abdominal pressure (and subtracted detrusor pressure), and flow rate. Some clinicians may also desire channels for electromyography and urethral pressure measurement. However, despite all the advances, the clinician performing the study remains the most important constant in data collection and interpretation. Adding this capability is costly but allows one to perform the most comprehensive study possible. In addition to the necessary urodynamic hardware and software, a fluoroscopy unit and room of adequate size are required. External strain gauge transducers located "between" the patient and the urodynamic machine have been popular for years. Pressurized tubing (to avoid dampening or dissipation of the pressure) extends from the pressure transducer to the catheters placed in the patient. An electronic cable or "wireless transmission" brings the signal from the transducer to the urodynamic machine. Traditionally, a water-filled system was used in which the entire system from transducer to patient is filled with water. Because this system depends on the transmission of pressure through fluid (water), it is crucial that there are no air bubbles in the transducer or tubing. The pressurized tubing transmission lines should be lucent to allow for easy recognition of air in the line. Air-charged catheters use a miniature, air-filled balloon placed circumferentially around a polyethylene catheter. External forces on the balloon of the catheter are transmitted to the air-filled catheter lumen and communicated to an external semiconductor transducer. Air-charged catheters have several practical advantages over fluid-filled pressure lines because there is no fluid connection between the patient and the urodynamic equipment-just air. This means there is no hydrostatic pressure effect to account for, so there is no need to position anything at the level of the symphysis pubis, and there is no need to flush the system through to exclude air (essential when using a fluid-filled system). Also, there are no artefactual fluctuations in pressure produced when the patient moves. There is comparative evidence for the use of air-charged catheters to measure urethral pressure and Valsalva leak point pressure. One study showed Uroflowmeters Urine flow rate or uroflow can be determined by a number of different types of devices or uroflowmeters. Modern uroflowmeters use weight, electrical capacitance, or a rotating disc to determine urinary flow rates. The two most common techniques used today are the weight transducer or load cell method and the rotating disk method. With the load cell, the voided "weight" is measured and is then differentiated with respect to time to determine the flow rate. In the rotating disc method, the urine stream is directed onto a rotating disc, and the power necessary to keep a disc rotating at a constant rate is measured. The electronic dipstick flowmeter measures the electrical capacitance of a dipstick mounted in a collecting chamber. The output of the signal is proportional to the accumulated volume, and the volumetric flow rate is determined by differentiation. The weight transducer method is simple, reliable, and accurate regardless of the site of stream impact, but it requires that the density of urine be set. The rotating disc method is also reliable and accurate, and it provides a direct measurement without the need for differentiation of volume with respect to time. Electronic flowmeters provide a range of electronically read flow parameters Chapter 114 Urodynamic and Video-Urodynamic Evaluation of the Lower Urinary Tract 2559 with graphical depiction of the uroflow and have sufficient precision for clinical use with error rates of 1% to 8% in voided volume and 4% to 15% in flow rate (Susset, 1983). Most systems allow for calibrations for various fluids such as radiographic contrast. Electromyography Muscle depolarization must be detected by an electrode placed in or near the muscle. Surface electrodes are self-adhesive skin patch electrodes that are applied over the skin of the anal sphincter (Barrett, 1980). Surface electrodes have a significant advantage compared with the needle electrode regarding patient convenience and comfort. However, the surface electrodes provide an inferior signal source and must be precisely placed to provide an adequate signal source. Compared with the surface electrode, placement of the needle electrode has the disadvantage of being uncomfortable for the patient, especially if more than one attempt at placement of the electrode is required to obtain an adequate signal.

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The neural crest cells continue to invade the adrenal cortex until they achieve a central position surrounding the adrenal vein by the 18th week of gestation gastritis remedies diet order imodium uk. At birth gastritis of the antrum order imodium 2mg visa, the fetal adrenal gland is twice the weight of an adult adrenal gland but has not completed development gastritis symptoms in telugu 2mg imodium for sale. After birth gastritis diet ����������� effective 2mg imodium, only a small rim of fetal cortex begins to atrophy and will be completely resorbed by 12 months of age (Mitty gastritis recovery diet buy generic imodium pills, 1988; Walczak and Hammer gastritis zinc order generic imodium on-line, 2354 Chapter 106 Pathophysiology, Evaluation, and Medical Management of Adrenal Disorders 2355 Superior adrenal arteries Middle adrenal arteries R. Adrenal vascular supply demonstrating inflow from the superior, middle, and inferior adrenal arteries bilaterally. Whereas the right adrenal vein drains directly into the posterior inferior vena cava, the left adrenal vein often communicates with the inferior phrenic vein before draining into the left renal vein. The three layers of the adrenal medulla (glomerulosa, fasciculata, and reticularis) produce mineralocorticoids (aldosterone), glucocorticoids (cortisol), and sex steroids (adrenal androgens and estrogens), respectively. As the fetal cortex is being resorbed, the zona glomerulosa and fasciculata of the adult cortex continue to develop, but the zona reticularis will not complete differentiation until 3 years of age, reflecting the relative late importance of sex steroid production by this part of the adrenal cortex (Barwick et al. In addition to the well-established roles of cells located within the three zones of the adrenal cortex, there is mounting data on the potential importance and role of adrenocortical stem cells in the normal development and hemostasis of the adrenal gland (Walczak and Hammer, 2014). Cases of unilateral adrenal agenesis are rare and are often associated with unilateral renal agenesis (Else and Hammer, 2005; Nakada et al. However, because adrenal and renal development are separate processes, this association is likely spurious and is the result of limited radiographic evaluation of the ipsilateral adrenal gland in cases of renal agenesis. Most often, adrenal gland development occurs normally in the absence of ipsilateral renal unit development, malrotation, or malascent. In these cases, the adrenal glands are often discoid in shape and located in their normal position within the retroperitoneum (Mitty, 1988). The zona reticularis, the innermost layer of the cortex, consists of round dark-staining cells and predominantly produces sex steroids, such as adrenal estrogens and androgens (MacLennan et al. More common anomalies of adrenal gland development include accessory adrenal tissue and adrenal heterotopia. Accessory adrenal tissue, also known as adrenal rests, can be composed of cortical or medullary tissues. Because of the close proximity of the adrenal gland and genitourinary organ development, adrenal rests can be found anywhere along the path of gonadal descent within the retroperitoneum. Although adrenal rests can be found in up to 50% of neonates, the tissue typically atrophies and is found in only approximately 1% of adults (Barwick et al. Adrenal heterotopia results from incomplete separation of primitive adrenal mesoderm from adjacent organs such as the liver or kidney, resulting in partial or complete incorporation of the gland into the adjacent organ. Anatomy the right and left adrenal glands are located within the Gerota fascia at the levels of the 11th and 12th ribs and share several important anatomic relationships, including being located cephalad to the upper pole of the kidneys and anterior to the crus of the diaphragm. The close juxtaposition of these organs to the adrenal gland explains why lesions of adjacent organs, such as leiomyomas or diverticuli of the greater curvature of the stomach, may be confused for an adrenal lesion. As with most endocrine organs, the blood supply to the adrenal gland is redundant. From the subcapsular plexus, some branches continue directly to the medulla, and others form sinusoids supplying the adrenal cortex. On the venous side, medullary veins coalesce to form the adrenal vein, which is surrounded by medullary tissue within the adrenal gland. On the left side, the adrenal vein is long compared with the right and is joined by the inferior phrenic vein before draining into the left renal vein. The overlapping of both arterial and venous anatomy makes partial adrenalectomy possible with little risk for subsequent adrenal infarction. Anomalous venous drainage is noted in up to 9% of patients and is an important consideration when performing adrenal vein sampling (Ford et al. The principal lymphatic drainage of the adrenal glands is through the paracaval lymph nodes on the right and the para-aortic lymph nodes on the left. The autonomic innervation of the adrenal glands includes predominantly preganglionic sympathetic fibers off the sympathetic trunk directly to the chromaffin cells of the adrenal medulla, whereas postganglionic fibers originating from the splanchnic ganglia provide innervation to the adrenal cortex. Parasympathetic innervation to the adrenal cortex and medulla is not well defined; however, animal models suggest that parasympathetic branches originating from the vagus nerve may be present. Adrenal Cortex Physiology As part of a multistep synthetic pathway, numerous enzymes of the adrenal cortex catalyze conversion of essential steroid hormones from the common precursor cholesterol. Instead, steroids diffuse passively into the cell and bind to their respective receptors intracellularly. As a result, the glomerulosa cells of this tissue are the sole source of aldosterone-the primary human mineralocorticoid (Rainey, 1999). Aldosterone regulates electrolyte metabolism by stimulating epithelial cells of the distal nephron to reabsorb Na+ and Cl-, while secreting H+ and K+. Although aldosterone levels have a profound effect on total body Na+, concentration of the ion does not change, whereas reabsorption of sodium is accompanied by reuptake of free water. Therefore aldosterone primarily affects total body volume and not sodium concentration (Table 106. Electrolyte balance in epithelial cells of the submaxillary salivary glands and the large intestine are also under mineralocorticoid control; however, the physiologic importance of this phenomenon is likely minimal (Bastl and Hayslett, 1992). For this reason, the zona glomerulosa is the only region of the adrenal cortex that does not atrophy on pituitary failure (Hubbard et al. Directly beneath the capsule is the cortex, which consists of three zones: the zona glomerulosa, the zona fasciculata, and the zona reticularis. The zona glomerulosa consists of small polyhedral cells with scant eosinophilic cytoplasm and dark round nuclei. The essential function of the glomerulosa is the production of mineralocorticoids, predominantly aldosterone. Steroid hormone synthesis beginning with cholesterol and resulting in mineralocorticoid, glucocorticoid, and androgen production in the adrenal cortex. The physiology of this axis is discussed in more detail in the Cushing Syndrome section later in this chapter (Jacobson, 2005). Production of cortisol by the adrenal glands follows a strict circadian schedule, with the majority of the hormone being secreted in the early morning (Jacobson, 2005). Renal potassium secretion Zona Reticularis the zona reticularis is the innermost zone of the adrenal cortex. Moreover, aberrations in production of these hormones during development are responsible for significant pathology and result in the clinical entity known as congenital adrenal hyperplasia (Finkelstein and Shaefer, 1979; Hubbard et al. The pathophysiology of this pathway is discussed in the Testing for Aldosterone Hypersecretion section later in this chapter. Exogenous steroids are useful in promoting transplant tolerance and in treating autoimmune disorders. Instead, this portion of the adrenal gland, which lies at the center of the gland, is an integral part of the autonomic nervous system. Chromaffin cells of the medulla are innervated by preganglionic sympathetic fibers of T11 to L2, making them analogous to cells of the sympathetic ganglia. The effects of these catecholamines are mediated through their binding to adrenoreceptors located on target organs. The nature of these effects depends on the adrenoreceptor types or subtypes located and stimulated on a particular end organ (Table 106. The function of this enzyme is potentiated by the presence of glucocorticoids, thereby creating one of the few physiologic links between the adrenal cortex and the medulla. Similar to the physiology that controls norepinephrine release at synaptic nerve terminals, the storage and release of adrenal catecholamines involves intracellular vesicles. The figure simplifies the metabolic pathway of norepinephrine and epinephrine degradation to highlight those metabolic products that play a role in routine clinical practice. Key enzymes involved in catalysis of metabolic conversions are indicated in italic font. The metabolism of catecholamines is complex, and some controversy exists about the physiologic relevance of each pathway (Eisenhofer et al. The majority of adrenal catecholamine metabolism occurs at the scene of production in cells of the adrenal medulla themselves (Eisenhofer et al. Indeed, over 90% of metanephrine (epinephrine metabolite) and some 20% or more of normetanephrine (a norepinephrine metabolite) in the bloodstream are derived from the adrenal medulla. Therefore, a measurable rise in the level of these metabolites is very useful when diagnosing potential pheochromocytomas (see Assessment of Function of Adrenal Masses section later in this chapter) (Eisenhofer et al. Hypercortisolism secondary to excessive production of glucocorticoids by the adrenal cortex is defined as Cushing syndrome (Orth and Liddle, 1971). The disease is rare and occurs in 2 to 5 of every 1 million people per year (Lindholm et al. Diagnosis and treatment of Cushing syndrome is multifaceted, often requiring cooperation of internists, endocrinologists, neurosurgeons, and adrenal surgical experts (Newell-Price et al. The urologist must understand the comprehensive pathophysiology of hypercortisolism and have particularly advanced expertise in the aspects of this complex disease for which adrenalectomy is required. The zona fasciculata of the adrenal cortex secretes up to 20 mg of cortisol every day (Arlt and Stewart, 2005). A fluent understanding of this classic neuroendocrine negative feedback system is critical for the successful management of the patient with Cushing syndrome. Even small perturbations of this physiologic rhythm are considered pathologic (Jacobson, 2005; Sam and Frohman, 2008). Exogenous Cushing syndrome is a result of iatrogenic glucocorticoid administration. Exogenous Cushing syndrome is the most common cause of hypercortisolism in patients of the Western world (Newell-Price et al. Synthetic glucocorticoids are frequently used in treatment of many conditions, and Cushing syndrome can result from the administration of even low doses of exogenous steroids orally, topically, or by inhaled preparations (Hopkins and Leinung, 2005; Newell-Price et al. A careful patient history is therefore essential in the evaluation of all patients with Cushing syndrome. The clinician also must be cognizant of the possibility that the patient either is unaware of his or her steroid use. Large macroadenomas 1 cm or greater are found in only about 5% of cases (Newell-Price et al. Up to two-thirds of individuals with Cushing disease are female (Scott and Orth, 1990). These corticotropin-producing tissues are nearly always malignant and account for approximately 10% of Cushing syndrome (Porterfield et al. The timing and onset of hypercortisolism varies and can precede the diagnosis of an extra-adrenal malignancy by many years, resulting in diagnostic difficulties and the clinical conundrum wherein a subclinical pituitary adenoma is suspected but not radiographically identified (Aniszewski et al. Moreover, hypercortisolism in end-stage debilitated cancer patients is almost certainly underdiagnosed (Orth, 1995). Bilateral adrenal enlargement in a patient with advanced metastatic adenocarcinoma of the pancreas. Adrenal neoplasms and rare forms of bilateral adrenal disease are responsible for this group of conditions (Lacroix and Bourdeau, 2005; Newell-Price et al. Cortisol-secreting benign adenomas of the adrenal gland are responsible for approximately 10% of Cushing syndrome and often result from a dominant unilateral hyperplastic nodule, although multifocal bilateral functional adrenal hyperplasia may also occur. Less than 10% of adrenal masses are bilateral and often present a diagnostic challenge (Lacroix and Bourdeau, 2005; Pasternak et al. Radiographically undetectable benign adrenal cortisol-producing lesions may also be responsible for cases of subclinical Cushing syndrome (Rossi et al. The Cushingoid phenotype resolves for most patients within 7 to 9 months after adrenalectomy; however, it can persist for several years in some individuals (Sippel et al. The condition is characterized by multiple large (up to 4-cm) nodules replacing the glands, with each adrenal gland weighing over 60 g (Iacobone et al. Bilateral macronodular hyperplasia is observed as a feature of the McCune-Albright syndrome, which also includes polyostotic fibrous dysplasia, dermatologic manifestations, and other endocrine abnormalities (Lacroix and Bourdeau, 2005). The cortical tissue surrounding the nodules is atrophic, and the adrenal medulla is free from disease (Lacroix and Bourdeau, 2005). Clinical characteristics of Cushing syndrome vary considerably among affected patients. Many of the classic symptoms of hypercortisolism, such as central obesity, moon facies, buffalo hump, proximal muscle weakness, easy bruisability, and abdominal striae, are nonspecific. It is the combination of these and other clinical signs that should raise suspicion and prompt potential screening for Cushing syndrome (Findling and Raff, 2005). Cushing syndrome also results in systemic symptomatology that is identical to the highly-prevalent metabolic syndrome, such as central obesity, dyslipidemia, insulin resistance, and hypertension (Pivonello et al. Screening for Cushing syndrome is usually beyond the scope of urologic practice; however, it is important for urologists to appreciate the relatively common occurrence of hypogonadal hypogonadism in men with Cushing syndrome. A low threshold for initiating a hypercortisolism workup should exist for these men with libido or erectile problems, low testosterone, and low gonadotropin levels (Findling and Raff, 2005; Pivonello et al. Up to 50% of patients with Cushing syndrome exhibit urolithiasis; therefore stone formers with cushingoid features also should receive a hypercortisolemia evaluation. It is interesting to note that definitive treatment of Cushing syndrome in these patients reduces the risk for stone formation but does not bring the risk back to that of the general population (Faggiano et al. Obvious clinical signs of Cushing syndrome are absent, and the diagnosis is made when a metabolic workup for an incidentally discovered adrenal mass reveals hypercortisolemia (Sippel and Chen, 2004). In the past, the disease entity was referred to as pre-Cushing syndrome, noncushingoid Cushing syndrome, preclinical Cushing syndrome, subclinical autonomous glucocorticoid hypersecretion, and subclinical Cushing syndrome; however, in 2016 the Clinical Practice Guidelines from the European Society of Endocrinology and the European Network for the Study of Adrenal Tumors recommended the term autonomous cortisol secretion (Fassnacht, et al. Nevertheless, the term subclinical Cushing syndrome continues to be used in the literature (Yanase et al. Classically, the disease entity applies to patients who are found to have elevated cortisol levels on a metabolic workup of an adrenal incidentaloma. Nearly 10% of patients in one large series of adrenal incidentalomas were found to have the condition (Mantero et al. Patients can also fall under the umbrella of this diagnosis when Cushing syndrome is discovered during screening. For instance, when patients with type 2 diabetes and poor glucose control are screened for hypercortisolism, some 2% have subclinical Cushing syndrome (Catargi et al. Adrenalectomy in the setting of subclinical Cushing syndrome may improve glucose control and hypertension and result in weight loss (Midorikawa et al.