Mark P. Cain, MD, FAAP

• Professor of Urology, Department of Urology,
• Riley Hospital for Children,
• Indiana University School of Medicine,
• Indianapolis, Indiana

A guidewire is subsequently passed into the main portal vein blood glucose images 500 mg actoplus met purchase visa, the tract is balloon dilated diabetes diet in kannada cheap actoplus met 500 mg buy on line, and then following portography diabetes pathophysiology buy 500 mg actoplus met free shipping, an expandable stent is inserted diabetes symptoms numbness and tingling discount 500 mg actoplus met overnight delivery. Failure of endoscopic therapy is most common in patients with Child-Turcotte-Pugh class C cirrhosis blood sugar level chart order 500 mg actoplus met with amex. Surgical shunts are contraindicated in patients with Child-Turcotte-Pugh class C cirrhosis, and the choice of shunt is determined by portal anatomy and the likelihood of liver transplantation. Liver transplantation is rarely used as a therapeutic option in the setting of an acute variceal bleed and can realistically be offered to only those patients stable enough to undergo the procedure. Recently, covered metal stents have been used as an alternative to esophageal balloon tamponade for the control of acute variceal hemorrhage in the setting of an endoscopic treatment failure. These shunts are relatively easy to construct, avoid dissection in the porta hepatis, and can be ligated at the time of liver transplantation. Improved survival after variceal hemorrhage over an 11-year period in the Department of Veterans Affairs. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal hemorrhage. Prognostic significance of bacterial infection in bleeding cirrhotic patients: a prospective study. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Application of endoscopy in improving survival of cirrhotic patients with acute variceal hemorrhage. Self-expandable metal stents in the treatment of acute esophageal variceal bleeding. Results of a randomized trial of end-to-side portacaval shunt and distal splenorenal shunt in alcoholic liver disease and variceal bleeding. Further report of a prospective randomized trial comparing distal splenorenal shunt with end-to-side portacaval shunt. The Emory prospective randomized trial: selective versus nonselective shunt to control variceal bleeding. Prospective comparative clinical trial with distal splenorenal and mesocaval shunts. Once the acute bleeding has been controlled, patients should be evaluated for placement of a portosystemic shunt with the goal of maintaining a hepatic venous pressure less than 10 mm Hg. Pearls and Pitfalls · Over the last decade, advances in the management of acute variceal bleeding have resulted in a reduction in the overall mortality associated with acute bleeding. The prevalence and risk factors associated with esophageal varices in subjects with hepatitis C and advanced fibrosis. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. Improved survival after variceal bleeding in patients with cirrhosis over the past two decades. Prognostic value of early measurements of portal pressure in acute variceal bleeding. Assessment of the risk of bleeding from esophageal varices by continuous monitoring of portal pressure. Somatostatin treatment and risk stratification by continuous portal pressure monitoring during acute variceal bleeding. Variceal bleeding and portal hypertension: has there been any progress in the last 12 months? Transjugular intrahepatic portasystemic shunt vs surgical shunt in good-risk cirrhotic patients: a case-control comparison. Decision-analysis of transjugular intrahepatic portosystemic shunt versus distal splenorenal shunt for portal hypertension. Transjugular intrahepatic portosystemic shunt: efficacy for the treatment of portal hypertension and impact on liver transplantation. Endoscopic variceal sclerosis compared with distal splenorenal shunt to prevent recurrent variceal bleeding in cirrhosis. Shunt surgery versus endoscopic sclerotherapy for long-term treatment of variceal bleeding. Distal splenorenal shunt versus endoscopic sclerotherapy in the prevention of variceal rebleeding. Randomized trial of portacaval shunt, stapling transection and endoscopic sclerotherapy in uncontrolled variceal bleeding. Distal splenorenal shunt versus endoscopic sclerotherapy for long-term management of variceal bleeding. Conversion of failed transjugular intrahepatic portosystemic shunt to distal splenorenal shunt in patients with Child A or B cirrhosis. Distal splenorenal shunt: role, indications, and utility in the era of liver transplantation. Three decades of experience with emergency portacaval shunt for acutely bleeding esophageal varices in 400 unselected patients with cirrhosis of the liver. Liver function and encephalopathy after partial vs direct side-to-side portacaval shunt: a prospective randomized clinical trial. Extrahepatic portal hypertension treated by anastomosing inferior mesenteric vein to left portal vein at Rex recessus. Experience with the Rex shunt (mesenterico-left portal bypass) in children with extrahepatic portal hypertension. There are two clinical and pathophysiological pulmonary abnormalities usually associated with portal hypertension, and often liver cirrhosis. These syndromes appear to be paradoxical responses by the pulmonary vascular endothelium to the adverse effects of portal hypertension often associated with liver disease. The integrity of the endothelium is vital for vasoregulation, antithrombosis, laminar blood flow, selective permeability to hematopoietic cells and nutrients, and the regulation of growth of the surrounding smooth muscle tissue. These two pathological changes may be seen in the same lung, but one entity usually predominates. Diffusion limitation and ventilationperfusion mismatch appear to be predominant factors. The hyperdynamic circulation (high rate of blood flow) found in cirrhotic patients decreases the exposure time of the red blood cell to the alveolus, further worsening the diffusion impairment. Red blood cells, which possess a similar diameter, travel through the capillaries in single file. This configuration minimizes the distance required for oxygen diffusion and facilitates oxygen transfer to red cells. However, the oxygen saturation as measured by pulse oximetry (Spo2) has been shown to overestimate arterial oxygen saturation (Sao2), both in patients with cirrhosis and controls. Echogenic shadows are normally visible only in the right heart, because they are filtered by the pulmonary microcirculation. With an intracardiac shunt, microbubbles appear in the left heart within three heartbeats of their appearance in the right heart. In the presence of intrapulmonary vasodilatation, albumin aggregates pass through to the systemic circulation. Computed tomography is helpful when pulmonary arteriovenous malformation is suspected. This may be a factor when considering the use of venovenous bypass, because the risk for air emboli is a recognized complication. However, unique postoperative complications have been described, including pulmonary hypertension,87,88 cerebral embolic hemorrhage,89 and postoperative desaturation requiring prolonged mechanical ventilation. The chambers of the right heart are initially opacified with microbubbles (A), followed by delayed opacification of the left heart (B). This may need aggressive diuresis or, if there is significant renal dysfunction, the institution of shortterm continuous venovenous hemodialysis. This practice is derived from the benefits of oxygen therapy in other pulmonary disorders. Anecdotal evidence suggests that exercise tolerance and quality of life are improved. Improvement in gas exchange occurs in over 85% of patients, although the length of time for hypoxemia to normalize is variable and may be more than a year in some patients. Although statistically different, the Pao2 of patients denied transplant was not clinically dissimilar to that of patients who underwent transplant (47 versus 52 mm Hg, respectively). However, a fourth of these patients required oxygen for 11 to 31 days, and some hospitalizations exceeded 3 months, suggesting both high acuity and a considerable commitment to long-term critical care. Improved survival after liver transplantation in patients with hepatopulmonary syndrome. In the absence of liver transplantation the condition progresses and is associated with increased mortality. Transplantation before hypoxemia is severe (Pao2 <50 mm Hg) may improve outcomes and result in less need for postoperative ventilator support. Clinical Features and Incidence For the past 50 years hepatologists have been aware that pulmonary hypertension has an association with portal hypertension. The initial reports linking pulmonary hypertension to cirrhosis were based upon autopsies. Chest x-ray examination can have normal results, or it may demonstrate cardiomegaly, prominent pulmonary arteries, and peripheral pruning of vessels. The prognostic implication in pediatric patients is similar to that of adults based upon a limited number of published reports. The presence of patent portal and hepatic veins allows percutaneous shunt closure. Positive screening results necessitate right heart catheterization for definite diagnosis. However, subsequently case reports appeared describing nonembolic pulmonary hypertension associated with portal hypertension. The pulmonary circulation has a substantial capacity for recruiting normally closed vessels. This patient had improved exercise tolerance and survived 7 years without liver transplantation. It is vital that both right and left ventricular anatomy and function are well characterized. C, D, and E, Pentachrome stain illustrates the black elastic demarcation separating the thickened intima from the medial layer of the vessel. Pulmonary hypertension after liver transplantation: case presentation and review of the literature. Any dilatation of the right heart chambers must be noted as a risk factor for liver transplantation. Right heart dysfunction or failure may result in graft congestion and malfunction. Most patients with liver cirrhosis will have a downregulation of the -receptors or more overt manifestation of cirrhotic cardiomyopathy. The diagnostic features are an early to late diastolic filling ratio (E/A ratio) of less than 1, a prolonged deceleration time of greater than 200 msec, a prolonged isovolumetric relaxation time of greater than 80 msec, enlarged left and right atria, an abnormal pattern of contractility, decreased wall motion, increased wall thickness, resting ejection fraction of less than 55%, and a prolonged ratio of preejection period to left ventricular ejection time of greater than 0. In one report the sensitivity and negative predictive value of this test was 100%. These include cardiac valvular disease, pulmonary emboli, collagen vascular disease, human immunodeficiency virus, schistosomiasis, oral ingestion of appetite suppressants, and toxic oil ingestion. Other therapies, including epoprostenol and bosentan, can cause hepatic injury as evidenced by hepatocellular enzyme level elevations. More recently case reports have highlighted improvements in pulmonary hemodynamics with the use of epoprostenol and other prostanoids,160,164-166 endothelin receptor antagonists such as bosentan,167-173 and phosphodiesterase inhibitors such as sildenafil. Epoprostenol appeared to have no significant effect on liver biochemical profiles. Only one of the 13 that died was treated preoperatively with epoprostenol (for 3 months). Three epoprostenol analogues have been evaluated (iloprost, beraprost, and treprostinil). Treprostinil is a stable prostanoid with pharmacological effects similar to those of epoprostenol, with the exception of an elimination half-life of 4. The 18 patients who received bosentan had higher 1-, 2- and 3-year survival rates compared with 13 patients treated with inhaled ilioprost. Liver enzyme level elevations were seen in one patient in the bosentan group but normalized after a dose reduction. Transaminase level elevations with these drugs appear to be less frequent than with bosentan, 3% to 5% versus 11%, respectively. Although some reports of combination therapy have shown mixed results, a number of reports show benefits. Theoretically portal pressures could increase with shunt occlusion, worsening ascites and increasing the likelihood of variceal bleeding. However, the effects of shunt occlusion on pulmonary blood flow are likely to be beneficial by two mechanisms, through both a decrease in total pulmonary blood flow and the diversion of blood to the liver, where vasoactive mediators may be metabolized. They also noted that mortality did not correlate with the severity of liver disease, a finding supported by other reports. Liver transplantation and pulmonary hypertension: pathophysiology and management strategies. Combined organ transplant should be reserved for patients who are not expected to survive an isolated organ transplant. If renal dysfunction is significant, then continuous venovenous hemodialysis should be considered. However, the need for long-term therapy increases the risk for progression of underlying liver disease. Six of 10 patients on long-term epoprostenol died while awaiting liver transplant.

Hydrochloric acid kills bacteria, aids protein digestion, provides the necessary pH for pepsin to start protein digestion, and stimulates the flow of bile and pancreatic juice diabetes definition uk 500 mg actoplus met purchase overnight delivery. Secretion of hydrochloric acid depends on stimulation of receptors in the membrane of parietal cells by histamine, acetylcholine (vagal stimulation), and gastrin diabetes medications for dogs generic 500 mg actoplus met with visa. Blockade of receptors with specific antagonist drugs produces Stomach the stomach is a specialized organ of the digestive tract that stores and processes food for absorption neuro metabolic disease generic 500 mg actoplus met with mastercard. The ability to secrete hydrogen ions in the form of hydrochloric acid is a hallmark of gastric function blood glucose software buy actoplus met 500 mg visa. Gastric Secretions Total daily gastric secretion is approximately 2 L with a pH of 1 diabetes insipidus pituitary 500 mg actoplus met purchase otc. Blockade of muscarinic receptors is produced by atropine or the more specific anticholinergic pirenzepine. Pharmacologic manipulation of gastric fluid pH has special implications in the management of patients considered to be at risk for pulmonary aspiration during the perioperative period. Intrinsic factor, which is essential for absorption of vitamin B12 from the ileum, is secreted by parietal cells. For this reason, destruction of parietal cells, as is associated with chronic gastritis, produces achlorhydria and often pernicious anemia. Chief Cells Pepsinogens secreted by chief cells undergo cleavage to pepsins in the presence of hydrochloric acid. G Cells Gastrin is secreted by gastric antral cells (G c ells) into the circulation, which carries this hormone to responsive receptors in parietal cells to stimulate gastric hydrogen ion secretion. Gastrin also increases the tone of the lower esophageal sphincter and relaxes the pylorus. Clinical manifestations of delayed gastric emptying include anorexia, persistent fullness after meals, abdominal pain, and nausea and vomiting. In addition to volume, another factor that influences the rate of gastric emptying is the composition of the liquids. Emptying of neutral, isoosmolar, and calorically inert solutions is rapid (250 mL of 500 mL of normal saline is emptied in 12 minutes). A small amount of water (up to 150 mL) to facilitate administration of oral medications shortly before the induction of anesthesia does not produce sustained increases in gastric fluid volume and could even contribute to gastric emptying. High lipid and/ or caloric content (glucose) slows the emptying of solids from the stomach. Delayed gastric emptying of solids is the most consistent abnormality in diabetics with gastroparesis and is the most predictably responsive to pharmacologic manipulation. Nevertheless, as diabetes progresses, it is possible that gastric retention of liquids will also occur. The existence of delayed gastric emptying in gastric ulcer disease is controversial. Some data suggest a slowing of gastric emptying of solids but not liquids in the presence of gastric ulcers. Although obesity and pregnancy are often assumed to slow gastric emptying, there are also data that fail to confirm this slowing, whereas other data suggest accelerated gastric emptying in obese individuals. Certain drugs, including opioids, b-adrenergic agonists, and tricyclic antidepressants, may slow gastric emptying. Alcohol, at least in concentrations present in wine, does not signifi antly affect gastric emptying of liquids or solids. Higher concentrations of alcohol, such as present in whiskey, do cause slowing of gastric emptying. The mechanism of this slowing is not clear but may be due to hyperosmolarity, changes in gastric acid secretion, or damage to gastric mucosa. Elemental diets, probably due to their high concentration of amino acids and hyperosmolarity, take longer to empty from the stomach than does blenderized food of comparable caloric composition. Cigarette smoking has been shown to delay emptying of solids although it may accelerate emptying of liquids. Gastric prokinetic drugs such as metoclopramide may speed the emptying of solids and liquids. Gastric Emptying Prior to Elective Surgery Clear liquids can be administered to adult patients scheduled for elective operations until 2 hours before induction of anesthesia without increasing gastric fluid volume. Central and peripheral m opioid receptors can regulate gastric emptying, and opioid-induced delay in gastric emptying can be reversed with naloxone, which acts simultaneously at both central and peripheral sites. The demonstration that methylnaltrexone, a selective peripheral-acting opioid antagonist, attenuates morphineinduced changes in the rate of gastric emptying indicates that peripheral opioid receptors modulate this response in humans (see Chapter 7). The slope of the plot of impedance versus time allows calculation of the emptying half-time of a meal. Th principal benefit of the bioimpedance method is that it is noninvasive and avoids gastric intubation or exposure to radioactivity. A limitation is that the subject must not move because alterations in body posture may alter baseline impedance readings and thus invalidate the recording. Another possible source of error is that gastric secretions might decrease the conductivity of gastric contents, thus reducing total surface impedance and producing inaccurate emptying rates. For this reason, deionized water may be used as the "test meal" because it does not appear to provoke sufficient gastric secretions to alter impedance. The area under the plasma concentration curve of acetaminophen after oral administration is determined by the rate of gastric emptying, because acetaminophen is not absorbed from the stomach but is rapidly absorbed from the small intestine. Absorption from the Stomach the stomach is a poor absorptive area of the gastrointestinal tract because it lacks the villus structure characteristic of absorptive membranes. As a result, only highly lipidsoluble liquids such as ethanol and some drugs such as aspirin can be significantly absorbed from the stomach. This center receives input from multiple sites including the chemoreceptor trigger zone in the floor of the fourth ventricle, from the vestibular apparatus, from cortical centers and the gastrointestinal tract. The blood­brain barrier is poorly developed around the chemoreceptor trigger zone, and emetic substances present in the circulation are readily accessible to this site. Likewise, dopamine and acetylcholine may provide emetic signals to the chemoreceptor trigger zone. Chapter 32 · Gastrointestinal Physiology 679 the role of specific opioid receptors in emetic responses is unresolved. Following stimulation of the vomiting center (directly or indirectly via neural pathways), vomiting is mediated by efferent pathways including the vagus and phrenic nerves, and innervation of the abdominal musculature. The initial manifestation of vomiting often involves nausea in which gastric peristalsis is reduced or absent and the tone of the upper small intestine is increased and gastric reflux occurs. Ultimately, the upper portion of the stomach relaxes while the pylorus constricts and the coordinated contraction of the diaphragm and abdominal muscles leads to expulsion of gastric contents. Risk factors for postoperative nausea and vomiting include female sex, young age (children), history of motion sickness, abstinence from tobacco, and obesity (perhaps reflecting emetic anesthetic drugs stored in adipose tissue). When more than 50% of the small intestine is resected, the absorption of nutrients and vitamins is so compromised that development of malnutrition is likely. Secretions of the Small Intestine Mucus glands (Brunner glands) present in the first few centimeters of the duodenum secrete mucus to protect the duodenal wall from damage by acidic gastric fluid. Stimulation of the sympathetic nervous system inhibits the protective mucus-producing function of these glands, which may be one of the factors that causes this area of the gastrointestinal tract to be the most frequent site of peptic ulcer disease. The crypts of Lieberkühn contain epithelial cells that produce up to 2 L d aily of secretions that lack digestive enzymes and mimic extracellular fluid, having a pH of 6. This fluid provides a watery vehicle for absorption of substances from chyme as it passes through the small intestine. The most important mechanism for regulation of small intestine secretions is local neural reflexes, especially those initiated by distension produced by the presence of chyme. The epithelial cells in the crypts of Lieberkühn continually undergo mitosis, with an average life cycle of approximately 5 days. This rapid growth of new cells allows prompt repair of any excoriation that occurs in the mucosa. This rapid turnover of cells also explains the vulnerability of the gastrointestinal epithelium to chemotherapeutic drugs (see Chapter 42). The epithelial cells in the mucosa of the small intestine contain digestive enzymes that most likely are responsible for digestion of food substances because they are absorbed across the gastrointestinal epithelium. These enzymes include peptidases for splitting peptides into amino acids, enzymes for splitting disaccharides into monosaccharides, and intestinal lipases. Small Intestine the small intestine consists of the duodenum (from the pylorus to the ligament of Treitz), the jejunum, and the ileum (ending at the ileocecal valve). There is no distinct anatomic boundary between the jejunum and ileum, but the first 40% of small intestine after the ligament of Treitz is often considered the jejunum. The small intestine is presented with approximately 9 L of fluid daily (2 L from the diet and the rest representing gastrointestinal secretions), but only 1 to 2 L of chyme enters the colon. Chyme moves through the 5 m of small intestine at an average rate of 1 cm p er minute. As a result, it takes 3 to 5 hours for chyme to pass from the pylorus to the ileocecal valve. On reaching the ileocecal valve, chyme may remain in place for several hours until the person eats another meal. Active transport of sodium ions in the small intestine is important for the absorption of glucose, which is the physiologic basis for treating diarrhea by oral administration of saline solutions containing glucose. Bacterial toxins as from cholera and staphylococci can stimulate the chloride-bicarbonate ion exchange mechanism, resulting in life-threatening diarrhea consisting of loss of sodium, bicarbonate, and an isosmotic equivalent of water. Secretions of the Colon Epithelial cells lining the colon secrete almost exclusively mucus, which protects the intestinal mucosa against trauma. The alkalinity of the mucus due to the presence of large amounts of bicarbonate ions provides a barrier to keep acids that are formed in the feces from attacking the intestinal wall. Irritation of a segment of colon as occurs with bacterial infection causes the mucosa to secrete large quantities of water and electrolytes in addition to mucus, diluting the irritating factors and causing rapid movement of feces toward the anus. Pancreas the pancreas lies parallel to and beneath the stomach, serving as both an endocrine (insulin or glucagon) and exocrine gland. Regulation of Pancreatic Secretions Pancreatic secretions are regulated more by hormonal than neural mechanisms. For example, secretin is released by duodenal mucosa in response to hydrochloric acid. Th s hormone enters the circulation and causes the pancreas to produce large amounts of alkaline fluid necessary to neutralize the acidic pH of gastric fluid. In addition to the release of secretions, the presence of food in the duodenum causes the release of a second polypeptide hormone, cholecystokinin. Cholecystokinin also enters the circulation and causes the pancreas to secrete digestive enzymes (trypsins, amylase, lipases). Trypsins are activated in the gastrointestinal tract by the enzyme enterokinase, which is secreted by the gastrointestinal mucosa when chyme is exposed to the mucosa. Damage to the pancreas or blockade of a pancreatic duct may cause pooling of proteolytic enzymes, resulting in acute pancreatitis due to autodigestion by these enzymes. In general, pancreatic secretions are stimulated by the parasympathetic nervous system and inhibited by the sympathetic nervous system. Colon the functions of the colon are absorption of water and electrolytes from the chyme and storage of feces. The circular muscle of the colon constricts and, at the same time, strips of longitudinal muscle (tinea coli) contract, causing the unstimulated portion of the colon to bulge outward into baglike sacs, or haustrations. Vagal stimulation causes segmental contractions of the proximal part of the colon and stimulation of the pelvic nerves causes explosive movements. Splenic flexure Hepatic flexure Transverse colon Descending colon Ascending colon Ileum Haustra Tenia coli References 1. Cricoid pressure decreases lower oesophageal sphincter tone in anaesthetized pigs. Large volume gastroesophageal reflux: a rationale for risk reduction in the perioperative period. Continuous hypopharyngeal pH m easurements in spontaneously breathing anesthetized outpatients: laryngeal mask airway versus tracheal intubation. Relationship of the motor activity of the antrum, pylorus, and duodenum to gastric emptying of a solid­liquid mixed meal. Effects of giving water 20­ 450 mL with oral diazepam premedication 1­2 h before operation. Gastric emptying in normal subjects-a reproducible technique using a single scintillation camera and computer system. Epigastric impedance: a noninvasive method for the assessment of gastric emptying and motility. Measurement of gastric emptying rates by radioactive isotope scanning and epigastric impedance. The production of energy involves the oxidation of nutrients (carbohydrates, fats, and proteins) that results in creation of high-energy phosphate bonds in which energy is stored for life processes, with carbon dioxide and water produced as side products. This ubiquitous molecule is the energy storehouse for the body, providing the energy necessary for essentially all physiologic processes and chemical reactions. Active transport is required to maintain the distribution of ions necessary for multiple cellular processes including the propagation of nerve impulses. For adults, total energy expenditure averages 39 kcal/ kg in males and 34 k cal/kg in females. Approximately 20 kcal/kg is expended as basal metabolism necessary to maintain integrity of the cell membrane and other energyrequiring tasks essential for life. In the resting state, the basal expenditure of calories is equivalent to approximately 1. As the level of activities increase above the basal state, the caloric (and oxygen) requirements increase in proportion to the energy expenditure 682 required (Table 33-1). Fat forms the major energy storage depot because of its greater mass and high caloric value. The high caloric density and hydrophobic nature of triglycerides permit efficient energy storage without adverse osmotic consequences. Carbohydrate Metabolism Carbohydrates comprise a group of organic compounds that include sugars and starches and, in addition to carbon, contain hydrogen and oxygen in the same ratio as water (2:1). Three disaccharides are important in human biology-sucrose: glucose and fructose; lactose: glucose and galactose; and maltose: glucose and glucose.

The central chemoreceptor increases or decreases minute ventilation according to the cerebral spinal fluid pH to maintain normocapnia43 diabetes type 1 nutrition education purchase actoplus met on line amex. Ventilation will increase in a linear fashion as Paco 2 rises until a maximal stimulation somewhere over a Paco 2 of 100 mm Hg is reached or until the respiratory mechanics will no longer permit an increase in minute ventila- tion diabetes insipidus serum sodium order actoplus met on line amex. Opioids, sedatives, and most general anesthetics decrease the respiratory response to hypercapnia diabetes symptoms dog buy generic actoplus met 500 mg online. Peripheral Chemoreceptors the peripheral chemoreceptors are located primarily in the carotid bodies at the bifurcation of the carotid arteries and also in aortic bodies above and below the aortic arch diabetes mellitus type 2 case history discount actoplus met 500 mg visa. Although there is some tonic activity from these peripheral chemoreceptors, they do not normally stimulate ventilation until the Pao 2 falls to below a threshold of approximately 70 to 80 mm Hg medications for diabetes 500 mg actoplus met order with visa. This threshold will be lowered in individuals who are adapted to altitude and in some chronic respiratory or congenital hypoxic cardiac diseases. The peripheral chemoreceptors also are sensitive to changes in arterial pH and Paco 2, and acidosis will increase the hypoxic drive (dashed line B in. The hypoxic drive due to the peripheral chemoreceptors is decreased by volatile anesthetics, even in very low concentrations such as 0. Other Neural Connections to the Medullary Respiratory Centers the entire airway from the mucosal lining of the nose and mouth to the distal bronchi has both afferent and efferent neural connections to the central respiratory neurons. These connections are responsible for many of the normal respiratory reflexes such as the phasic inspiratory dilation of the upper airway during inspiration to maintain patency of the supra-glottic airway. Irritants in the airway trigger cough and sneeze reflexes via these neuronal connections. The lung has stretch receptors that, in the nonsedated state, respond to regional changes in compliance associated with atelectasis by triggering a recruitment maneuver such as a sigh or a yawn (if you are yawning as you read this, hopefully it is to recruit your lungs and not because the content is boring). Passive stretching of the lungs can result in either inhibition of inspiration (Herring-Breuer reflex) or gasping (Heads reflex) depending on the clinical context. The pulmonary capillaries are densely innervated by unmyelinated nerves (C fibers). This innervation is not important during normal ventilation but may be responsible for causing a sensation of dyspnea when the capillaries become engorged during congestive heart failure. There are several recognized abnormal patterns which involve dysfunction of the central chemoreceptors. Cheyne-Stokes respiration is a pattern of 10- to 20-second periods of apnea followed by periods of hyperventilation. Altered Physiologic Conditions Anesthesia Nunn47 showed that during anesthesia and spontaneous ventilation, gas exchange was altered by shunt and inhomogeneous V/Q ratios. Brismar and colleagues48 in 1985 demonstrated using computed tomography that within 5 minutes of the induction of anesthesia, dependent regions of the lung developed an increase in density consistent with atelectasis. It is now accepted that this occurs in dependent lung regions in approximately 90% of patients who undergo general anesthesia using a wide variety of agents. Initiation of paralysis with neuromuscular blocking agents and positive pressure ventilation creates a reversal of this motion with the nondependent or superior aspect of the diaphragm undergoing the greatest displacement with each ventilated breath. Absorption atelectasis can occur when the rate of gas uptake into the blood exceeds the rate of ventilation of the alveolus. The extreme condition is total occlusion of an airway which isolates the alveolar gas in the distal alveolar and respiratory airways. The gas pressure within this compartment initially is nearly at atmospheric pressure. However, given that mixed venous blood continues to perfuse this area, and the fact that the sum of the gas partial pressures within mixed venous blood is subatmospheric, gas uptake from the occluded compartment by blood continues and the alveoli collapses. Computer modeling has demonstrated that the rate of gas absorption from unventilated areas is dependent on the initial Fio 2. Again, this process is augmented by the presence of a high Pao 2 and a rapid rate of gas uptake. Loss of alveolar surfactant may play a role in alveolar instability at low alveolar volumes and collapse. Therefore, atelectatic regions of the lung may be predisposed to recurrence of collapse because of reduced levels of surfactant, increased alveolar surface tension and, the aforementioned mechanisms, all contributing to reduced alveolar volumes. During anesthesia and positive pressure ventilation in the prone position, the majority of diaphragm displacement during inspiration will remain in the dorsal (now the nondependent) portions of the thoraces and ventilation will be more homogeneously distributed in the lungs compared to the supine position. Matching of ventilation to perfusion will usually be superior in the prone position when compared with the supine position. In these patients in the supine position, pulmonary edema collects in the parenchyma of the dorsal portions of the lung. The effects of the lateral position will be discussed in the "One-Lung Ventilation" section. Position In the spontaneously breathing patient, awake or during anesthesia, the majority of gas exchange is due to caudal displacement of the diaphragm, which occurs primarily in the dorsal portions of the thoraces. Thus, matching of ventilation/ perfusion is decreased with induction of anesthesia and further decreased with paralysis and positive pressure ventilation. These disorders all involve variable degrees of upper airway obstruction and apnea during normal sleep. At a certain point, the increases in ventilation and cardiac output will not be able to supply adequate oxygen to the tissues for aerobic metabolism and further increase in muscle activity will require anaerobic metabolism producing lactic acid. It is most often the accumulation of lactate in tissues causing muscle dysfunction which limits prolonged exercise and not a limitation on minute ventilation or cardiac output. Increased cerebral blood flow due to hypoxia is opposed in part by the cerebral vasoconstriction due to hypocapnia but may lead to cerebral edema. Chronic acclimatization to altitude involves a variety of cellular and metabolic changes such as a resetting of the peripheral chemoreceptors and polycythemia. Anesthesia at mild elevations is generally uncomplicated as long as oxygen saturation is monitored and adequate supplemental oxygen is provided. Most modern commercial vaporizers deliver reasonably accurate dosages of volatile anesthetics at modest elevations (,6,000 ft) Pressure in the air-filled cuff of an endotracheal tube or laryngeal mask airway will increase and decrease significantly with changes in ambient pressure, which may be associated with medical air transport. Treatments are given with a high Fio 2, usually from a tight-fitting mask for several hours and repeated as required. A high Pao 2 in the neonate can cause retrolental fibroplasias, damaging the retinal of the eye. However, the compliance of the chest wall in newborns and infants is very high due to the absence of ossification of cartilages. All airways are proportionately smaller in infants than adults and airway resistance is higher, resulting in increased work of breathing at rest and particularly during upper or lower airway infections. The narrowest portion of the upper airway is at the cricoid cartilage until age 5 years. HbF hemoglobin has a low P50 (18 to 19 mm Hg), which increases oxygen loading in the placenta but decreases oxygen unloading in the tissues. The elderly: changes in the respiratory system with age include decrease of muscle tone in the dilators of the pharynx, predisposing to upper airway obstruction during anesthesia. The lung parenchyma loses elastic support tissue resulting in an increase of lung compliance, but the chest wall increases in stiffness so the net effect is an overall decrease in respiratory system compliance. The mean Pao 2 of healthy patients will decline to approximately 80 mm Hg at age 70, after which it remains stable. Chronic Respiratory Disease Chronic respiratory disease is commonly divided into two major categories: obstructive and restrictive. Age Infants and children: the overall compliance of the respiratory system is low in newborns and increases until late adolescence. Any individual patient may have one or all of these conditions, but the dominant clinical feature is impairment of expiratory airflow. Right ventricular function becomes critical in maintaining cardiac output as the pulmonary artery pressure rises. Chronic recurrent hypoxemia is the cause of the right ventricular dysfunction and the subsequent progression to cor pulmonale. These bullae will often be asymptomatic unless they occupy more than 50% of the hemithorax, in which case the patient will present with findings of restrictive respiratory disease in addition to their obstructive disease. A bulla is a localized area of loss of structural support tissue in the lung with elastic recoil of surrounding parenchyma. This means that during normal spontaneous ventilation, the intra-bulla pressure is actually slightly negative in comparison to the surrounding parenchyma. However, whenever positive pressure ventilation is used, the pressure in a bulla will become positive in relation to the adjacent lung tissue and the bulla will expand with the attendant risk of rupture, tension pneumothorax, and bronchopleural fistula. During positive pressure ventilation, the risk of bulla rupture and tension pneumothorax must always be kept in mind. Although the cells surrounding the bulla appear compressed, this is only due to redistribution of elastic forces. It is not positive pressure inside the bulla which causes this appearance of surrounding compression. Flow-limitation is present in normal patients only during a forced expiratory maneuver. During quiet expiration in the normal patient, the pressure in the lumen of the airways always exceeds the intrapleural pressure because of the upstream elastic recoil pressure, which is transmitted from the alveoli. Flow-limitation occurs particularly in emphysematous patients, who primarily have a problem with loss of lung elastic recoil and have marked dyspnea on exertion. This variable mechanical compression of airways by overinflated alveoli is the primary cause of the airflow obstruction in emphysema. Severely flow-limited patients are at risk for hemodynamic collapse with the application of positive pressure ventilation due to dynamic hyperinflation of the lungs. Even the modest positive airway pressures associated with manual ventilation with a bag/mask at induction can lead to hypotension because these patients have no increased resistance to inspiration but a marked obstruction of expiration. In some of these patients, this has contributed to the "Lazarus" syndrome in which patients have recovered from a cardiac arrest only after resuscitation and positive pressure ventilation were discontinued. It can be measured by end-expiratory flow interruption, a f eature available on most intensive care ventilators. This is particularly a problem at the start of minimally invasive thoracic surgery when surgical visualization in the operative hemithorax is limited and in patients with emphysema who have delayed collapse of the nonventilated lung due to decreased lung elastic recoil. Although nitrous oxide is even more effective than oxygen in speeding lung collapse (because of its solubility), it is not commonly used in thoracic anesthesia because many patients may have blebs or bullae. However, the lowest acceptable saturation will be higher in patients with organs at risk of hypoxia due to limited regional blood flow. Reports for the period 1950 to 1980 describe an incidence of hypoxemia (arterial saturation,90%) of 20% to 25%. Several factors aid and impede this redistribution and these are under the control of the anesthesiologist to a variable degree. Extracorporeal Ventilatory Support Various devices to supplement or replace the gas exchange function of the lung have been available clinically for the past several decades. These devices have been associated with a high incidence of complications, particularly cerebral hemorrhage and infarction, and have met with questionable outcome results in several studies. However, gradual progress in the technology has seen a resurgence of use of these devices. During extracorporeal ventilation, less injurious mechanical ventilation strategies can be used on the native lungs with relatively normal Fio 2 and tidal volumes to allow some regression of the disease process in the lungs. Palate and hypopharynx-sites of inspiratory narrowing of the upper airway during sleep. Ketamine activates breathing and abolishes the coupling between loss of consciousness and upper airway dilator muscle function. Bronchial inflammation and responses to deep inspiration in asthma and chronic bronchitis. Errors in tracheal pressure recording in patients with a tracheostomy tube-a model study. Electroencephalographic evidence for pre-motor cortex activation during inspiratory loading in humans. Simple methods of estimating oxygen consumption and the efficiency of the muscles of respiration. The interdependent contributions of gravitational and structural features to perfusion distribution in a multiscale model of the pulmonary circulation. Compendium of physical activities: classifi ation of energy costs of human physical activities. Physiology and pathophysiology at high altitude: considerations for the anesthesiologist. Two temporal components within the human pulmonary vascular response to 2h of isocapnic hypoxia. Influence of mixed venous oxygen tension (PvO2) on blood flow to atelectatic lung. Absence of parasympathetic control of pulmonary vascular pressure-flow plots in hyperoxic and hypoxic dogs. Hypoxic pulmonary vasoconstriction: cyclic adenosine diphosphate-ribose, smooth muscle Ca21 stores and the endothelium. Role of airway nitric oxide on the regulation of pulmonary circulation by carbon dioxide. Factors influencing the arterial oxygen tension during halothane anaesthesia with spontaneous respiration. Pulmonary densities during anesthesia with muscular relaxation-a proposal of atelectasis. Gas uptake from an unventilated area of the lung: computer model of absorption atelectasis. Positive end-expiratory pressure redistributes regional blood flow and ventilation differently in supine and prone humans. The pharmacology of the airways will be considered first, then the pharmacology of the pulmonary circulation, and finally, the intrinsic action of the lungs on a variety of exogenous and endogenous substances. Pharmacology of the Airways Pharmacologic agents administered via the lungs take advantage of the interface between air and blood allowing for rapid uptake of drugs into the bloodstream or immediate use by cells that populate the airway.

Syndromes

• Is it the feet?
• Diarrhea
• Flank pain or low back pain
•  If organs are showing through the wound, do not try to push them back into place.
• Shock
• Ovarian torsion (twisted Fallopian tube)
• Skin reaction (erythema nodosum)
• Infection (pneumonia, bloodstream infection, peritonitis)
• Your heart valve has been damaged by endocarditis (infection of the heart valve).
• Kawasaki disease

The estrogen receptor resides in the cytosol and, upon occupation by estradiol, is transported to the nucleus, where it activates genes (including those genes that encode proliferation molecules) containing estrogen-response elements blood sugar after eating actoplus met 500 mg order with amex. Tamoxifen binds to estrogen receptors and disrupts receptor interactions with estrogen in some but not all estrogen-responsive tissues diabetes mayo clinic discount 500 mg actoplus met amex. For example, tamoxifen is antiestrogenic in breast and ovarian tissue but is estrogenic in the uterus, liver, and bone blood sugar jumping up 60 points actoplus met 500 mg for sale. As a result, tamoxifen is effective in the prevention and treatment of breast cancer but produces undesired estrogen side effects including deep vein thrombosis (,1% of patients), endometrial cancer (about 0 diabetes symptoms treatment and prevention generic 500 mg actoplus met otc. In addition, tamoxifen lowers plasma cholesterol concentrations and increases bone density diabetes test fasting generic 500 mg actoplus met with amex. The response to tamoxifen is proportional to the degree of expression of estrogen receptors in the breast cancer. Tamoxifen is of little benefit in women with breast cancer that does not express hormone receptors. After surgical removal of the primary breast cancer, adjuvant treatment of women with tumors that are hormone-positive decreases the odds of recurrence by more than 30%. Other antiestrogens that may have greater selectivity for breast estrogen receptors include raloxifene, toremifene, and fulvestrant. Antiandrogens Antiandrogens such as flutamide, bicalutamide, and nilutamide are competitive antagonists of the interactions between androstenedione and androgen receptors. Flutamide is a nonsteroidal antiandrogenic that possesses pure antiandrogenic activity when metabolized to its hydroxylated derivative. Administered with other drugs that decrease androgen production, flutamide is an effective treatment for hormone-dependent prostate cancer. Androgenic blockade results in feminizing side effects in men, including gynecomastia, hot flashes, and loss of facial hair. Skeletal muscle weakness and development of osteoporosis reflect a male menopause­like state. At levels of methemoglobinemia of greater than 35%, the pulse oximetry readings tend to approach a minimal level of 85%. Vaccines are also being developed that may include genetic manipulation of cancer cells to make them more antigenic and thus susceptible to immune responses. Two types of vaccines aimed at preventing infection related to subsequent development of cancer have been approved by the U. Inhibition of aromatase blocks the conversion of androgens to estrone in peripheral tissues including breast tissue. Inhibition of aromatase is an effective treatment for postmenopausal women with breast cancer, in which the greatest source of estrone comes from conversion of androstenedione to estrone in liver, skeletal muscles, and fat. Exemestane is a steroidal aromatase inhibitor that binds to the enzyme complex and promotes enzyme degradation. A partial medical hypophysectomy is produced by luteinizing hormone­releasing hormone agonists, such as leuprolide, buserelin, and goserelin, which inhibit secretion of follicle-stimulating hormone and luteinizing hormone by downregulating receptors that respond to these hormones. The result is insignificant plasma concentrations of sex hormones and palliation of breast and prostate cancer. Prolonged succinylcholine apnoea resulting from acquired deficiency of plasma cholinesterase. Chemotherapyassociated pulmonary toxic reactions during treatment for breast cancer. Nephrotoxicity from chemotherapeutic agents: clinical manifestations, pathobiology, and prevention/ therapy. Perioperative cardiovascular collapse in a patient previously treated with doxorubicin. Bleomycin pharmacology: mechanism of action and resistance, and clinical pharmacokinetics. Bleomycin therapy and anaesthesia: the possible hazards of oxygen administration to patients after treatment with bleomycin. Development of acute lung injury after the combination of intravenous bleomycin and exposure to hyperoxia in rats. Pulmonary toxicity after treatment with bleomycin along or in combination with hyperoxia. Vincristine therapy for children with acute lymphoblastic leukemia impairs conduction in the entire peripheral nerve. The development of relatively safe and effective psychotherapeutic drugs has made it possible to effectively treat as ambulatory patients many individuals with depression and anxiety disorders. Antidepressants and anxiolytics are the drugs most likely to be prescribed by primary care physicians for the treatment of depression in adults. Lithium, anticonvulsants, and antipsychotic drugs are useful for treatment of bipolar disorders and psychotic disorders including schizophrenia. It is estimated that up to 10% o f the population is treated for a depressive illness at some time in life, and mood disorders requiring antidepressant therapy are an increasingly frequent occurrence in the elderly population in whom side effects may be less well tolerated due to coexisting disease. It is well accepted that anesthesia can be safely administered to patients being treated with drugs used to treat mental illness. Nevertheless, it remains important to remain alert for potential drug interactions. The precise mechanism by which antidepressants work is unknown, but they appear to act by altering noradrenergic neurotransmission and/or serotoninergic neurotransmission (see Table 43-2). This suggests that antidepressants work by increasing the amount of norepinephrine and serotonin in synapses. Nevertheless, the most important observation not explained by this hypothesis is the time course of clinical improvement. Perhaps adaptive changes including downregulation of neurotransmitter receptors are necessary before evidence of clinical improvement appears. These drugs are also effective in treatment of social phobia and posttraumatic stress disorder. The broad spectrum of effectiveness of antidepressants does not imply a common pathophysiology but rather reflects the diverse roles of monoamine neurotransmitters in the human nervous system. Antidepressants are logically classified based on their chemical structures and their acute neuropharmacologic 822 Chapter 43 · Drugs Used for Psychopharmacologic Therapy 823 Table 43-1 Clinical Uses of Antidepressant Drugs Unipolar and bipolar depression Panic disorder Social phobia Posttraumatic stress syndrome Neuropathic pain Migraine prophylaxis Obsessive-compulsive disorder Bulimia Childhood attention defi it hyperactivity disorder There is abundant evidence that serotonin receptors are involved in the etiology of anxiety. Potent inhibition of serotonin reuptake appears to be necessary for effectiveness in the treatment of obsessive-compulsive disorders. Because fluoxetine has a prolonged elimination halftime (1 to 3 days for acute administration and 4 to 6 days for chronic administration), the drug can be taken every other day. An active metabolite, norfluoxetine, has an elimination half-time of 4 to 16 days. Side Effects the most common side effects of fluoxetine are nausea, anorexia, insomnia, sexual dysfunction, agitation, and neuromuscular restlessness, which may mimic akathisia. Appetite suppression associated with fluoxetine therapy may help patients achieve weight loss. The long elimination half-time of fluoxetine appears to prevent withdrawal symptoms induced by abrupt discontinuance of the drug. As a result, this drug may increase the plasma concentrations of drugs that depend on hepatic metabolism for clearance. For example, the addition of fluoxetine to treatment with a tricyclic antidepressant drug may result in a two- to fivefold increase in the plasma concentration of the tricyclic drug. Several cardiac antidysrhythmic drugs as well as some b-adrenergic antagonists may be metabolized by the same enzyme system that is inhibited by fluoxetine, resulting in potentiation of these drug effects. Compared with fluoxetine, sertraline may cause more gastrointestinal symptoms (nausea, diarrhea) but may be less likely to cause insomnia and agitation. This drug has a relatively short elimination half-time (24 hours), and there are no active metabolites. The levels of paroxetine in breast milk are greater than levels in patients receiving fluoxetine or sertraline. Paroxetine produces less inhibition of hepatic cytoplasmic P-450 enzymes than is fluoxetine. Enhancement of the anticoagulant eff ct of warfarin reflects competition for common protein-binding sites. Escitalopram is simply the S isomer of citalopram, which is the more pharmacologically active stereoisomer. Chapter 43 · Drugs Used for Psychopharmacologic Therapy 825 Fluvoxamine Fluvoxamine is effective in the management of obsessivecompulsive disorders. Bupropion Bupropion, which is structurally related to amphetamine, is effective in the treatment of major depression, producing improvement in 2 to 4 weeks. The mechanism of action of bupropion is obscure but may include inhibition of dopamine and norepinephrine reuptake. Unlike tricyclic antidepressants, venlafaxine does not produce anticholinergic effects or postural hypotension. At high doses, a modest but persistent increase in diastolic blood pressure occurs in 5% to 7% of patients. Some studies have suggested that venlafaxine may be beneficial in patients with neuropathic pain. The elimination half-time is 5 hours and that of its active metabolite is 11 hours. Duloxetine Duloxetine is a serotonin and noradrenaline reuptake inhibitor, similar to venlafaxine. Trazodone Trazodone inhibits serotonin reuptake and may also act as a serotonin agonist via an active metabolite. Common side effects of trazodone include sedation, orthostatic hypotension, nausea, and vomiting. This drug lacks effects on conduction of cardiac impulses but on rare occasions has been associated with cardiac dysrhythmias. Nefazodone Nefazodone is chemically related to trazodone but with fewer a1-adrenergic blocking properties. The risk of sedation and priapism may be less than in patients treated with trazodone. Although tricyclic antidepressants are highly eff ctive, they have been supplanted as first-line drugs in many clinical situations because of their unfavorable side effect profile (largely resulting from their anticholinergic, antiadrenergic, and antihistaminic properties). Measurement of plasma drug levels for the tricyclics imipramine, desipramine, and nortriptyline can be useful in guiding therapeutic decisions. Generally, plasma levels should not exceed 225 ng/mL when imipramine is administered. Plasma levels should not exceed 125 ng/mL when desipramine is administered, and the therapeutic range for nortriptyline is 50 to 150 ng/mL. It is preferable to taper tricyclic and tetracyclic antidepressants during a 4-week period to avoid the risk of withdrawal symptoms (chills, coryza, muscle aches). These symptoms have been attributed to supersensitivity of the cholinergic nervous system. Chronic Pain Syndromes the tricyclic antidepressants (especially amitriptyline and imipramine), in doses lower than those used to treat depression, may be useful in the treatment of chronic neuropathic pain and other chronic pain syndromes including fibromyalgia. Because many chronic pain syndromes include an inflammatory component, it is possible that the clinical efficacy of tricyclic antidepressants in chronic pain patients is due to inhibition of an overactive inflammatory system. Structure­Activity Relationships the structure of tricyclic antidepressants resembles that of local anesthetics and phenothiazines. Similar to local anesthetics, tricyclic antidepressants include a hydrophobic portion linked to an amide via a linear intermediate moiety. Tricyclic denotes the three-ring chemical structure of the central portion of the molecule. Imipramine, which is the prototype of the tricyclic antidepressants, differs from phenothiazine only in the replacement of the sulfur atom with an ethylene linkage to produce a seven-membered central ring. Maprotiline is a tetracyclic antidepressant with a clinical profile that resembles imipramine. Mechanism of Action Tricyclic antidepressants act at several transporters and receptors, but their antidepressant effect is likely produced by blocking the reuptake (uptake) of serotonin and/or norepinephrine at presynaptic terminals, thereby increasing the availability of these neurotransmitters. These drugs can be categorized into tertiary amines, which inhibit reuptake of both serotonin and norepinephrine (amitriptyline, imipramine, clomipramine) and secondary amines, which are primarily norepinephrine reuptake inhibitors (desipramine, nortriptyline). Despite the prompt onset of this effect, the development of a therapeutic antidepressant effect is inexplicably delayed for 2 t o 3 w eeks. For this reason, there is doubt that antidepressant effects are totally due to an accumulation of biogenic amines in the brain. Furthermore, some drugs without effects on uptake of biogenic amines are effective antidepressants. It seems likely that potentiation of monoaminergic neurotransmission in the brain is only an early event in a complex cascade of events that eventually results in an antidepressant effect. Indeed, chronic administration of these drugs is associated with (a) decreased sensitivity of postsynaptic b1 and serotonin2 receptors and of presynaptic a2 receptors, and (b) increased sensitivity of postsynaptic a1 receptors. Pharmacokinetics Tricyclic antidepressants are efficiently absorbed from the gastrointestinal tract after oral administration, reflecting high lipid solubility. Therapeutic plasma concentrations (parent drug plus the pharmacologically active demethylated metabolites) are 100 t o 300 ng/ mL, whereas toxicity is likely at levels greater than 500 ng/mL. Tricyclic antidepressants are strongly bound to plasma and tissue proteins, which, in combination with high lipid solubility, results in a large volume of distribution (up to 50 L/kg) for these drugs. The long elimination half-time (17 to 30 hours) and wide range of therapeutic plasma concentrations make once-daily dosing intervals eff ctive. Metabolism Tricyclic antidepressants are oxidized by microsomal enzymes in the liver with subsequent conjugation with glucuronic acid. The individual variation in rate of metabolism Chapter 43 · Drugs Used for Psychopharmacologic Therapy 827 between patients is 10- to 30-fold.

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