Intratumoral Bacillus Calmette-Guérin immunotherapy prior to surgery for carcinoma of the lung: results of a prospective randomized trial.

A prospective randomized trial of preoperative intratumoral therapy with Bacillus Calmette-Guérin (BCG) was conducted in non-small cell lung cancer patients. Eighty-eight patients (48 BCG-treated and 40 control subjects) were entered into the study; three control subjects were removed from data analysis because histology revealed pathology other than non-small cell lung cancer. There were no differences between BCG-treated and control patients in sex, age, cigarettes smoked per day, pack-years of cigarette smoking, white blood cell count, or number of peripheral blood lymphocytes. Toxicity of BCG was limited to transient malaise and fever (average peak temperature, 38.7 degrees C). There was no significant difference in outcome (recurrence or survival) between BCG-treated and control groups with Stage I or Stage III tumors; there were too few Stage II tumors for separate statistical analysis. Outcome was not affected within or between the two treatment groups by tuberculin skin test status. Combining both treatment groups, Stage III patients had a worse outcome than did Stage I-II patients, non-squamous cell tumor patients (large cell and adenocarcinoma) had worse outcomes than did squamous cell tumor patients, and men had a worse outcome than women. We conclude that, although preoperative intratumoral BCG therapy is safe, it does not lengthen disease-free interval or prolong survival in patients with non-small cell lung cancer.

Further evidence for ATP uptake by rat tissues.

Intact rat soleus muscles or hemidiaphragms were incubated at 37 degrees C for 1 h in 1.0 ml of Krebs-HCO3 buffer containing 10 mM glucose, 5 mM (8-14C)-labelled ATP and (alpha-32P)-labelled ATP together with 5 mM MgCl2 under an atmosphere of 95% O2-5% CO2. Samples of the incubation medium and tissue extract were subjected to electrophoretic separation and the radioactivity present as adenine nucleotides was counted. Extensive degradation of the added nucleotides was observed in the presence of both tissues. The concentrations of 14C-labelled and 32P-labelled ATP found in the muscle and diaphragm indicated that ATP was present within the muscle and diaphragm cells. By maintaining higher concentrations of ATP in the medium, ATP uptake in both tissues exhibited a saturation-type kinetics. These results provide further evidence for intracellular uptake of ATP and also suggest that the transport of ATP into the cell could be a carrier-mediated process.

Effects of ATP-MgCl2 and adenosine-MgCl2 administration on intracellular ATP levels in the kidney.

The effects of exogenous administration of 1 mM [8-14C]ATP-MgCl2 and adenosine-MgCl2 on intracellular accumulation of adenine nucleotides were examined in isolated, perfused rat kidneys. The kidneys were made filtering or non-filtering by increasing the colloid oncotic pressure of the perfusate solution in order to assess the relative contributions of the glomerular and peritubular routes in the uptake of the nucleotides. The results indicate that: although labeled ATP is undetectable in the perfusate after 20 min, there is a significant accumulation of labeled ATP in the tissue and although labeled adenosine-MgCl2 administration also leads to labeled intracellular ATP, the total intracellular ATP is much less than with ATP-MgCl2 administration.

Effect of hydrocortisone and dexamethasone on xylose uptake by isolated rat soleus muscle.

To determine the effects of glucocorticoids on sugar uptake, xylose uptake by isolated rat soleus muscle of bilaterally adrenalectomized animals was studied. The results indicate that in vitro addition of 10-4 M hydrocortisone, dexamethasone or hydrocortisone sodium succinate had no inhibitory effect on basal xylose uptake. In the presence of both low and high medium insulin, the above steroids failed to inhibit insulin-stimulated uptake. When the concentration of hydrocortisone sodium succinate was increased to 10-2 M, insulinstimulated uptake was decreased. The results thus indicate that glucocorticoids at concentrations observed under physiological or pathological conditions do not inhibit basal or insulin-stimulated sugar uptake.

Improved renal function using adenosine triphosphate-magnesium chloride in preservation of canine kidneys subjected to warm ischemia.

Previous studies have shown that adenosine triphosphate-magnesium chloride (ATP-MgCl2) administered after 30 to 60 min of renal ischemia ameliorated the resulting acute renal failure in different species of animals. The purpose of this study was to determine whether addition of ATP-MgCl2 to the perfusate during renal preservation, prior to transplantation, might improve renal function. Dog kidneys were subjected to normothermic ischemia for 35 min, after which they were preserved by pulsatile perfusion for 24 hr at 7 C. The perfusate contained albumin in a balanced electrolyte solution with an without ATP-MgCl2. Following 24 hr of pulsatile perfusion, the kidneys were autotransplanted and renal function was determined 3 days post-transplantation. The results indicated that dog kidneys subjected to ischemia followed by perfusion preservation developed severe oliguric renal failure 3 days after transplantation. However, if ATP-MgCl2 was added to the perfusate, such kidneys demonstrated markedly improved renal function and ATP levels. These results indicate that kidneys which have been subjected to episodes of warm ischemia could be salvaged by addition of ATP-MgCl2 to the perfusate.

A debate on the subject "Are SIRS and MODS important entities in the clinical evaluation of patients?" The con position.

SIRS, MODS, and MOF are not diseases or even syndromes. They are simply clinical descriptors of people that are sick. They are symptoms and signs of various stages of illness progressing to death in the modern organ supporting ICU. They are catchy, popular acronyms but they cannot be treated specifically, and then only by support of organ functions. To help our patients and improve morbidity and mortality we must focus on specific diseases. Although ventilator associated pneumonia and pancreatitis may both produce an inflammatory response, cytokine-mediator activation and SIRS, they must each be treated in a different way. I believe that SIRS has led us astray.

Multiple organ failure, multiple organ dysfunction syndrome, and the systemic inflammatory response syndrome-where do we stand?

Multiple organ failure, multiple organ dysfunction syndrome, and the systemic inflammatory response syndrome are problems of medical progress and intensive care units (ICUs) and require prevention of organ failure through excellent patient care. New concepts in prevention include: 1) the need to improve microcirculatory blood flow (Mbf) early after injury or illness, 2) stopping or controlling injury or infection by early definitive operation when necessary, 3) a zero defect operation is necessary, 4) necrotic tissue and an overwhelming inflammatory burden are problems and should be lessened when possible, 5) adequate resuscitation to improve Do2, Vo2, and organ blood flow is necessary, 6) supporting metabolism and the GI tract may decrease complications of injury and sepsis, 7) support of host defense and/or immunomodulation to decrease the incidence of sepsis, and 8) treating the patient and the illness or injury, not just the mediators. Experimental evidence in animals and human volunteers for concepts, mechanisms, and treatment of injury or illness can be substantial and persuasive, but it may be difficult to demonstrate efficacy in sick patients. Clinical situations are variable and complex. It is difficult to dissect out, identify, and control or block a single factor or mediator. All biologic processes require a level of activity that can be hazardous in excess but dangerous if decreased or eliminated. Stimulation of our natural defense or control mechanisms of inflammation, replacement of lost or decreased factors, and better understanding of the interrelationships and mechanisms of inflammation will contribute to therapy. Whether blockade of mediators or treatment of the manifestations of diseases or injuries will have substantial impact remains to be learned. A single magic bullet for complex and diverse illnesses is not likely to appear or to be successful. In this review it was not possible to describe many of the observations and recommendations in this immense and complex field. I apologize to those whose work I have inadvertently not included.

Systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF): are we winning the battle?

The problems of inflammation and infection leading to organ dysfunction and failure continue to be the major problems after injury and operations and with intensive care for many diseases and problems. When SIRS goes to MODS and MOF, the mortality becomes high, ranging from 30-80% depending on the number of failed organs. In spite of this, there have been recent exciting discoveries and contributions to patient care. A reasonable question then is, are we making progress and if so, can we document it? Are the incidence and mortality of MOF decreasing? The literature comparing care over some years suggests a decrease in ICU mortality in patients with severe organ failure, a decrease in elective surgical mortality, and improvement in the results of care and outcome for trauma patients. Review of problems occurring in sick and injured patients indicates that certain problems are decreasing in frequency, such as renal failure and ARDS after trauma, stress gastrointestinal bleeding, and abdominal abscesses, and these should improve outcome. There are a number of exciting therapies that help certain patients but not everyone. These controversies challenge us to focus on where and when there are positive benefits. Risk factors for MOF are addressed to focus on early intervention. The possibilities of multiple therapeutic agents are described. Finally, we describe and emphasize our recommendation to strive to prevent MODS and SIRS.

Trauma management in the 21st century.

Predicting the future can be interesting but difficult, particularly because of the exciting developments in the science of injury, inflammation, sepsis, and shock. Considering what has happened between 1895-1995, it is difficult to contemplate what will happen in the next 100 years. Will change accelerate in the 21st century? So far, our scientific knowledge and capability have exceeded the ability to care for injured and operated patients. Much of the future will depend upon society's ability to control violence and prevent injury. Most of the factors resulting in death after injury are beyond the control of those caring for patients or those studying patient problems. Thus the major risk factors for death after trauma are injury severity, the age of the patient, the problems of shock, and end-stage organ injury. If we are to decrease mortality from injury, we must work to prevent injury and decrease the severity of injury while improving our capabilities to care for the injured. New rapid diagnostic procedures, immediate therapy at the scene of the injury, portable or flying resuscitative and therapeutic units, and better understanding of the need for the inflammatory response in contrast to the disaster produced by an overwhelming inflammatory response will help. The major hazard for predicting the future in the management of injured patients could be predicting that something cannot be done. We recognize now that almost anything can be done if we learn enough and understand the problems sufficiently well. The Shock Society is dedicated to that purpose.

MEGX (monoethylglycinexylidide): a novel in vivo test to measure early hepatic dysfunction after hypovolemic shock.

A quantitative liver test based on the formation of the lidocaine metabolite monoethylglycinexylidide (MEGX), was used to evaluate the effect of hemorrhagic shock at 40 mmHg for 90 min on Sprague-Dawley rats. After 2 h of stabilization, lidocaine was injected (2 mg/kg). A second group received volume resuscitation with Ringer's lactate over 1 h (15 mL/kg) after shock, and after 1 h of stabilization lidocaine was administered. These groups were compared to control animals. Blood samples were drawn at 0 time (baseline), prior to lidocaine injection, and at 10, 15, 30, and 60 min after lidocaine injection. MEGX values in shocked animals were significantly lower than in the control group; in animals receiving volume resuscitation, levels were higher than the shocked animals without resuscitation, but did not reach control levels. Thus, shock produced a significant depression of hepatocyte function, which was partially reversed by Ringer's lactate resuscitation. The MEGX test appears to be a suitable tool for clinical evaluation and therapeutic intervention after shock.

Successful emergency replacement of the ascending aorta and aortic and mitral valves in the Marfan syndrome.

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.

Selection of coronary bypass. Anatomic, physiological, and angiographic considerations of vein and mammary artery grafts.

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.

Severe coarctation of the aorta with pulmonary edema. An unusual presentation of a traumatic aortic aneurysm.

A patient with an unrecognized rupture of the ascending aorta developed severe pulmonary edema three weeks following the initial injury. This is a distinctly unusual manifestation of this injury. Emergency resection of the traumatic aneurysm was required to reverse the rapidly deteriorating clinical situation. The early recognition and surgical treatment of this lesion would have avoided this complication.

Preoperative chemotherapy and radiotherapy for esophageal carcinoma.

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.

Catheter-induced pulmonary artery perforation. Mechanisms, management, and modifications.

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.

Surgical treatment of unstable angina by saphenous vein and internal mammary artery bypass grafting.

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.

Treatment with verapamil and adenosine triphosphate-MgCl2 reduces cyclosporine nephrotoxicity.

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.

Effect of sepsis on tissue adenine nucleotide levels.

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.

Evidence for enhanced uptake of adenosine triphosphate by muscle of animals in shock.

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.

Na+ minus K+ transport and adenosine nucleotides in the lung in hemorrhagic shock.

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.