Awakenings to the pathogenicity of urease and the requirement for continuous long term therapy.

Urease is an enzyme found in plants and bacteria, but not mammals. It catalyzes the conversion of urea to carbon dioxide and ammonia. Ammonia shortens the life span of cells; and higher concentrations cause tissue necrosis and cytolysis. Twenty percent of total body urea is converted to ammonia by bacterial urease in the colon. Small injections of urease immunize animals by producing antiurease, a gamma globulin, which inactivates urease. Immunization eliminates the colonic conversion of urea to ammonia. Injection of urease produces ammonia intoxication making immunization hazardous. Although previously impossible, a non enzymatic urease antigen was synthesized by covalently bonding jack bean urease with glutaraldehyde. This antigen stimulated the production of antiurease that inactivates native urease. Helicobacter pylori, a potent urease producer, has been implicated in peptic ulcer, gastritis and other inflammatory bowel lesions. The pathogenicity of H pylori is dependent on its urease production. Immunization to urease can render H pylori non pathogenic. Cirrhotics develop encephalopathy and hyperammonemia because their livers fail to convert all the ammonia in portal venous blood to urea and collaterals develop by passing the liver. Colonic ammonia increases the turnover rate of colonic mucosa. Ammonia absorbed into the portal venous system is transported to the liver where it is reconverted to urea. Absorbed ammonia adversely influences liver function. Infections with urease producing organisms destroy the renal parenchyma and produce struvite stones. Urease immunization aids colonic healing and prevents uremic colitis. Absorbed ammonia is a noxious influence on the liver. Animals immunized to urease regenerate the liver faster and are less susceptible to hepatotoxins. Immunization to urease ameliorates cirrhosis. Proteus and other urease producers become non toxic and do not damage the renal parenchyma. Urease is responsible for the pathogenicity of infections with urease producing organisms. Immunization to urease renders urease producing organisms non pathogenic.

The mythology of povidone-iodine and the development of self-sterilizing plastics.

The predominance of elemental iodine as a chemical antiseptic has been established during a century. Free iodine is effective for treatment and prevention of infection. Iodophors, such as povidone-iodine, have replaced elemental iodine in clinical use. Toxic absorption of povidone-iodine occurs from all tissues except intact adult skin, to which its use should be restricted. Povidone-iodine binds iodine so firmly that insufficient free iodine is released to be effective for treating or preventing infection. It is a weak antiseptic that is marginally acceptable as a disinfectant for adult skin. The shortcomings of povidone-iodine stimulated a search for iodophors that would liberate therapeutically effective concentrations of free iodine. These investigations led to a new self-sterilizing plastic formed by the complexing of polyurethane and iodine.

Closed endarterectomy. Preferred operation for aortoiliac occlusive disease.

Closed endarterectomy using the LeVeen plaque cracker was performed on isolated, clamped segments of the unopened aorta, iliac, and femoral arteries. The results of this type of endarterectomy have been analyzed for 111 patients who were followed up from 2 1/2 to nine years. The five-year patency rate was 99%. After nine years, 96.5% of the vessels that underwent surgery remained functionally and radiographically patent. Closed endarterectomy is a substantial improvement over conventional open or half-closed endarterectomy. The closed endarterectomy takes less time, entails little or no blood loss, and is accomplished through a retroperitoneal approach. The aortofemoral bypass graft is inferior to the closed endarterectomy in morbidity, mortality, patency, and alleviation of impotence. Late complications with bypass grafts, using synthetic material, are more numerous and life-threatening.

The place of the peritoneovenous shunt in the treatment of ascites.

The peritoneovenous shunt (PVS) is a safe procedure; all of its complications have been found to be preventable. Disseminated intravascular coagulopathy (DIC) can be a life threatening complication but has been completely eliminated by draining the ascitic fluid at the time of surgery, as it is caused by the introduction of excessive quantities of peritoneal fluid into the venous system. Peritoneal fluid is rich in tissue plasminogen activator (TPA), which is inhibited by epsilon aminocaproic acid. This substance has been successfully used to treat postshunt coagulopathy. The salt retention associated with ascites is related to a diminished plasma volume, a condition further aggravated by diuretic drugs. A PVS should be inserted if the patient does not respond to a salt restricted diet. Occult peritonitis occurs in 10% of cirrhotic ascites. The shunt does not prevent this, and a high percentage of late shunt failures are caused by fibrinopurulent debris in the valve. The valve system should not contain a pump, which disseminates infection and causes fatal emboli; pumping and flushing are seldom remedial and often dangerous. Because the complications of the shunt are all preventable, the indications for the shunt should be liberalized.

Recanalization of occluded superior vena cava for replacement of LeVeen shunt catheter.

Successful percutaneous replacement of the venous limb of a LeVeen peritoneovenous shunt with the use of angioplastic technique is reported. This method may be a first line of treatment in patients with intractable ascites and a failing shunt caused by chronic occlusion of the superior vena cava.

Coagulopathy post peritoneovenous shunt.

In 1942, 53% of medically treated patients with cirrhosis were dead 6 months after the onset of ascites. Only 30% survived 1 year. This dismal outlook has improved only slightly with advances in medicine. Yet, some internists reject the peritoneovenous shunt (PVS) for this fatal condition even if they are aware that a diminished blood volume causes the abnormal sodium retention responsible for ascites. Their objections are based on life-threatening complications of PVS, especially post shunt coagulopathy (PSC). Blood shed into the peritoneal cavity becomes incoagulable. Such blood is immediately coagulated by a protocoagulant (soluble collagen) and concurrently lysed by tissue plasminogen activator (TPA) secreted by the peritoneal serosa. Wide zones of lysis surround peritoneal tissue placed on fibrin plates. Large volumes of ascitic fluid infused into circulating blood simulates the fate of blood shed into the peritoneal cavity with lysis playing the major role. Addition of ascitic fluid to normal platelet-rich plasma in vitro initiates clot lysis on thromboelastogram (TEG). Epsilon-aminocaproic acid (EACA) counteracts this lysis. EACA and clotting factors normalize the TEG and arrest PSC. Disposal of ascitic fluid at surgery prevents or ameliorates PSC. Mild PSC was encountered only twice in 150+ consecutive patients (1.3%) with only one case being clinically significant (0.6%). Severe PSC occurred seven times in 98 early shunt patients whose ascitic fluid was not discarded. Severe PSC requires shunt interruption and control of bleeding with clotting factors and EACA. Peritoneal lavage with saline prevents the recurrence of PSC on reopening the shunt. In four patients, EACA and clotting factors were adequate to arrest coagulopathy. Three earlier patients died of PSC before its cause and treatment were understood. Proper management eliminates this life-threatening complication, and PSC cannot be considered a deterrent to PVS. Disseminated intravascular coagulopathy (DIC) is produced in experimental animals only by the injection of thrombin or thromboplastin. PSC is a distinct entity differing from DIC; EACA and not heparin is the antidote for PSC.

The LeVeen shunt.

Ascites is the end result when the rate of conversion of plasma to peritoneal fluid exceeds the rate of reabsorption from the peritoneal cavity. Physiologic therapy demands the return of this fluid to the plasma volume from whence it arose. The peritoneovenous shunt was devised to accomplish this. If precautionary measures are followed, complications are avoided. The shunt can be accomplished with a mortality under 1% in uncomplicated cirrhosis without jaundice or hydrothorax. Postoperative coagulopathy and infection are avoidable complications. Shunt failure is partly preventable and can almost always be remedied. Patients must be carefully followed to prevent late sepsis: care must be even more rigorous than that given to implanted artificial heart valves, because of the lower resistance of cirrhotics to infection. The cause of death in ascites untreated by shunts is early renal failure that is averted by the shunt. The shunt does not prevent rupture of esophageal varices, a frequent mode of late mortality. Varices require separate therapy. Because the shunt is effective with minimal morbidity and mortality, the indications for a peritoneovenous shunt should be liberalized.

Peritoneovenous shunt occlusion. Etiology, diagnosis, therapy.

Electronic pressure testing of every LeVeen valve has practically eliminated mechanical malfunction as a cause of shunt failure. Nonetheless, failures do occur and in a series of 240 cases, early or late shunt failure occurred in 29 patients. Thirty-five additional cases of failures were either referred by other physicians over a period of 6 years or information and x-rays were accumulated by direct contact. Shunt failure becomes manifest by a sudden reaccumulation of ascites in patients with a previously functioning shunt. In immediate failure, the ascites may fail to disappear after surgery or reaccumulate if removed. Ideally, caval clotting should be first excluded by x-ray visualization of the superior vena prior to injection of the shunt with contrast agent. Shuntograms are done with fine-bore needles. The venous pressure is also measured. The entry of contrast into the vena cava without pooling indicates a patent venous limb. The contrast will empty from the venous tubing with forceful inspiration if the entire system is patent. The venous tube will not clear if the valve or peritoneal collecting tubes are blocked. Only the valve and collecting tube need then be replaced if contrast enters the cava but does not leave the venous tubing. Occluded valves must not be flushed to restore patency since inflammatory exudate and cellular debris are erroneously identified as "fibrin flecks." Histology and culture are mandatory. Immediate and early failure are often caused by malposition of the venous tubing. Malplacements can often be diagnosed simply by chest x-rays. Intraoperative injection of methylene blue into the venous tubing establishes a satisfactory washout prior to wound closure. Fresh clots in the vena cava can be dissolved by the slow injection of streptokinase into the venous tubing. Other patent veins are chosen for access. Patients having repeat surgery after clotting must be heparinized to prevent a similar recurrence. Flushing blood clots from the cava can be fatal.

Management of ascites with hydrothorax.

Hydrothorax occurs in 5.3 percent of ascitic patients. Our experience with 22 cases forms the basis of this report. Of the 22 cases, 21 were spontaneous and 1 was due to transdiaphragmatic incision. Eighteen occurred on the right side. Usually fluid enters the chest through tiny defects in the diaphragm. These defects are often covered by pleuroperitoneum, but the high abdominal pressure raises a bleb on the superior surface of the diaphragm. Rupture produces hydrothorax. The ascites is often relieved with the onset of the hydrothorax. Blockage of the thoracic duct has produced chylous ascites. The thoracoabdominal communication is immediately confirmed by a scan of the chest and abdomen after intraperitoneal injection of technetium-99 colloid. Fluid is tapped from the chest immediately before intraperitoneal injection. The rate at which the technetium-99 enters the chest is related to the size of the defect in the diaphragm. A significant transfer should occur within 12 hours. Immediate transfer occurs with large defects. The ruptured blister on the diaphragm forms a one-way valve. Intrathoracic injection does not migrate into the peritoneal cavity. The valvular characteristics of the leak force ascitic fluid into the thorax because the differential pressure between the abdominal and pleural cavities is intensified by inspiration. If tension hydrothorax has occurred, urgent thoracocentesis and paracentesis may be required. A chest tube should not be introduced. The main principle of surgery is to supply a low resistance pathway for the return of fluid to the venous system and to eliminate the diaphragmatic defect by obliteration of the pleural space. A LeVeen peritoneovenous shunt is performed after emptying the abdomen of its fluid load. After completion of the shunt operation, the chest is emptied of fluid, and a sclerosing agent (tetracycline or nitrogen mustard) is injected into the pleural cavity. Closure of the defect is verified by technetium-99 labeled scans which also confirm shunt patency. With this regime, the defect closed or was rendered insignificant in 18 of 22 patients. One patient had a post-transdiaphragmatic surgical defect which was too extensive to be closed by the aforementioned procedures. One patient remained well but did not have closure of the defect, one patient with a ruptured hiatal hernia did not have closure, and one patient who had previous placement of a chest tube could not be closed. Therefore, 18 of 22 patients were successfully treated.

Radiofrequency thermotherapy, local chemotherapy, and arterial occlusion in the treatment of nonresectable cancer.

Localized radiofrequency thermotherapy (RFTT) has been effective by itself in debulking cancers but has not accomplished total eradication by itself. Occlusion of the regional artery supplying the tumor drastically reduces the arterial pressure distal to occlusion and further impairs tumor blood flow leading to an accentuation of the temperature differentiation achieved by the normal tissue and tumor. Radiofrequency thermotherapy with vascular occlusion is combined with direct injection of an effective chemotherapeutic agent into the tumor. Radiofrequency thermotherapy is performed after injection of chemotherapy using bleomycin and mitomycin C for squamous cell cancers and Adriamycin and mitomycin C for adenocarcinoma. There are no adverse systemic responses to the small dose of chemotherapy used and the combination therapy is effective in destroying the tumor.

Reversal of acute renal failure using hemodilution with hydroxyethyl starch.

Acute renal failure (ARF) was induced in two groups of unilaterally nephrectomized dogs by occluding the renal artery, vein, and ureter of the remaining kidney for 2 hours. The control group (Group I), had no therapy; in the experimental group (Group II), isovolemic hemodilution was carried out using 6% hydroxy ethyl starch (HES) as diluent. The hematocrit in the experimental animals was lowered from 41.62 +/- 3.6% to 23.75 +/- 5.2% after renal occlusion. The mean arterial pressure and the mean pulmonary arterial pressure were unchanged in either group. Cardiac output increased following hemodilution from 1.66 +/- 0.35 to 2.70 +/- 0.50 L/min while it remained unchanged in Group I. Control animals developed ARF characterized by progressive rise in serum creatinine concentration and death. Only 1/7 Group I animals was alive on day 7 compared to 7/7 of Group II (p less than 0.01). ARF that developed initially in Group II began to resolve after day 4. There was a progressive and significant fall in serum creatinine concentration from 6.48 +/- 0.67 mg/dl on day 4 to 4.08 +/- 0.83 mg/dl on day 7 (p less than 0.001). Immediate isovolemic hemodilution with HES can reverse ARF induced by ischemia.

Evaluation of peritoneovenous shunt patency with Tc-99m labeled microspheres.

The LeVeen peritoneovenous shunt (PVS) was investigated in 40 cirrhotic patients with refractory ascites. Five millicuries of Tc-99m-tagged human albumin microspheres (15-36 microns) were injected into the peritoneal cavity between the umbilicus and the left anterior superior iliac spine. The radiotracer was always detectable by scintigram in the lungs when the shunt was patent. In case of malfunction, by contrast, the radioactivity was either restricted to the venous tube or confined below the diaphragm for at least 4 hr. In the presence of complete obstruction, whereas the tube was not visualized after peritoneal injection, it was outlined by direct injection of 2 mCi of Tc-99m albumin microspheres into its subcutaneous tract, where it crossed the 12th rib, immediately above the valve. This technique sufficed to establish whether the site of obstruction was at the valve or in the tubing itself. In one patient, poor visualization of the tube and a delayed image of the lungs was caused by partial occlusion of the valve with fibrinoid debris. This radiotracer method proved simple, quick, and led to an immediate selective replacement when the shunt was not patent. Therefore, the use of this test is recommended for a definitive diagnosis, since there were neither false negatives nor false positives. No complications such as embolism or bacterial infection were encountered with Tc-99m human albumin microspheres, which are excellent tracers.

Radiofrequency-induced hyperthermia: computer simulation of specific absorption rate distributions using realistic anatomical models.

A description is given of a computer simulation technique which predicts the specific absorption rate (SAR) distribution within the human body resulting from the application of radiofrequency electromagnetic energy. The method uses an extension to the principle of over-relaxation of electric potentials and the basis of the simulation is a realistic three-dimensional model derived from both dielectric and anatomical data. Two of the principal means of applying radiofrequency hyperthermia, namely the use of capacitive electrodes and inductive coils, have been provided for. The accuracy of the simulation has been favourably tested using an agar split-phantom and an infrared thermograph camera. The simulations can be used to assist the design and clinical use of radiofrequency applicators, and examples are given of the application of both an inductive coil and switched capacitive electrodes to heat the thorax.

Effects of isovolumic hemodilution on massive pulmonary emboli.

Massive pulmonary emboli obstruct the pulmonary outflow tract and release vasoactive amines that further increase vascular resistance in the pulmonary vascular bed. Lowering blood viscosity by isovolumic hemodilution has been suggested as a possible therapeutic modality to increase pulmonary blood flow. This study was performed to determine if hemodilution could affect the aberrancies caused by massive emboli. Ten pairs of mongrel dogs were instrumented and injected with autologous clot until pulmonary artery (PA) pressure rose to 40 mm Hg. One doe was then isovolumically hemodiluted to a hematocrit of two thirds of control with Ringer's lactate. Hemodynamic data, including PA, and arterial and pulmonary capillary wedge pressure (PCW), were obtained immediately following injection of the clot and one hour later. Following this, the dog was sacrificed and all clot was removed and weighed. Three dogs in the control group arrested and could not be resuscitated, while two dogs in the hemodiluted group survived arrest. The hemodynamic data was identical in the two groups. Clots in the control group weighed 9.6 +/- 7 grams while retrieved clot in the hemodiluted dogs was 3.6 +/- 2. Although the hemodynamic data was similar for both groups, the survival rate and decrease in the size of the clot was significantly favorable in the hemodiluted dogs to encourage further study on this technique.

Prehepatic hyperalimentation.

A technique for prehepatic infusion of parenteral nutrients is described. Portal vein hyperalimentation allows hepatic modification and control of the infused nutrients before delivery of these substances into the general circulation and theoretically should reduce the incidence of metabolic complications of hyperalimentation. The clinical experience with prehepatic infusions is reported and the metabolic investigations are described. Transumbilical catheters provided prehepatic delivery of parenteral nutrients for 1 month after esophagogastrectomy for esophageal malignancy without serious infection or portal vein thrombosis. Close surveillance of blood glucose and serum osmolarity demonstrated metabolic stability during the infusion period. Nitrogen balance studies showed better nitrogen economy than is achieved by infusion of similar solutions into the central systemic circulation. Indirect calorimetry indicated that the nitrogen used for production of energy was less than the amount supplied by prehepatic infusions. The same basic liver function abnormalities encountered with systemic infusion of hyperalimentation solutions were noted. The patients gained weight after esophagogastrectomy and did not experience the attrition from malnutrition which usually occurs in the first several months after esophageal resection.