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Background: Giant paraesophageal hiatal hernia (GPEH) presents a risk of catastrophic complications that include massive bleeding, strangulation, and perforation and should be repaired. Controversy persists as to the surgical approach and whether an antireflux repair is required., Methods: This study reviews the experience with 100 patients with GPEH who underwent surgical repair between 1967 and 1999. Eighty patients underwent an elective operation, and 20 patients underwent an emergency procedure for complications of GPEH. The gastroesophageal junction was above the hiatus ("combined" hernia with sliding component) in 23 patients and in the abdomen in 77 patients, including 3 patients with a true parahiatal hernia., Results: A thoracic approach was used in 18 patients, mostly early in our experience; postoperative gastric volvulus requiring transabdominal repair developed in 2 patients. The remaining 82 patients underwent an abdominal repair, with temporary gastrostomy to prevent gastric displacement in 75 patients; the hernial sac was resected, and the hiatus was reconstructed in all of the patients. Thirty-five patients with reflux on preoperative work up underwent a fundoplication, with gastroplasty in 2 patients because of a short esophagus. No patient has experienced hernia recurrence. Whereas symptomatic relief was excellent in all patients with elective repair, mild reflux was present in 2 patients after emergency operation. There were no deaths among the patients who underwent elective operation; there were 2 hospital deaths among those patients who underwent emergency operation (10%)., Conclusions: GPEH should be repaired soon after recognition. Reflux should be evaluated before the operation, and if present, fundoplication should be part of the repair along with the reduction of the hernia, excision of the sac, gastropexy, and crural closure. These are best achieved with an abdominal approach.

From October 1986 to January 1991, 47 patients with esophageal cancer (29 squamous, 18 adenocarcinoma) were treated with simultaneous radiotherapy (3000 or 3600 cGy) and chemotherapy (infusional 5-fluorouracil, cisplatin) delivered during a 5-week period. This treatment was well tolerated; 44 patients (94%) completed a full course of therapy, 40 (85%) had relief from dysphagia, and 21 (45%) noted either weight gain or no net weight loss. One patient (2%) died of complications (tracheoesophageal fistula, perforated ulcer) during chemotherapy and radiotherapy. The remaining 46 patients were referred for operation. Six refused because of excellent relief of their dysphagia, and one was denied operation. Thirty-nine patients went to operation, and 34 (83%) had lesions that were resectable. Eight of the 39 surgically treated patients (21%) had no evidence of residual tumor identified in the resected specimens. One of these complete responders died 7 weeks postoperatively after multiple complications (3% operative mortality rate). Three of the remaining seven have also died since the operation, one of recurrent cancer and two with no known recurrent disease. Actuarial survival in this present series was significantly better than that of our 1980 to 1985 historical control patients (p less than 0.005). There was no difference between patients with squamous carcinoma and those with adenocarcinoma with regard to the prevalence of complete response or long-term survival. Survival of the seven patients who did not undergo operation was comparable with that of the 34 patients in whom esophagectomy was performed. This study suggests that combined preoperative chemotherapy plus radiotherapy for esophageal cancer is well tolerated, provides excellent palliation of symptoms, allows for a high rate of resectability, is equally effective for squamous carcinoma and adenocarcinoma, and provides encouraging early results with regard to long-term survival. The data also call into question the role of esophagectomy, particularly in patients who have a complete response to preoperative therapy.

Despite various interventions, the mortality rate after acute hepatic failure remains extremely high. Although it has been shown that administration of regenerating liver cytosol (RLC) after hepatic failure improves the survival rate of animals, the sequence in which various hepatic functions are altered after acute hepatic failure and their improvement by RLC remain unknown. To study this, fulminant hepatic failure in rats was produced by intraperitoneal injection of 1.5 gm/kg D-galactosamine (GAL). Twenty-four hours after 68% hepatectomy in normal rats, RLC was prepared and 4 ml of this solution (40 to 50 mg protein) was injected intraperitoneally in other animals at 6 or 24 hours after GAL administration. The long-term survival rate was 19.4% in the GAL-vehicle (control) group, 26.7% in the GAL-treated rats given liver cytosol from normal rats, and 72.2% (p less than 0.01 compared with both groups) in rats given RLC even 24 hours after GAL administration. Reticuloendothelial function was depressed at 24 and 48 hours after GAL administration; however, treatment with RLC but not vehicle or normal liver cytosol at 6 or even 24 hours after GAL administration significantly improved reticuloendothelial function 24 hours after GAL administration. DNA synthesis (an indicator of cell proliferation) did not increase in any group 24 hours after GAL administration; however, it increased strikingly at 48 hours in the GAL-RLC groups. Serum bilirubin levels were also lower in the RLC group 48 hours after GAL administration. Thus RLC administration improved survival, reticuloendothelial function, DNA synthesis, and hepatocyte function after GAL-induced acute hepatic failure. Improvement of reticuloendothelial function by RLC occurred before stimulation of DNA synthesis and appears to play an important role in improving survival after hepatic failure.

Six cases of pulmonary artery perforation associated with the use of Swan-Ganz catheters are reviewed. Risk factors included pulmonary hypertension, anticoagulation, and hypothermia. The mechanisms leading to perforation were clarified by the use of postmortem studies employing isolated whole lung preparations. These studies revealed that perforation results from (1) tip perforation of vasculature, (2) eccentric balloon configuration propelling the balloon through the vessel wall, and (3) balloon inflation disrupting the pulmonary artery (mean intraballoon pressure 250 mm Hg). Early clinical symptoms include hemoptysis of bright red blood and/or hypotension. Immediate evaluation may necessitate examination with a fiberoptic bronchoscope and "wedge" angiogram. If massive hemoptysis occurs, isolation of the unaffected lung by endobronchial intubation is mandatory. Pneumonectomy or lobectomy may be required. Revised guidelines for catheter insertion and pulmonary capillary wedge pressure (PCWP) measurements are presented. Finally, consideration is given to redesigning the pulmonary artery flow-guided catheter, particularly for use in patients undergoing cardiac operations with systemic anticoagulation. Modifications should be directed at (1) softer catheter tip with temperature-insensitive body, (2) low-pressure balloon, and (3) balloon pressure relief valve.

Although it has been shown that infusion of adenosine triphosphate (ATP)-magnesium chloride (MgCl2) proved beneficial in the treatment of shock, it is not known whether this effect is due to improvement in the microcirculation or to direct provision of energy. In searching for the mechanism of this, we have now examined the in vitro uptake of ATP by soleus muscle of animals in shock. Rats were bled to a mean arterial pressure of 40 mm. Hg and so maintained for 2 hours. Following death the two soleus muscles from each animal were removed and incubated in Krebs-HCO3 buffer containing 10 mM. of glucose, 5 mM. (8--14C) of ATP, 5 mM. (8--14C) of ADP, or 0.5 mM. (8--14C) of adenosine, and 5 mM. of MgCl2 for 1 hour under an atmosphere of 95 percent O2 to 5 percent CO2. Following homogenization and centrifugation, samples of the muscle extract and the medium were subjected to electrophoresis to separate the various nucleotides. The concentrations of the several nucleotides in medium and muscle were calculated from the radioactivity observed in each fraction. The uptake of 14-C-ATP by muscles from animals in shock was three times greater than was the uptake by control muscles. This leads us to conclude that the beneficial effect of ATP-MgCl2 to animals in shock could be due to provision of energy directly to tissues in which ATP levels were lowered.

A 37-year-old man with the Marfan syndrome and chronic mitral regurgitation suffered an acute dissecting aneurysm of the ascending aorta with aortic regurgitation. Emergency replacement of the mitral valve, aortic valve, and ascending aorta was carried out, and the patient made an uneventful recovery. He is doing well 18 months after surgery. This is the first reported case of survival from such a procedure in the face of acute dissection with Marfan's syndrome. Indications for elective surgery are discussed and the uncertainties about the prognosis outlined. Continued reporting of the results and follow-up data are necessary for final assessment of the surgical treatment of the cardiovascular manifestations of this disease.

Mechanical ventilation with positive end-expiratory pre-sure (PEEP) is widely used to treat ventilatory failure complicating pulmonary infection. The present experiment was carried out to test the hypothesis that PEEP is beneficial in an experimental model of canine pneumonia studied for 24 hours. Sixteen mongrel dogs were assigned to ventilation with either zero end-expiratory pressure (ZEEP) or 10 cm H2O PEEP. Pneumonia was induced in half of each group by intratracheal inoculation with Pseudomonas. Tissues for quantitative bacteriology and pathology were obtained at the time of death at 24 hours. Three of four infected-ZEEP dogs died before 24 hours. The geometrical mean of quantitative bacterial counts from infected-ZEEP lobes was 2.0 X 10(6) (+/-3.9) (organisms/gm of tissue), while the mean of the infected-PEEP lobes was 1.7 X 10(4) (+/-3.6) (p less than 0.05). Semiquantitative pathology scores indicated greater injury to the ZEEP-infected than to the PEEP-infected lungs. Quantitative bacteriology and microscopic evidence of parenchymal injury were positively correlated. Thus PEEP-treated animals had lower quantitative bacterial counts, less microscopic pulmonary damage, and improved survival. The advantage conferred by PEEP may be due to facilitation of local mechanisms of pulmonary defense against infection, to increased systemic resistance to sepsis, or to both.

Hemorrhagic shock was produced in conscious rats by cannulating the subclavian arteries and bleeding the animals to a mean arterial pressure of 40 mm. Hg, which was maintained for one hour (early shock) or 2 hours (late shock). Analysis of diaphragm (working muscle) showed that there was a significant decrease in adenosine triphosphate (ATP), adenosine diphosphate (ADP), and creatine phosphate levels beginning with early shock, whereas in soleus muscle (resting muscle) these changes were not observed until late shock. Decreases in adenine nucleotides of diaphragm were less than in working organs such as liver and kidney in early shock. This suggests that the extent of decrease in adenine nucleotides during shock may be related to the metabolic activity of the organ.

A murine model was used to test the effects of various therapeutic modalities on the rate of death following intra-abdominal sepsis as produced by cecal ligation and puncture (CLP). There were no deaths among sham-operated control mice after ether anesthesia, whereas CLP produced a mortality rate of 100% by 24 hours. When CLP was followed at 16 hours by excision of the cecum and saline peritoneal lavage (CLPE), the mortality rate was 20% at 24 hours and 60% at 72 hours. The therapeutic modalities consisted of gentamicin (1.5 mg/kg) alone or in combination with methylprednisolone (50 mg/kg) or tuftsin (1 mg/kg) administered before CLP and at 16 and 24 hours after CLP. Separate groups of animals also received only methylprednisolone or tuftsin, a tetrapeptide produced by the spleen. Compared with the mortality rate in the CLPE group, mortality at 24 and 72 hours was decreased for gentamicin alone (0% and 10%, respectively), tuftsin alone (10%, 40%), or the two in combination (0%, 20%). As compared with CLPE, methylprednisolone led to increased mortality rates at 24 and 72 hours (70%, 80%). The data (significant at P less than 0.01, X2 analysis) suggest that gentamicin and tuftsin may improve the rate of early survival after intra-abdominal sepsis in this Model. Steroids do not seem to be beneficial and may, in fact, be harmful.

During a 3 year period, direct myocardial revascularization was performed on an urgent basis in 48 patients with intermittent resting chest pain which persisted more than 24 hours despite in-hospital medical therapy and was accompanied by electrocardiographic changes representative of ischemia. Sixteen patients had saphenous vein (SV) grafts exclusively, and 32 patients each had one or two internal mammary artery (IMA) grafts with or without additional vein grafts. Follow-up ranges from 5 to 41 months (mean, 22 months). Twelve patients had single grafts to the left anterior descending coronary artery (LAD), 18 had double grafts, 16 had triple grafts, and 2 had quadruple grafts. The LAD required grafting in every patient. There was one operative death (2 per cent) and one late death from noncardiac causes. There were two (4 per cent) early postoperative myocardial infarcts and no late infarcts. Actuarial analysis projects a survival rate of 96 per cent 3 years postoperatively. Eighty-one per cent of the survivors are in Functional Class I, 17 per cent are in Class II, and 2 per cent are in Class III. All patients had postoperative angiography 2 weeks after operation. Eighty-six per cent of the SV grafts and all IMA grafts were open. No significant differences were observed between mean preoperative and postoperative left ventricular end-diastolic pressures or ejection fractions, but these parameters were noted to improve after operation in several patients. The remarkably high early and late survival rates, the low incidence of myocardial infarction, and the excellent functional results after rather long follow-up indicate that emergency coronary revascularization provides an effective therapy for unstable angina. The use of IMA grafts, when feasible, is a safe and possibly preferable approach in these patients.

The immunoregulatory events leading to the generation of suppressor T cells after burn injury were studied by means of a mouse burn model. Immunoresponsiveness was assessed on various postburn days with a primary in vitro mixed lymphocyte reaction (MLR). Responses of burned mice were depressed between 3 and 14 days after burn. Suppression became significant 5 days after burn and remained so through 14 days after burn. The Ly-t surface phenotype of T cells was studied on days 5 and 7 after burn. On day 5 burn, T cells responsible for suppression bore an Ly-1+, 2- phenotype. By postburn day 7 suppressor T cells bore an Ly-1-,2+ phenotype. These observations are consistent with the notion of feedback suppression after burn injury, wherein Ly-1+, 2- T cells induce a subset of Ly-1+,2+ T cells, thereby generating Ly-1-,2+ suppressor effector T cells. An attempt was made to uncouple the putative suppressor inducer and the suppressor effector using low doses of cyclophosphamide (CY). A single dose of 25 mg CY/kg resulted in transient restoration of depressed burn responses. By using multiple sequential doses of CY, this restorative effect could be prolonged through 8 days after burn. A dosage schedule that restores responses of burn cells without affecting responses of control cells is presented.

Results of direct coronary revascularization with 511 grafts in 213 patients from 1971 to 1974 are reviewed. To improve an early saphenous vein graft (SVG) patency of 84 per cent in the first 85 patients, we have used internal mammary artery grafts (IMAG), when possible, since January, 1973. In 1973 to 1974, 15 patients had SVG's only (36 grafts) and 113 received one or two IMAG's with or without additional SVG's (total 282 grafts); in 26 we used a crossed double IMAG. Forty-seven of 48 patients with unstable angina survived and did well. Flows in SVG's and IMAG's were comparable. Flows in right IMAG's to diagonal or marginal vessels were higher than in right IMAG's to right or left anterior descending (LAD) vessels. In 12 patients with both SVG and IMAG, there was no difference in flow response of either graft to vasoactive drugs. Survival, functional, and patency results with IMAG's were as good as or better than results with SVG's. We conclude that IMAG's yield higher patency and comparable flow rates to SVG's and should be used when the IMA approximates the recipient artery in size and when a high pulsatile free flow is measured from the end of the graft. IMAG's are also safe and feasible for unstable angina.

Tissue adenine nucleotides were measured in rats to determine if there is depletion of energy stores associated with sepsis. Peritonitis was produced by cecal ligation and cecal puncture. At 16 to 24 hours after ligation, rats which were lethargic but still normotensive (late sepsis) and showed clinical and laboratory confirmation of peritonitis-sepsis were stunned by a blow on the head, and small pieces of tissue were removed and frozen. Adenine nucleotides were measured enzymatically. In late sepsis adenosine triphosphate (ATP) levels in liver and kidney decreased significantly; however, no significant decreases were observed in the diaphragm or gastrocnemius muscle. Hydrogen polarograph measurements of hepatic blood flow indicated that flow was decreased markedly at this stage of peritonitis. A second group of rats was prepared in the same manner, except they were studied 10 hours after ligation (early sepsis). Most rats at this stage of sepsis appeared to be only mildly ill; however, blood cultures obtained from six rats so prepared all were positive. These rats did not show any decrease in either hepatic blood flow or tissue adenine nucleotides. Thus the changes in adenine nucleotides observed in late sepsis (lpw-flow septic rats) are similar to those seen during early hemorrhagic shock and suggest inadequate perfusion associated with peritonitis as the cause.

Our previous studies have shown a salutary effect of adenosine triphosphate-magnesium chloride (ATP-MgCl2) administered to animals in shock. The presence of adenine nucleotide converting enzymes on cell surfaces and the ability of nucleotides to act at the cell surface have been recognized also. To investigate the fate of administered or externally applied ATP and to determine whether it would be subjected to increased degradation with shock, the soteus muscles from rats subjected to hemorrhagic shock and from control animals were incubated in the presence of ATP, adenosine diphosphate (ADP), or adenosine monophosphate (AMP) with MgCl2. Comparable degradation of the added nucleotides was observed with both control muscles and those from bled animals. Adenylate kinase activity was detected to the same extent in the medium after incubation with both groups of muscles, but other enzymes were not, suggesting that the latter enzymes were located on the exterior surface of the muscle cell. Thus with shock there was no increase in the breakdown of the nucleotides by the enzymes on the muscle surface (ATPase, AMPdeaminase) or the cellular enzyme, adenylate kinase.

Nephrotoxicity is a serious side effect that limits the use of cyclosporine (CyA) as an immunosuppressive agent. The purpose of this study was to develop a model of CyA nephrotoxicity in the isolated perfused rat kidney and to evaluate the effects of adenosine triphosphate (ATP)-MgCl2 and verapamil treatment on this model. Kidneys were perfused for 90 minutes in a 7.5% albumin-Krebs-HCO3 solution containing 3H-inulin (glomerular marker) and 5.0 micrograms/ml 14C-cytochrome C (cyt) (marker of tubular protein absorption). After 10-minute equilibration, perfusate and urine samples were collected with 10-minute clearance periods. After two control clearance periods, 500 ng/ml CyA was added to the perfusate. In some experiments, 1 micrograms/ml of verapamil was added 10 minutes before CyA and in others 2 mmol/l ATP-MgCl2 was added with CyA. Cyt and inulin radioactivity, [Na+] and [K+], were measured in perfusate and urine. Tissue ATP levels were also determined. The results demonstrate that CyA treatment leads to a marked depression of glomerular filtration rate (GFR), tubular absorption of protein, urine output, and renal flow. ATP-MgCl2 cotreatment improved GFR, tubular absorption, and renal perfusate flow but the increase in urine output was not dramatic. Verapamil pretreatment markedly improved GFR and urine and renal perfusate flow but not tubular function. The combination of verapamil and ATP-MgCl2 treatment with CyA returned GFR to control values, significantly improved tubular absorption, urine and renal perfusate flow, and enhanced renal tissue ATP of isolated kidneys to levels seen in vivo. These data lead us to conclude that ATP-MgCl2 cotreatment with CyA after verapamil pretreatment greatly reduces the nephrotoxic potential of this immunosuppressive agent.

This study was undertaken to determine the effects of hemorrhagic shock on cellular energy production and utilization in the lung. Energy-dependent Na+ minus K+ transport was measured by quantitating tissue cation changes during a cold (0.5 degrees C.) and a subsequent warm (37 degrees C.) incubation of lung slices from rats in late hemorrhagic shock and from unbled control rats. Active Na+ extrusion and K+ reaccumulation by the tissue were observed upon rewarming of lung slices from shock animals. Whereas K+ reaccumulation was not altered with shock, the rate of Na+ extrusion was approximately 40 percent higher. The measurement of the intracellular water content with cold and warm incubations showed no alterations with shock. Extracellular water increased with chilling in shock tissue but not in normal tissue. Lung tissue contents of adenosine triphosphate, adenosine disphosphate, or adenosine monophosphate were likewise unaltered. Thus cellular energy utilization or production in the lung was not damaged by hemorrhagic shock but a tendency toward increased interstitial water seemed to be present.