Prof. Dr. Konrad Reinhart

• Director of Clinic for Anaesthesiology and Intensive Care
• University of Jena
• Erlanger Allee 101
• 07747 Jena
• Germany

Liver transplantation for classical maple syrup urine disease: long-term follow-up in 37 patients and comparative United Network for Organ Sharing experience erectile dysfunction quiz discount dapoxetine 30 mg line. Liver transplantation in children with glycogen storage disease: controversies and evaluation of the risk/benefit of this procedure erectile dysfunction pills names discount dapoxetine 60mg on line. Long-term results of living donor liver transplantation for glycogen storage disorders in children which antihypertensive causes erectile dysfunction purchase dapoxetine line. Familial hypercholesterolemia: a genetic defect in the low-density lipoprotein receptor homeopathic remedy for erectile dysfunction causes generic 90mg dapoxetine with mastercard. The role of orthotopic liver transplantation in the treatment of ornithine transcarbamylase deficiency erectile dysfunction cure order on line dapoxetine. Treatment of ornithine transcarbamylase deficiency in girls by auxiliary liver transplantation: Conceptual changes in a living-donor programs erectile dysfunction remedies fruits order 30mg dapoxetine fast delivery. Persistent acitrullinemia after liver transplantation for carbamylphosphate synthetase deficiency. Current role of liver transplantation for methylmalonic acidemia: A review of the literature. Combined liver-kidney transplant for the management of methylmalonic aciduria: a case report and review of the literature. Progressive neurologic disability in methylmalonic acidemia despite transplantation of the liver. Metabolic stroke in methylmalonic acidemia five years after liver transplantation. Evaluation and management of patients with propionic acidemia undergoing liver transplantation: a comprehensive review. Cardiomyopathies in propionic aciduria are reversible after liver transplantation. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Portacaval shunt and liver transplantation in treatment of familial hypercholesterolemia. Normal cholesterol levels with lovastatin (Mevinolin) therapy in a child with homozygous familial hypercholesterolemia following liver transplantation. Successful treatment of angina pectoris with liver transplantation and bilateral internal mammary bypass graft surgery in familial hyper cholesterolemia. Normal levels of lipoproteins including lipoprotein(a) after liver-heart transplantation in a patient with homozygous familial hypercholesterolaemia. Lipids and lipoprotein changes after heart and liver transplantation in a patient with homozygous familial hypercholesterolemia. Liver transplantation for familial hypercholesterolemia before the onset of cardiovascular complications. Hepatocyte transplantation for the low-density lipoprotein receptor­deficient state. Orthotopic liver transplantation in the treatment of complications of type 1 Gaucher disease. Replacement therapy for inherited enzyme deficiency: Liver orthotopic transplantation in Niemann-Pick disease type A. Niemann-Pick disease: sixteen-year follow-up of allogeneic bone marrow transplantation in a type B variant. Chronic non-hemolytic hyperbilirubinemia with glucuronyl transferase deficiency: clinical, biochemical, pharmacodynamic and genetic evidence for heterogeneity. Chronic unconjugated hyperbilirubinaemia without overt signs of haemolysis in adolescents and adults. Crigler-Najjar syndrome: An unusual course with development of neurologic damage at age eighteen. Crigler-Najjar syndrome type I: Treatment by home phototherapy followed by orthotopic hepatic transplantation. Orthotopic liver transplantation in children: Two-year experience with 47 patients. Orthotopic liver transplantation for Crigler-Najjar type I disease in six children. Liver transplantation in patients with cystic fibrosis: analysis of United Network for Organ Sharing Data. Combined heartlung-liver, double lung­liver, and isolated liver transplantation for cystic fibrosis in children. Liver and intestinal transplantation in a child with cystic fibrosis: a case report. Enzymological diagnosis of primary hyperoxaluria type 1 by measurement of hepatic alanine:glyoxylate aminotransferase activity. Successful treatment of primary hyperoxaluria type I by combined hepatic and renal transplantation. Early liver transplantation for primary hyperoxaluria type I in an infant with chronic renal failure. Long term results of liver-kidney transplantation in children with primary hyperoxaluria. Pre-emptive liver transplantation in primary hyperoxaluria type I: a controversial issue. Long-term results of pre-emptive liver transplantation in primary hyperoxaluria type I. Oxalate kinetics and reversal of the complications after orthotopic liver transplantation in a patient with primary hyperoxalosis type I awaiting renal transplantation. Incidence of renal and liver rejection and patient survival rate following combined liver and kidney transplantation. Combined liver-kidney transplantation in patients with cirrhosis and renal failure: effect of a positive cross-match and benefits of combined transplantation. Treatment of Crigler-Najjar type 1 disease: relevance of early liver transplantation. Quantitation of transplanted hepatic mass necessary to cure the Gunn rat model of hyperbilirubinemia. Auxiliary partial orthotopic liver transplantation for Crigler-Najjar syndrome type I. Restoration of liver function in Gunn rats without immunosuppression using transplanted microencapsulated hepatocytes. A step toward liver gene therapy: efficient correction of the genetic defect of hepatocytes isolated from a patient with Crigler-Najjar syndrome type 1 with lentiviral vectors. Cystic fibrosis: Its influence on the liver, biliary tree, and bile salt metabolism. Transplantation for cystic fibrosis: Outcome following early liver transplantation. Liver transplantation in children with cystic fibrosis: A long term longitudinal review of a single centers experience. Radiological and histological improvement of oxalate osteopathy after combined liverkidney transplantation in primary hyperoxaluria type 1. Reversal of oxalosis cardiomyopathy after combined liver and kidney transplantation. Primary hyperoxaluria: Simultaneous combined liver and kidney transplantation from living related donor. Combined liver-kidney transplantation for primary hyperoxaluria type I in young children. Combined liverkidney and isolated liver transplantations for primary hyperoxaluria type 1: the European experience. Inferior survival after liver + kidney transplantation for children with primary hyperoxaluria. Idiopathic neonatal iron storage involving the liver, pancreas, heart, and endocrine and exocrine glands. Rapid development of hepatocellular siderosis after liver transplantation for neonatal hemochromatosis. High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis. Treatment of neonatal hemochromatosis with exchange transfusion and intravenous immunoglobulin. Familial Reye-like syndrome: a presentation of medium-chain acyl coenzyme A dehydrogenase deficiency. Octanoic acidemia and octanoylcarnitine excretion with dicarboxylic aciduria due to defective oxidation of medium-chain fatty acids. Sudden child death and "healthy" affected family members with medium-chain acylcoenzyme A dehydrogenase deficiency. Recognition of medium-chain acyl-CoA dehydrogenase deficiency in asymptomatic siblings of children dying of sudden infant death or Reyelike syndromes. Mitochondrial respiratory chain defect: a new etiology for neonatal cholestasis and early liver insufficiency. End-stage liver disease as the only consequence of a mitochondrial respiratory chain deficiency: no contra-indication for liver transplantation. Bone marrow transplant in a case of mucopolysaccharidosis I Scheie phenotype: Skin ultrastructure before and after transplantation. Bone marrow transplantation for Hurler syndrome: assessment of metabolic correction. Interestingly, liver transplantation for malignancy in the pediatric population has historic significance. Liver transplantation of a child afflicted with a hepatoblastoma unresectable by conventional approach results in an excellent outcome with multiple institutional and cooperative studies reporting survival rates greater than 80%. In this chapter we will discuss the management of children with primary hepatic malignancy, focusing on recent developments in the use of liver transplantation. A child who has a hepatoblastoma can present in a variety of fashions ranging from an asymptomatic abdominal mass found by a primary caregiver to an acute abdomen secondary to tumor rupture. On occasion the size of the tumor will be so large as to cause respiratory distress or failure to thrive because of loss of abdominal domain. The epithelial cell 28 TransplanTaTion for HepaTic Malignancy in cHildren 347 type can be further divided into fetal, embryonal, and small cell undifferentiated variants. As with many malignancies, abnormalities in gene expression are thought to play a role; however, the specific mechanism by which the tumor develops remains unclear. Patients who are afflicted with the genetic conditions of Beckwith-Wiedemann syndrome, its variant hemihypertrophy, and familial adenomatous polyposis are found to have an increased incidence of hepatoblastoma and need close surveillance in childhood. Diagnosis Blood tests obtained from a child with a hepatoblastoma will often show anemia, thrombocytosis, and leukocytosis. Radiographic analysis is essential in the diagnosis and treatment of a child in whom a hepatoblastoma is suspected. The proximity of the tumor and the presence of thrombus within the portal vein and major hepatic veins or inferior vena cava can be determined by the same imaging modalities or by ultrasonography. Tissue diagnosis by definitive resection or biopsy obtained via a percutaneous, open, or laparoscopic approach is necessary to establish the diagnosis. Staging Over the past 15 years the staging systems for patients afflicted with hepatoblastoma have evolved significantly. In this system, tumors at the time of diagnosis are staged by radiographic analysis according to the number of sectors of the liver in which tumor is present. In addition to the intrahepatic extent of disease, the involvement of a hepatic or portal vein, the presence of extrahepatic spread, and the presence of metastatic disease are documented. Treatment Strategy Complete surgical resection of the primary liver lesion remains the most crucial intervention required to achieve long-term survival. In children who present with tumor confined to a single lobe of the liver without vascular involvement, standard lobectomy followed by adjuvant chemotherapy is indicated. Historically over 60% of children presented with lesions unresectable by conventional surgery, and the outcome was poor due to residual disease after attempted resection. In 1982 Evans et al17 reported a significant improvement in the outcome of children treated with a combination of adjuvant chemotherapy followed by surgical resection. This finding dramatically altered the strategy for treatment of children with hepatoblastoma. Over 75% of lesions initially felt to be unresectable will decrease sufficiently in size with neoadjuvant chemotherapy to allow conventional resection. The combination of adjuvant chemotherapy followed by conventional resection has improved the prognosis of children with hepatoblastoma such that 70% to 80% will achieve long-term survival. In spite of these improvements, some patients after adjuvant chemotherapy will have tumor that remains unresectable by conventional resection. It is these patients who benefit from total hepatectomy and orthotopic liver transplantation. Although initial studies on the outcome of orthotopic liver transplantation for hepatoblastoma reported mixed results, multiple studies have documented the efficacy of this form of treatment Table 28-2). Transplantation can also be used for salvage after attempted conventional resection in which residual disease remains, although some studies suggest that these patients have worse outcome. On occasion the tumor size at the time of presentation is so large that it may compromise the respiratory status of the patient. The time required for adjuvant chemotherapy to induce tumor shrinkage may leave the patient ventilator dependent for a prolonged period of time. If the lesion has decreased in size to allow for conventional resection, surgery is performed. If the lesion remains too large to resect after four cycles of chemotherapy, the patient is listed for transplantation. In some of our patients we have used living related transplantation so as not to prolong the use of chemotherapy while waiting for an appropriate organ.

It is likely that a greatly increased understanding of the molecular and cellular mechanisms underlying fibrosis will be required to overcome the hurdles necessary to create effective and safe therapies for cirrhosis impotence erectile dysfunction dapoxetine 90mg free shipping. Activation of mouse natural killer T cells accelerates liver regeneration after partial hepatectomy erectile dysfunction exam video order 90 mg dapoxetine with mastercard. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration top erectile dysfunction doctor buy dapoxetine overnight delivery. The same questions can be applied to cirrhosis; a large majority of patients with chronic liver disease never develop cirrhosis erectile dysfunction forums order 90mg dapoxetine. Indeed erectile dysfunction and diabetes leaflet buy dapoxetine line, the host response to injury is likely as important or even more important than the inciting agent or disease erectile dysfunction doctors in brooklyn purchase 90 mg dapoxetine with amex. At a minimum, an improved ability to assess prognosis would enhance the management of patients with acute and chronic liver disease. For example, new forms of therapy might focus on modifying the early inflammatory events, interrupting apoptotic- and growth-inhibitory pathways, and providing temporary liver support to allow time for hepatic regeneration and repair. However, as noted earlier, specifically inhibiting apoptosis may be problematic in that this may redirect cells toward the generally more destructive necrotic cell death pathway and also potentially promote cancer. Because some of the same molecular pathways critical in liver regeneration are 3 Molecular and cellular Basis of liver failure 20. Relationships between deficits in tissue mass and transcriptional programs after partial hepatectomy in mice. Hypertrophy and unconventional cell division of hepatocytes underlie liver regeneration. Gene expression during the priming phase of liver regeneration after partial hepatectomy in mice. Loss of c-Met disrupts gene expression program required for G2/M progression during liver regeneration in mice. Cyclophilin D deficiency protects against acetaminophen-induced oxidant stress and liver injury. Mechanisms of hepatocyte injury, multiorgan failure, and prognostic criteria in acute liver failure. Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries. Platelet-derived growth factor isoform expression in carbon tetrachloride-induced chronic liver injury. New insights into the anti-fibrotic effects of sorafenib on hepatic stellate cells and liver fibrosis. Myosin mediates contractile force generation by hepatic stellate cells in response to endothelin-1. The great success of liver transplantation has produced a ripple effect on many other medical and scientific disciplines and, in particular, on general and hepatobiliary surgery. The anatomical principles, technical refinements, and basic scientific underpinnings of liver transplantation have immediate relevance to the work of surgeons with interests in nontransplant hepatobiliary surgery, trauma surgery, surgical critical care, and surgical education. The addition of transplantation as a therapeutic option for patients who were previously considered at high risk for standard surgical therapy, such as patients with potentially resectable hepatic malignancies in the setting of cirrhosis, has changed management algorithms and enabled more aggressive resections. This chapter examines the effects of the liver transplantation experience on modern liver surgery. This delicate homeostasis is further balanced by the remarkable capacity of the liver to expand hepatocyte mass rapidly in response to changing metabolic demands or significant hepatic injury. Simultaneous advances in critical care, perioperative management, pharmacology, and oncology have paralleled the advances in liver transplantation over the last 5 decades, stimulating a rapid growth of research in hepatic regeneration, ischemiareperfusion injury, and acute liver failure. The discovery that early activation of the cytokines interleukin-6 and tumor necrosis factor- serves to trigger the regenerative response has been further explored. The generation of genetically modified mice with alterations in the expression levels of growth factors, cytokines, and their receptors and the use of these mice in liver regeneration studies have provided some exciting results, including characterization of synergistic functions of transforming growth factor- and activin, the role of insulin-like growth factors and the insulin system in liver regeneration, and the contribution of hepatocyte growth factor. Finally, growing evidence suggests that the same cytokinedependent activation processes that drive hepatic regeneration are also responsible for the physiological and histological changes typically seen in posttransplant ischemia-reperfusion injury. It may offer a better understanding of the phenomenon of small-for-size syndrome, characterized by prolonged cholestasis and graft dysfunction after partial and living donor liver grafts. Dotted lines indicate that the variant artery may be accessory (if branch shown by dotted line is present) or replaced (if absent). Arterial variants have long been recognized,11 and portal venous and biliary anomalies are also recognized with growing frequency. Portal vein trifurcation or an aberrant branch from the left portal vein supplying the right anterior lobe was the most frequent anomaly Table 4-2). The high incidence of biliary complications after split and living donor liver transplantation has led to a greater interest in the common variants of biliary anatomy Table 4-3). The right triangular ligament has been divided, the liver is elevated upward and to the left, and the suprahepatic and infrahepatic venae cavae are surrounded with tapes. The approach in which total exposure of the upper abdomen is gained via a transverse upper abdominal incision, with selective use of a sternal extension, has largely eliminated the highly morbid right thoracotomy as a component of elective liver surgery. Liver Trauma the liver and spleen are the solid viscera most commonly injured in major abdominal trauma. The increasing experience with split and living donor liver transplantation and the wider application of surgical treatment for hepatic malignancies obligate familiarity with these anatomical variations, which will provide challenges in complex reconstructions. Recognition of the anatomy of the dual hepatic blood supply and dependence of hepatocellular carcinoma on the arterial supply has enabled transcatheter techniques to direct chemotherapy, radioactivity, and embolization material via the hepatic artery to treat these tumors. Liver Resection Over the past 30 years, developments in liver resection and liver transplantation have been intertwined. As an example, the surgical treatment of isolated caudate lobe lesions, once considered extremely hazardous, is now easily accomplished using methods of caval preservation (the piggyback technique) and generous exposure gained by dividing the gastrohepatic ligament. Although early experience relied almost exclusively on drainage through a Roux-en-Y choledochojejunostomy,51 later studies showed that preservation of the delicate blood supply to the bile duct would allow reconstruction using a duct-to-duct anastomosis. The blood supply was found to arise from the right hepatic and cystic arteries above and the retroduodenal branch of the gastroduodenal artery below. Currently the preferred reconstruction is by choledochocholedochostomy when the recipient common bile duct is available, reserving the more difficult and timeconsuming Roux-en-Y choledochojejunostomy for a donor-recipient size mismatch or an inadequate recipient bile duct. Considerable experience in bile duct reconstruction has grown from the living donor liver transplantation, in which multiple small-caliber ducts are frequently encountered. Biliary complications include leaks, strictures, and problems with the Roux-en-Y limb. These include nuclide cholescintigraphy and magnetic resonance cholangiography to demonstrate routes of bile flow and invasive procedures such as percutaneous transhepatic cholangiography, endoscopic retrograde cholangiography, stricture dilation, and stent placement for definitive therapy of specific complications. Liver transplantation encompasses crucial anatomical and technical lessons for the general surgeon, represents an important component of surgical training in the era of minimally invasive surgery, and has provided a profound stimulus to technical and scientific innovation in the surgery of liver disease. This fertile interaction among related surgical disciplines should not be overlooked when the benefits of the procedure are tallied. Pearls and Pitfalls · Similar cytokine-dependent activation processes drive the physiological and histological changes in hepatic regeneration and ischemia-reperfusion injury. This places training of open biliary and upper gastrointestinal surgery in jeopardy. The concept of a hepatobiliary service that performs advanced procedures-including liver resection, complex biliary reconstruction, and liver transplantation-is important to surgical training, affords the trainees a concentrated exposure to open biliary surgery, and provides a balance and a foundation to the laparoscopic methods. Aspects of a transplant service, especially performing the organ procurement operation on brain-dead donors and preparing the liver graft on the back bench, expose trainees to this privileged and delicate anatomical area in a more relaxed and less stringent setting, thus allowing for teaching, exploration, and demonstration of anatomical relationships and surgical techniques. Prediction of poor outcome in patients with acute liver failure-systematic review of prediction models. Clinical implications of advances in the basic science of liver repair and regeneration. What is critical for liver surgery and partial liver transplantation: size or quality? Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages. Largely because of the innovations derived from the liver transplant experience, the face of liver surgery has 4 11. The hepatic, cystic and retroduodenal arteries and their relations to the biliary ducts with samples of the entire celiacal blood supply. Anatomical variations and surgical strategies in right lobe living donor liver transplantation: lessons from 120 cases. Portal vein normal anatomy and variants: implication for liver surgery and portal vein embolization. Total vascular isolation and in situ cold perfusion for management of severe liver trauma. Management of severe hepatic trauma by two-stage total hepatectomy and subsequent liver transplantation. Venovenous bypass and hepatic vascular isolation as adjuncts in the repair of destructive wounds to the retrohepatic inferior vena cava. Benefits of liver transplantation surgical techniques in the management of extensive retroperitoneal tumors. Intermittent hepatic vein­total vascular exclusion during liver resection: anatomic and clinical studies. Continuous versus intermittent portal triad clamping for liver resection: a controlled study. A prospective, randomized, controlled trial comparing intermittent portal triad clamping versus ischemic preconditioning with continuous clamping for major liver resection. Randomized clinical trial of ischaemic preconditioning in major liver resection with intermittent Pringle manoeuvre. In situ and ex situ in vivo procedures for complex major liver resections requiring prolonged hepatic vascular exclusion in normal and diseased livers. Techniques for liver parenchymal transection: a meta-analysis of randomized controlled trials. Technical aspects of biliary reconstruction in adult living donor liver transplantation. Biliary anatomy as applied to pediatric living donor and split-liver transplantation. Stratifying risk of biliary complications in adult living donor liver transplantation by magnetic resonance cholangiography. Donors were usually identified from within a transplant center, and the organs obtained were transplanted into a patient from that center. Occasionally media sources were used successfully to help obtain an organ for an individual recipient. At the same time the Ad Hoc Committee of the Harvard Medical School published their criteria for defining brain death. Brain death was legally recognized with the passage of the Uniform Brain Death Act in 19786 and the Uniform Determination of Death Act in 1980. Organs were 64 offered mainly using recipient waiting time, with little importance given to recipient need or illness. In fact, much of the preceding policy was developed in the context of kidney transplantation, with the rules later applied to liver transplantation. Before 1997, livers were allocated based on a point system composed of waiting time and patient location (intensive care, hospitalized, ambulatory). Within the different status categories, waiting time was still the most important determinant of ranking. There was concern that the system could be "gamed," and there continued to be a vast regional disparity in waiting times and severity of illness at the time of transplant. Following a report issued by the Institute of Medicine,13 the Final Rule was amended in 1999 and set forth several performance goals. These included "more accessible, equitable and efficient allocation of organs," setting "minimal suitability criteria for transplant candidates," and "distribution of organs over as broad a geographical range as possible. Any allocation scheme must take several ethical principles into careful consideration. For example, directing the next available liver to the sickest candidate is just, as is giving equal access to organs to people of different ages or racial backgrounds, even though outcomes may vary. Second is the principle of utility, which addresses the greater benefit of an intervention or the needs of society as a whole. For example, a utilitarian approach would favor allocating organs to those with the best chance of survival. For example, patients have the right to refuse an organ, and donors have the right to direct an organ to a specific individual. Finally, the principles of benevolence (doing good) and nonmalfeasance (doing no harm) are as applicable to organ allocation as they are to other human endeavors, such as research involving human subjects. Using only the principle of justice, one could argue that everyone should be transplanted, regardless of how sick they were or how poor the predicted outcome. A totally utilitarian approach, such as only transplanting candidates with the best outcomes, would also not be considered fair. Should we not offer livers to retransplant candidates because they do worse than primary transplants? Individual autonomy must be respected, but we do not allow people to actively harm themselves, nor would we allow people to choose what race or gender should receive their organs. These ethical principles are at the core of the current liver allocation system in the United States. This reflects a purposeful advantaging of the pediatric population to compensate for infrequency of suitably sized and age-appropriate organs. The United States is divided into distribution units for the purpose of liver allocation. If there are no local candidates with a score of 35 or higher, the liver must first be offered regionally.

In contrast erectile dysfunction statistics age order dapoxetine without prescription, invasive cancers are often seen in women aged 50 to 70 years erectile dysfunction doctors in richmond va order dapoxetine discount, and they spread rapidly erectile dysfunction medications cost dapoxetine 60mg low cost. Each tumour type has a histologic pattern similar to a part of the upper genital tract erectile dysfunction of organic origin purchase generic dapoxetine on-line. As much as 50% of benign serous epithelial tumours undergo secondary malignant change erectile dysfunction of diabetes order dapoxetine discount, but only 5% mucinous cysts undergo malignant transformation erectile dysfunction fertility treatment order generic dapoxetine line. They tend to remain confined to the ovaries for long and predominantly occur in the pre-menopausal age groups (30­50 years). They are associated with a good n Epithelial proliferation with papillary formations and pseudostratification. Only serous and mucinous epithelial tumours fall into this group of borderline ovarian tumours. Nonepithelial Malignancies of the Ovary Non-epithelial malignancies of the ovary account for 10­ 20% of all malignancies of the ovary. The details of these types are as follows: Germ cell malignancies are derived from the primordial germ cells of the ovary. This explains why the tumour is rich in alphafetoproteins and alpha-l-antitrypsin. Histologically, the tumour characteristically presents with papillary projections composed of a central core of blood vessels enveloped by immature epithelium. Most of these patients are children or young women, presenting with abdominal pain and a pelvic mass. Although considered to be highly malignant, they respond to chemotherapy with good survival rate. Choriocarcinoma Rarely seen in a pure form, generally choriocarcinoma is a part of a mixed germ cell tumour. Its origin as a teratoma can be confirmed in prepubertal girls, when the possibility of its gestational origin can be definitely excluded. Histologically, the tumour shows a dimorphic population of syncytiotrophoblasts and cytotrophoblasts. The tumour is highly malignant, and metastasizes by blood stream to the lungs, brain, bones and other viscera. Embryonal Cell Carcinoma Embryonal cell carcinoma is a rare tumour accounting for about 5% of all germ cell tumours, and occurs in prepubertal girls. It is associated with the symptoms of precocious puberty and menstrual irregularities. The condition may be associated with fever due to torsion, rupture and haemorrhage. Although 20­25% of all ovarian neoplasms are germ cell tumours, only 3­5% of these are malignant. The incidence of malignant germ cell tumours is lower in Caucasian whites, but threefold higher in Asians and AfroAmericans. Dysgerminoma and pure germinomas do not secrete these markers, but secrete lactose dehydrogenase. Dysgerminomas are highly radiosensitive (although, radiotherapy leads to future infertility). They also respond well to chemotherapy without interfering with future fertility and therefore chemotherapy is preferred. They may also occur in late carcinoma of the breast, as seen in 30% of all autopsy material from breast cancer. Carcinomas of the corpus (10%) and cervix (1%) also metastasize to the ovary owing to the close relationship of their lymphatic drainage. Carcinoma of the corpus is 10 times more likely to metastasize to the ovary than the cervix. The reason for this is that the ovarian lymphatics drain the corpus directly whereas the cervical metastases tend to bypass the ovarian lymphatics and travel by way of the hypogastric and aortic glands. About 20% of clinically malignant ovarian tumours are secondary deposits from primary growths elsewhere. Dissemination to the ovaries takes place either by implantation from metastases within the peritoneal cavity or by retrograde lymphatic spread. Both ovaries are replaced by solid carcinomas and multiple secondary deposits are usually disseminated over the peritoneum. A curious feature is that the ovarian tumours are much larger than the other secondary deposits, which is explained by assuming that the ovaries offer a much better environment for the growth of malignant cells than the other intraperitoneal viscera. Ascites is common and other obvious peritoneal metastases are present, notably in the omentum which is often replaced by an enormous solid malignant plaque. The method of ovarian infiltration is either by surface implantation or by retrograde lymphatic permeation. Both methods are probably operative and histological examination is rarely able to reveal the route through which the metastases occurred. Endometrial hyperplasia occurs in 25­50% of patients, and endometrial carcinoma occurs in about 5% of cases. Theca cell tumour is more oestrogenic and more likely to cause endometrial cancer. Androblastomas or Arrhenoblastomas (Sertoli­Leydig Cell Tumours) Androblastomas or arrhenoblastomas occur commonly in the third and fourth decades of life. The women experience oligomenorrhoea followed by amenorrhoea, flattening of the breasts, acne, hirsutism, enlargement of the clitoris and finally a change in voice. The chief representative types in this subgroup are lipid or lipoid cell tumour, sarcoma of the ovary and chorioepithelioma. The lipid cell variety arises from the adrenal cortical cell rests that reside in the vicinity of the ovary. They may be associated with virilization, obesity, hypertension and glucose intolerance. Krukenberg Tumour this type of tumour should be diagnosed only if it conforms to the following pattern. There is no tendency to form adhesions with neighbouring viscera and there is no infiltration through the capsule. The tumour retains the shape of the normal ovary and has a peculiar solid waxy consistency although cystic spaces due to degeneration of the growth are common. Histologically, the tumour has a cellular or myxomatous stroma amongst which are scattered large signet-ring cells. The tumours are secondary growth in the ovary and most often arise from a primary carcinoma of the stomach (70%), large bowel (15%) and breast (6%). The Krukenberg tumour outstrips the primary growth in size, and unless the histology of the tumour is known, the case may be regarded as one of primary malignant ovarian carcinoma, particularly as the tumours are usually freely movable Sarcoma Ovarian sarcomas are rare. Many tumours labelled as sarcomas have been misdiagnosed histologically and are in reality, granulosa cell tumours or anaplastic carcinomas. Metastatic Carcinomas Ovarian metastases are commonly from the primary growth in the gastrointestinal tract, notably the pylorus, colon and, Chapter 40 · Ovarian Cancer 525 carcinoma of the body of the uterus. Any postmenopausal bleeding associated with an ovarian tumour should suggest the possibility of a coincident endometrial carcinoma, and this possibility always demands the removal of the uterus as well as the ovarian tumours. Metastases in the Uterus Advanced carcinoma of the ovaries becomes adherent to the surrounding structures so that the uterus is directly infiltrated by the growth. The peritoneal surface of the uterus is also infiltrated in some cases by carcinoma cells disseminated over the peritoneum. In rare cases, metastases form in the endometrium of the uterus as the result of carcinoma cells passing along the fallopian tube into the cavity of the uterus. In some cases of carcinoma of the ovaries, secondary deposits are formed in the vaginal walls, and such metastases correspond to those found in cases of chorioepithelioma and of carcinoma of the body of the uterus, when metastases form by retrograde lymphatic spread. Direct spread of the tumours occurs in the pouch of Douglas, paracolic gutter, sub-diaphragm on the right side, liver and peritoneal lining. The tumour has a solid waxy appearance with an intact capsule free of all adhesions. Metastases in Operation Scars It is not uncommon after the removal of malignant ovarian tumours for metastases to form in the operation scar and to spread to the adjacent skin. Spread by Way of Blood Stream It is rare for carcinoma of the ovaries to spread by way of the blood stream, but with very malignant tumours, metastases may be disseminated in this way. It is therefore important to obtain chest radiograph in all cases with malignant ovarian tumours. The tumours almost certainly arise by retrograde lymphatic spread; the carcinoma cells pass from the stomach to the superior gastric lymphatic glands which also receive the lymphatics from the ovary. Retrograde lymphatic spread can be demonstrated in early cases when carcinoma cells are found infiltrating the ovary by way of the lymphatics in the medulla. The regional lymphatic glands of the ovaries are the paraaortic and the superior gastric which are impalpable clinically. Sometimes, the malignant cells permeate to the mediastinal glands when they may ulcerate into the pleural cavity and cause pleural effusion. Sometimes, secondary deposits may be found above the left clavicle in the posterior triangle of the neck, where they have arrived via the main lymphatic ducts in the mediastinum. Once the peritoneum is involved, pelvic lymph nodes will be infiltrated with metastases. Bilateral Character of Ovarian Tumours Seventy per cent of primary ovarian cancers are bilateral, whereas nearly all secondary growths are bilateral. Even with malignant ovarian tumours, the two ovaries are attacked simultaneously by the disease and the involvement of one by secondary deposits from the other is exceptional. With secondary ovarian carcinomas, if the involvement is by retrograde lymphatic spread, one would expect both ovaries to be involved simultaneously. Similar remarks apply when implantation of carcinoma cells is the cause of development of secondary deposits in the ovaries. Coincident Carcinoma of the Ovaries and the Body of the Uterus Cases of coincident carcinoma of the ovaries and the body of the uterus are known. In some cases, the growth is primary in the body of the uterus and forms secondary deposits in the ovaries. In other cases, the primary growth is in the ovaries and secondary deposits reach the cavity of the uterus either by lymphatic permeation or by implantation via the fallopian tube. The secondary deposits of carcinoma of the ovaries rarely involve the liver, because the ovarian vessels belong to the systemic system and not to the portal system like those of the intestine and stomach. A woman with a malignant ovarian tumour is either an adolescent or of menopausal or postmenopausal age of low parity. Abdominal discomfort and pain, abnormal or postmenopausal bleeding and an abdominal lump are the characteristic features. Weight loss, cachexia and anaemia are the symptoms and signs of advanced stage of cancer. The malignant ovarian tumours are often bilateral, solid and present with ascites. The tumours are often fixed in the late stage and intraperitoneal metastasis may be palpable abdominally. The vaginal examination may reveal fixed nodules in the pouch of Douglas, apart from adnexal masses felt separate from the uterus. Unilateral nonpitting oedema of the leg, pleural effusion and enlarged liver are suggestive of advanced stage of the disease. A palpable ovary in a menopausal woman is likely to be malignant and should be investigated. Tissue markers mentioned earlier suggest the histological nature of the tumour, as well as decide the duration of postoperative chemotherapy or need for radiotherapy. Ultrasound shows a solid tumour with echogenic or cystic areas, a thick capsule with papillary projectors and a thick septum measuring more than 5 mm in a malignant tumour. An endometrial lining more than 4 mm in thickness with papillary projections in a perimenopausal woman is seen in a feminizing tumour and if endometrial secondaries are present. Doppler ultrasound showing low pulsatile index less than 1 and resistance index less than 0. Chapter 40 · Ovarian Cancer In a benign tumour, blood flow and vascularity is from the periphery to the centre. The tissue markers are useful during chemotherapy to decide the response and the duration of therapy in postoperative follow-up. Since debulking surgery is undertaken even in advanced stages, diagnostic laparoscopy has lost its importance. The incidence of recurrence is therefore less and disease-free interval prolonged. Instead, lately, imprint cytology of the specimen gives 90% sensitivity and 80% specificity, takes 20 min, is simple and less expensive. No postoperative chemotherapy is required, but follow-up is mandatory in young women. Postoperative chemotherapy and radiotherapy improve the survival and quality of life. The purpose of maximal debulking surgery is to reduce the amount of malignant tissue to be subjected to chemotherapy and relieve the woman of her symptoms. The response to chemotherapy improves with smaller residual tissue and thus remission period and survival is enhanced. Postoperative chemotherapy and radiotherapy depend upon the staging and the type of tumour. Interval Surgery Some advanced and bulky tumours are initially treated by chemotherapy for three cycles. This is followed by debulking surgery and postoperative chemotherapy as dictated by tissue marker. The disadvantages of laparoscopy are as follows: n n Management Laparotomy and maximal reduction is the primary and gold standard treatment in all ovarian malignant tumours. Surgical staging is followed by definitive surgery or debulking followed by chemotherapy or radiotherapy. Surgical staging involves systemic exploration of the undersurface of the diaphragm, liver, stomach, bowel and omentum. Ascitic fluid or peritoneal wash should be collected in heparinized bottles for cytology.

Dapoxetine 60 mg sale. ED REVERSER - Erectile Dysfunction Reverse System A ED PERMANENT CURE.

Other causes of infertility and abortions should be ruled out before myomectomy is undertaken erectile dysfunction after prostate surgery purchase dapoxetine 30mg on-line. A fibroid more than 12 weeks size and a pedunculated fibroid which can cause torsion erectile dysfunction medications injection cheap 60mg dapoxetine overnight delivery. An asymptomatic fibroid causing pressure on the ureter erectile dysfunction exercise video cheap 30mg dapoxetine, that is broad ligament fibroid and pressure on the bladder erectile dysfunction diet pills purchase dapoxetine 90mg mastercard, leaving residual urine and causing urinary infection erectile dysfunction bipolar medication discount dapoxetine 60mg line. Rapidly growing fibromyoma in a menopausal woman implying impending malignancy and requiring surgery erectile dysfunction treatment patanjali dapoxetine 90 mg sale. When the nature of the tumour cannot be ascertained clinically (laparotomy is needed in this occasion). The purpose of medical therapy is to control menorrhagia and improve haemoglobin before surgery or to shrink the fibroid, prior to surgery. In older women, successful medical therapy will allow women to reach menopause when the fibroid will shrink and cease to be a problem. However development of hirsutism and other side effects, as well as the cost, preclude its routine use. Asoprisnil, selective progesterone receptor modulator is better than mifepristone. This treatment in premenopausal women, young women with infertility caused by cornual fibroids eliminates the need for surgery. It is also useful in reducing vascularity besides size, preoperatively, and by causing amenorrhoea or reducing menorrhagia, restores the haemoglobin level. Shrinkage of the fibroid allows Pfannenstiel incision in abdominal operation, minimal invasive surgery or a vaginal hysterectomy instead of an abdominal hysterectomy and also reduces bleeding. They inhibit conversion of androgens to oestrogen in the ovaries and in peripheral fat, and shrink the fibroid by 50%. Surgery the techniques used are conventional myomectomy and hysterectomy, by laparotomy or laparoscopically. It is indicated in an infertile woman or a woman desirous of childbearing and wishing to retain the uterus. Myomectomy should be performed in the preovulatory menstrual cycle to reduce blood loss during surgery. Care should be taken not to injure the bladder while incising the parietal peritoneum, as the bladder may be elevated in cervical and low-lying anterior wall fibroids. The pelvic organs should be carefully inspected and the feasibility of myomectomy confirmed. An incision over the anterior uterine wall is preferred whenever possible and as many fibroids removed through minimal tunnelling incisions. The clamp should be applied from the pubic end of the abdominal wound and the round ligaments which will include the uterine vessels should be gripped. If the myomectomy clamp cannot be applied as in cervical fibroids, a rubber tourniquet will serve the purpose. The raw visceral area should be well-peritonized to prevent postoperative adhesions. The uterus remains bulky following myomectomy and requires to be anteverted by plicating the round ligaments with nonabsorbable sutures. Pregnancy rate of 40­50% has been reported following myomectomy and pregnancy loss reduced. Recurrence of fibroids in 5­10% cases is due to overlooking seedling fibroids at the time of surgery. Vaginal myomectomy is possible in cervical fibroids and pedunculated fibroid polypus and if more than 50% submucous fibroids project into the cavity. Hysteroscopic myomectomy has become possible for submucous fibroids not removable by the simple vaginal route. Myolysis, a technique of destruction of myoma tissue by laser or cautery, is a sophisticated technology practised by endoscopists. Unipolar, bipolar cautery and laser have been employed to remove the fibroma and obtain haemostasis. The fibroma is retrieved through posterior colpotomy, minilaparotomy or by Laparoscopic myomectomy is made easier and faster by newer instruments, morcellator, newer energy sources and newer suture materials. The bleeding is controlled by infiltration of myoma with vasoconstrictors and bilateral uterine artery ligation prior to myomectomy. A single portal laparoscopic surgery is a new innovative technique developed recently. Although a minimal invasive surgery, and without an abdominal scar, laparoscopic myomectomy can cause more bleeding because of nonapplicability of a haemostatic clamp and being an adhesiogenic procedure, takes longer to perform. Some use intercede (oxidized regenerated cellulose) to prevent or reduce adhesions. The major complication is rupture of the myomectomy scar during pregnancy or labour due to imperfect or inadequate suturing of the myomectomy wound. Menorrhagia was relieved in 80­90%, pressure symptoms in 40­70%, the volume decreased by 50% at the end of 3 months by 60% at 6 months and 75% at the end of 1 year. Infertility rate may increase following this technique because of postembolization pelvic adhesions. Associated inflammatory disease may also preclude the employment of this technique. Ischaemic pain suggests successful therapy, but can be unbearable and requires analgesia. Ovarian failure following accidental ovarian vessel blockage and premature menopause (up to 30%). Failure due to inadequate embolization caused by arterial spasm or tortuosity of the vessels. Extrusion of a subserous fibroid into the peritoneal cavity which requires retrieval. Skin burn Pain Nerve damage (rare) Advantages Noninvasive technique Local anaesthesia-takes 1 to 2 h to do No hospitalization No scar Quick recovery Fertility preservation technique Contraindications 1. Hysterectomy, the removal of the uterus, is indicated in a woman over 40 years of age, multiparous woman or when associated with malignancy. Uncontrolled haemorrhage and unforeseen surgical difficulties during myomectomy may also necessitate hysterectomy. However, subtotal hysterectomy may be performed in the presence of the proper selection of patients is key to clinical success and avoiding complications. The follow-up with ultrasound 6 months later is also necessary to observe the shrinkage of the fibroid and register success or failure of this treatment. Placenta accreta to reduce bleeding prior to placental removal, or caesarean delivery. Laparoscopic localized uterine artery occlusion using clips or electrodessication is being tried. This is a noninvasive technique and uses high-intensity focused ultrasound beam that heats and destroys the fibrous tissue. The ovaries may be conserved in a woman less than 50 years provided they are healthy. Advantages of subtotal hysterectomy are: n previous laparoscopy to confirm the absence of pelvic adhesions, size of the uterus and rule out pelvic pathology. In a difficult surgery, total hysterectomy may increase the surgical morbidity due to trauma to the bladder and denervation, causing difficult micturition and incontinence. This avoids an abdominal scar, minimizes pain, and shortens the recovery period and hospital stay. In benign conditions, the ovaries should be retained to avoid menopausal symptoms in a premenopausal woman provided they look normal. Atrophy of the ovaries has been reported due to kinking of the ovarian vessels, within 3­4 years of hysterectomy; they become nonfunctional and cause early menopause. However, in case of a cervical low anterior and posterior fibroid, and one encroaching into the broad ligament, the bladder, ureter and rectum are displaced from their normal anatomical position and are at risk of injury. In a cervical and huge anterior wall fibroid when the tumour overhangs the vaginal vault and is close to the bladder, it is prudent to perform myomectomy first. This allows a clear view of the vaginal vault and safeguards against bladder injury. Similarly, in a low posterior fibroid, the upper portion of the broad ligament may not be accessible until the fibroid is first enucleated. In a central cervical fibroid, and a huge posterior fibroid, hemi-section of the uterus and enucleation of the fibroid will allow safe hysterectomy. Postoperative infection such as wound infection, peritonitis, pelvic infection and embolism-chronic pelvic pain. Residual ovarian syndrome and atrophy of the ovaries due to decreased vascularity causing premature menopause in 2­3 years. Oral hormonal contraceptives should not be offered to her because the fibroid may grow in size under the hormonal influence. Emergency laparotomy is required in torsion of a fibroid and subcapsular haemorrhage. Rather similar tumours sometimes develop in the body of the uterus in old women, and in this way, three types of mixed tumours, namely the vaginal tumours of children, the grape-like sarcoma of the cervix, and the mixed tumours of the body of the uterus of old women can be distinguished. Cervical Fibroid this requires myomectomy or hysterectomy, usually, by bisecting the uterus, enucleating the fibroid and then following up with hysterectomy as required. Red degeneration is a result of softening of the surrounding supportive connective tissue. The capillaries tend to rupture and blood effuses out into the myoma causing a diffuse reddish discolouration of the same. There is an opinion stating that release of a biochemical haemolysin-like substance is responsible for the diffuse blood staining of the fibromyomatous tissues. Such a patient complains of severe pain in the abdomen and may present as an emergency admission for acute abdomen pain; examination reveals the pain to be restricted to the uterus at the site of the fibroid, and all other parameters remain stable. Such a patient is treated conservatively with bed rest and analgesics until the pain subsides. On rare occasions, when laparotomy is carried out, the myoma is seen to be dusky in appearance; its cut section has an appearance of cooked meat and is known to emit a fishy odour. Fibroids by their sheer size may cause respiratory embarrassment, retention of urine or obstructed labour. However, depending on their size and location, they may contribute to menstrual irregularities, dysmenorrhoea, infertility, pain in the abdomen, abdominal fullness, pressure symptoms and complications during pregnancy. Ultrasonography, laparoscopy and hysteroscopy help in establishing the diagnosis of uterine fibromyomas. Myomectomy is indicated in younger women desirous of retaining the childbearing function, whereas in elderly women, hysterectomy is the procedure of choice. They are adjuvants to surgery when a huge fibroid or multiple fibroids are encountered. Laparoscopy, hysteroscopy and arterial embolization provide minimal invasive surgery and have reduced the number of abdominal surgery in women with uterine fibroids. Laparoscopic myomectomy and uterine artery embolization are not recommended in women with infertility, because of pelvic adhesions and risk of scar rupture during pregnancy or in labour. Sengupta, Chattopadhyay, Varma: Textbook of Gynaecology for Postgraduates and Practitioners. Endometriosis is one of the most mysterious and fascinating benign gynaecological disorders. By definition, endometriosis is the occurrence of ectopic benign endometrial tissues outside the cavity of the uterus. These islands of endometriosis are composed of endometrial glands surrounded by endometrial stroma, and are capable of responding to a varying degree to cyclical hormonal stimulation. The disease owns a unique pathology of a benign proliferative growth process yet having the propensity to invade the normal surrounding tissues. The incidence is about 10%, but awareness of more cases is increasing on account of diagnostic laparoscopy. Characteristics of endometriosis n changing social patterns like late marriage and limitation of family size. It tends to occur more amongst the affluent class, and is frequently associated with infertility. Several theories have been propounded to explain endometriosis; chief among these are the following. Sampson observed that in cases of uncomplicated endometriosis, the fallopian tubes were usually patent. Several workers then questioned the viability of desquamated endometrium and its capacity to implant and grow. The occurrence of scar endometriosis following classical caesarean section, hysterotomy, myomectomy and episiotomy further supports this view. Lately, it has been suggested that hypotonia of the uterotubal junction influences the quantity of retrograde spill and occurrence of pelvic endometriosis. While proliferative endometrium is always seen, secretory endometrium depends upon the presence of progesterone receptors in the tissues. Blood oozing during menstruation in ectopic endometrium causes local adhesions in the pelvis. Aetiology Endometriosis is a proliferative hormonal dependent disease of the childbearing period. Its incidence appears to be on the increase, partly due to improvement in diagnostic techniques and partly due to Coelomic Metaplasia Theory Meyer and Ivanoff (1919) propounded that endometriosis arises as a result of metaplastic changes in embryonic cell rests of embryonic mesothelium, which are capable of responding to hormonal stimulation. Embryologically, Mьllerian ducts arise from these same tissues, hence such a transformation in later life seems plausible. Endometrial tissue has been retrieved in pelvic lymphatics in 20% women with endometriosis. Metastatic- lungs, umbilicus, scar endometriosis Hormonal Influence Whatever the initial genesis of endometriosis, its further development depends on the presence of hormones, mainly oestrogen.

Both metabolites have signifi antly less local anesthetic potency than ropivacaine erectile dysfunction medicine from dabur buy dapoxetine no prescription. However, in uremic patients, 2,6-pipecoloxylidide may accumulate and produce toxic effects erectile dysfunction funny images purchase dapoxetine 30mg on-line. The lipid solubility of ropivacaine is intermediate between lidocaine and bupivacaine erectile dysfunction heart discount dapoxetine 90 mg without a prescription. Dibucaine Dibucaine is a quinoline derivative with an amide bond in the connecting hydrocarbon chain erectile dysfunction for young males 90mg dapoxetine with visa. This local anesthetic is metabolized in the liver and is the most slowly eliminated of all the amide derivatives erectile dysfunction for young men order dapoxetine 30 mg without a prescription. Dibucaine is better known for its ability to inhibit the activity of normal butyrylcholinesterase (plasma cholinesterase) by more than 70%, compared with only approximately 20% inhibition of the activity of atypical enzyme impotence erecaid system esteem battery operated vacuum impotence device order 90mg dapoxetine with mastercard. Atypical plasma cholinesterases account for prolonged effects and toxicity of drugs such as succinylcholine and chloroprocaine that are metabolized by this enzyme. Laboratory evaluation of patients suspected of having atypical pseudocholinesterase is facilitated by measurement of the degree of enzyme suppression by dibucaine, a t est termed the dibucaine number. The exception to hydrolysis of ester local anesthetics in the plasma is cocaine, which undergoes significant metabolism in the liver. Systemic toxicity is inversely proportional to the rate of hydrolysis; thus, tetracaine is more likely than chloroprocaine to result in excessive plasma concentrations. Plasma cholinesterase activity and the hydrolysis rate of ester local anesthetics are slowed in the presence of liver disease or an increased blood urea nitrogen concentration. Plasma cholinesterase activity may be decreased in parturients and in patients being treated with certain chemotherapeutic drugs. Procaine Procaine is hydrolyzed to paraaminobenzoic acid, which is excreted unchanged in urine, and to diethylaminoethanol, which is further metabolized because only 30% is recovered in urine. Increased plasma concentrations of paraaminobenzoic acid do not produce symptoms of systemic toxicity. Chloroprocaine Addition of a chlorine atom to the benzene ring of procaine to form chloroprocaine increases by 3. Resulting pharmacologically inactive metabolites of chloroprocaine are 2-chloro-aminobenzoic acid and 2-diethylaminoethanol. Maternal and neonatal plasma cholinesterase activity may be decreased up to 40% a t term, but minimal placental passage of chloroprocaine confirms that even this decreased activity is adequate to hydrolyze most of the chloroprocaine that is absorbed from the maternal epidural space. As such, benzocaine is ideally suited for topical anesthesia of mucous membranes prior to tracheal intubation, endoscopy, transesophageal echocardiography, and bronchoscopy. The rate of hydrolysis varies, with chloroprocaine being most rapid, procaine being intermediate, and tetracaine being the slowest. Systemic absorption of topical benzocaine is enhanced by defects in the skin and mucosa as well as from the gastrointestinal tract should any of the local anesthetic be swallowed. The product Cetacaine is marketed as a combination of 14% benzocaine, 2% tetracaine, and 2% butamben in a topical applicator that acts as an atomizer. Methemoglobinemia is a rare but potentially life-threatening complication following topical application of benzocaine, especially when the dose exceeds 200 to 300 mg (see the section "Methemoglobinemia"). Cocaine Cocaine is metabolized by plasma and liver cholinesterases to water-soluble metabolites that are excreted in urine. Plasma cholinesterase activity is decreased in parturients, neonates, the elderly, and patients with severe underlying hepatic disease. Assays for the metabolites of cocaine in urine are useful markers of cocaine use or absorption (see the section "Cocaine Toxicity"). Nevertheless, placement of chloroprocaine in the epidural space may decrease the efficacy of subsequent epidural bupivacaine-induced analgesia during labor. For these reasons, adjustment of the pH of the chloroprocaine solution with the addition of 1 mL of 8. The pKa of local anesthetics used clinically is near 8, so that only a small fraction (about 3%) o f the local anesthetic exists in the lipid-soluble form. Alkalinization increases the percentage of local anesthetic existing in the lipid-soluble form that is available to diffuse across lipid cellular barriers. Adding sodium bicarbonate will speed the onset of peripheral nerve block and epidural block by 3 to 5 minutes. Use of Vasoconstrictors the duration of action of a local anesthetic is proportional to the time the drug is in contact with nerve fibers. For this reason, epinephrine (1:200,000 or 5 mg/mL) may be added to local anesthetic solutions to produce vasoconstriction, which limits systemic absorption and maintains the drug concentration in the vicinity of the nerve fibers to be anesthetized. Indeed, addition of epinephrine to a lidocaine or mepivacaine solution prolongs the duration of conduction blockade and decreases systemic absorption of local anesthetics by 20% to 30%. For example, the impact of epinephrine in prolonging the duration of conduction blockade and decreasing systemic absorption of bupivacaine and etidocaine is less than that observed with lidocaine, presumably because the greater lipid solubility of bupivacaine and etidocaine causes them to bind avidly to tissues. The duration of sensory anesthesia in Adjuvant Mixed with Local Anesthetics Dexmedetomidine has been used as an adjuvant in local anesthetic admixtures and a central effect is postulated for prolongation of the local anesthetic affect. Epinephrine added to a low dose of tetracaine (6 mg) increases the success rate of spinal anesthesia, whereas the success rate is not altered by epinephrine when the subarachnoid dose of tetracaine is 10 mg. Th a-adrenergic effects of epinephrine may be associated with some degree of analgesia that could contribute to the effects of the conduction blockade. The addition of epinephrine to local anesthetic solutions has little, if any, effect on the onset rate of local anesthesia. Decreased systemic absorption of local anesthetic due to vasoconstriction produced by epinephrine increases the likelihood that the rate of metabolism will match that of absorption, thus decreasing the possibility of systemic toxicity. Whenever local anesthetic solutions containing epinephrine are administered in the presence of inhaled anesthetics, the possibility of enhanced cardiac irritability should be considered. It is estimated that less than 1% of all adverse reactions to local anesthetics are due to an allergic mechanism. Esters of local anesthetics that produce metabolites related to paraaminobenzoic acid are more likely than amide local anesthetics, which are not metabolized to paraaminobenzoic acid, to evoke an allergic reaction. An allergic reaction after the use of a local anesthetic may be due to methylparaben or similar substances used as preservatives in commercial preparations of ester and amide local anesthetics. Cross-Sensitivity Cross-sensitivity between local anesthetics reflects the common metabolite paraaminobenzoic acid. A similar cross-sensitivity, however, does not exist between classes of local anesthetics. Likewise, an ester local anesthetic can be administered to a patient with a known allergy to an amide local anesthetic. Adverse Effects of Local Anesthetics the principal side effects related to the use of local anesthetics are allergic reactions and systemic toxicity due to excessive plasma and tissue concentrations of the local anesthetic. Conversely, hypotension associated with syncope or tachycardia when an epinephrine-containing local anesthetic solution is administered suggests an accidental intravascular injection of drug. Use of an intradermal test requires injection of preservative-free preparations of local anesthetic solutions to eliminate the possibility that the allergic reaction was caused by a substance other than the local anesthetic. Also in animal studies (dogs), at comparable dosages, bupivacaine and etidocaine cause severe arrhythmias without decreased myocardial contractility, whereas lidocaine caused the opposite, that is, depressed myocardial contractility without arrhythmia. Skeletal muscle twitching is often first evident in the face and extremities and signals the imminence of tonic-clonic seizures. Vivid fear of imminent death and a delusional belief of having died have been described in patients experiencing toxic reactions to local anesthetics administered for regional anesthesia and pain relief. The onset of seizures may refl ct selective depression of inhibitory cortical neurons by local anesthetics, leaving excitatory pathways unopposed. Plasma concentrations of local anesthetics are determined by the rate of drug entrance into the systemic circulation relative to their redistribution to inactive tissue sites and clearance by metabolism. Accidental direct intravascular injection of local anesthetic solutions during performance of peripheral nerve block anesthesia or epidural anesthesia is the most common mechanism for production of excess plasma concentrations of local anesthetics. For example, systemic absorption of local anesthetics is greatest after injection for an intercostal nerve bock, intermediate for epidural anesthesia, and least for a brachial plexus block. For this reason, it has been recommended that the plasma venous concentration of lidocaine be monitored when the cumulative epidural dose of lidocaine is. For example, accumulation of serotonin decreases the seizure threshold of lidocaine and prolongs the duration of seizure activity. There is an inverse relationship between the Paco 2 and seizure thresholds of local anesthetics, presumably refl cting variations in cerebral blood flow and resultant delivery of drugs to the brain. Increases in the serum potassium concentration can facilitate depolarization and thus markedly increase local anesthetic toxicity. Conversely, hypokalemia, by creating hyperpolarization, can greatly decrease local anesthetic toxicity. The threshold for neurotoxicity of lidocaine may be decreased when patients being treated with the antidysrhythmic drug mexiletine receive lidocaine during the perioperative period. For example, lidocaine in plasma concentrations of,5 mg/mL is devoid of adverse cardiac effects, producing only a decrease in the rate of spontaneous phase 4 d epolarization (automaticity). Nevertheless, plasma lidocaine concentrations of 5 t o 10 mg/mL, and equivalent plasma concentrations of other local anesthetics, may produce profound hypotension due to relaxation of arteriolar vascular smooth muscle and direct myocardial depression (see Table 10-2). As a result, hypotension reflects both decreased systemic vascular resistance and decreased cardiac output. Part of the cardiac toxicity that results from high plasma concentrations of local anesthetics occurs because these drugs also block cardiac sodium channels. At low concentrations of local anesthetics, this effect on sodium channels probably contributes to cardiac antidysrhythmic properties of these drugs. However, when the plasma concentrations of local anesthetics are excessive, sufficient cardiac sodium channels become blocked so that conduction and automaticity become adversely depressed. For example, pregnancy may increase sensitivity to cardiotoxic effects of bupivacaine, but not ropivacaine, as emphasized by occurrence of cardiopulmonary collapse with a smaller dose of bupivacaine in pregnant compared with nonpregnant animals. All local anesthetics depress the maximal depolarization rate of the cardiac action potential (Vmax) by virtue of their ability to inhibit sodium ion influx via sodium channels. In isolated papillary muscle preparations, bupivacaine depresses Vmax considerably more than lidocaine, whereas ropivacaine is intermediate in its depressant effect on Vmax. Less lipid-soluble lidocaine dissociates rapidly from cardiac sodium channels and cardiac toxicity is low. Furthermore, high plasma concentrations of bupivacaine may cause ventricular cardiac dysrhythmias through a direct brainstem effect. For example, seizure activity following an interscalene block with levobupivacaine was not associated with cardiac dysrhythmias or other signs of cardiovascular toxicity. In anesthetized dogs, bretylium, 20 mg/kg intravenously, reverses bupivacaine-induced cardiac depression and increases the threshold for ventricular tachycardia. In addition, slow or fractionated administration of all local anesthetics, but particularly bupivacaine, so as to detect systemic toxicity from accidental intravascular injection, should help decrease the risk of cardiotoxicity. For seizures that are not responsive to initial treatment, use of muscle relaxant such as succinylcholine or nondepolarizing blockers can help prevent acidosis and hypoxia associated with seizures. Multiple published cases have shown that intralipid can be successfully used for resuscitation, the mean total (bolus plus infusion) intralipid dose over the first 30 minutes was 3. The spectrum of this neurotoxicity may range from patchy groin numbness and persistent isolated myotomal weakness to cauda equina syndrome. If benzodiazepines are not readily available, small doses of propofol or thiopental are acceptable. Nevertheless, the incidence of transient neurologic symptoms is similar after intrathecal placement of 1 mg/kg of either 5% or 2% lidocaine in 7. The lithotomy position,93 early ambulation,94 and the glucose concentration and osmolarity of the anesthetic solution do not influence the incidence of transient neurologic symptoms. Cauda equina syndrome is most frequently associated with large central lumbar disc herniation, prolapse or sequestration with 50% to 60% patients having urinary retention on presentation. Nevertheless, this same complication has also been reported after intrathecal injection of 100 mg of 5% lidocaine through a 25-gauge needle. The etiology of this syndrome is uncertain, although thrombosis or spasm of the anterior spinal artery is possible, as well as effects of hypotension or vasoconstrictor drugs. This therapeutic effect, however, is short-lived because methylene blue may be cleared before conversion of all the methemoglobin to hemoglobin. Furthermore, continued absorption of highly lipophilic local anesthetics such as benzocaine from adipose tissue stores may continue to occur after methylene blue plasma concentrations are no longer therapeutic. Ventilatory Response to Hypoxia Lidocaine at clinically useful plasma concentrations depresses the ventilatory responses to arterial hypoxemia. Conversely, systemic absorption of bupivacaine, such as follows a brachial plexus block, stimulates the ventilatory response to carbon dioxide. Hepatotoxicity Continuous or intermittent epidural administration of bupivacaine to treat postherpetic neuralgia has been associated with increased plasma concentrations of liver transaminase enzymes that normalized when bupivacaine infusion was discontinued or lidocaine was substituted for bupivacaine. Drug-induced liver injury can be a direct toxic injury, an allergic reaction, or idiosyncratic metabolic abnormality. The hepatic dysfunction described seems most likely to represent an allergic reaction. Known oxidant substances include topical local anesthetics (prilocaine, benzocaine, and lidocaine), nitroglycerin, phenytoin, and sulfonamides. The diagnosis is confirmed by qualitative measurements of methemoglobin by cooximetry.