Effects of a combined drug regimen on tumour necrosis factor and plasma kallikrein activity in experimental endotoxaemia.

OBJECTIVE: To clarify the relationship between changes in haemodynamics, liberation of tumour necrosis factor and generation of plasma kallikrein, and to see if treatment with a combination of drugs was successful in preventing activation of tumour necrosis factor and plasma kallikrein in experimental endotoxic shock. DESIGN: Controlled study. MATERIAL: 22 juvenile pigs. INTERVENTIONS: 15 animals received 0.01 mg/kg endotoxin infusion, the rest being given the same volume of saline. 10 received no treatment, and 5 were given a combination of methylprednisolone, naloxone, ketanserin, promethazine, C1 esterase inhibitor, antithrombin III and aprotinin. MAIN OUTCOME MEASURES: Assessment of the liberation of tumour necrosis factor, generation of plasma kallikrein, and haemodynamic and cellular effects of endotoxaemia. RESULTS: There was a linear statistical relationship between decreases in cardiac output and increases in packed cell volume, and between increases in packed cell volume and plasma kallikrein activity. The combination treatment totally blocked all the effects of the infusion of endotoxin. CONCLUSION: Endotoxin affects several mediators, but combination treatment can prevent some of these effects.

Gastric banding for morbid obesity: five years follow-up.

This paper reports on a five year follow-up of 174 morbidly obese patients (132 women) with gastric banding performed between 1981 and 1985. Mean preoperative weight was 122.6 +/- 1.4 kg (s.e.m.) (body mass index (BMI) = 41.8 +/- 0.4 kg/m2) and mean overweight was 73.2 +/- 1.6%. After rapid weight loss during the first six months weight levelled off reaching a nadir at 12-18 months. At 12 months mean weight loss was 36.5 +/- 1.2 kg (BMI = 29.1 +/- 0.4 kg/m2). At 60 months BMI had increased to 32.3 +/- 0.6 kg/m2 (P < 0.05 vs. 12 and 24 months). Mean excess weight at 60 months was 33.5 +/- 2.4% with 47.5% of patients maintaining less than 30% overweight. There were no differences in relative weight loss between men and women and no differences between stomal diameter of 12 or 15 mm 60 months after the operation. Early post-operative complications occurred in 25 patients (14.4%), four of whom required reoperation. Three of these re-operations were for perforations, one of which was fatal. Forty-eight patients (28%) had altogether 60 late complications requiring 26 reoperations (14.9%). There has been a total of four deaths (one clearly unrelated, one unknown) in the series. We conclude that gastric banding is a simple and safe gastric restrictive operation that is effective in about 50% of patients weighing between 90-181 kg (BMI 33-69 kg/m2).

[Cost-benefit calculations in laparoscopic surgery. Substantial total benefits, but extra expenses for hospitals are required--reversed effect]. / Kostnad-nytte-beregninger ved laparoskopisk kirurgi. Store totalgevinster, men sykehusene påføres ekstrakostnader--omvendt gulroteffekt.

Based on data from our prospective comparative study, we calculated health care costs associated with cholecystectomy (n = 200) and appendectomy (n = 40) patients undergoing open and laparoscopic procedures respectively. Average costs associated with cholecystectomy were reduced from NOK 36,750 to NOK 14,050 (62% decrease) when the laparoscopic technique replaced the conventional open method. A similar comparative study focused on appendectomy was performed with 20 patients in each group, and the costs were reduced by altogether 56%. The potential for decrease in health care costs seems to be substantial, even though requiring investments in equipment and education. Mini-invasive surgery not only improves the quality of surgical treatment, but also increases the efficacy of health care investments.

Hemodynamic and proteolytic effects of intravenous injection of purified human plasma kallikrein.

To investigate the precise hemodynamic effects of purified human plasma kallikrein, small doses (0.3 U/kg) of this proteolytic enzyme were infused over 10 s in five pigs. Hemodynamic performance was evaluated by means of a Swan-Ganz catheter, and parameters of the plasma kallikrein-kinin, coagulation, and fibrinolytic systems were determined by means of chromogenic peptide substrate assays. The infusions of plasma kallikrein were followed by rapid decreases in mean arterial pressure (to 43 +/- 2% of baseline values) and increases in cardiac output (to 145 +/- 6% of baseline values), accounting for marked decreases in systemic vascular resistance, to 28 +/- 1% of initial values. Heart rate, mean pulmonary arterial, central venous, and pulmonary capillary wedge pressures did not change after the injection. Pulmonary vascular resistance decreased to 69 +/- 3% of baseline values. The hemodynamic changes gradually normalized during the following 10 min. Functional levels of prekallikrein, kallikrein, kallikrein inhibition, prothrombin, antithrombin III, plasmin, and antiplasmin were not affected by the injection or the resulting hemodynamic changes; the hematocrit and the number of circulating leukocytes or platelets were also unaffected.

On the value of giving a combination of drugs for the treatment of endotoxaemia in pigs.

OBJECTIVE: To see if treatment with a combination of drugs each directed at a different mediator was successful in preventing activation of those mediators in experimental endotoxic shock. DESIGN: Controlled study. MATERIAL: 40 juvenile pigs. INTERVENTIONS: 33 animals received 0.01 mg/kg endotoxin infusion, the rest being given the same volume of saline; 10 of the 33 received no treatment. Of the remaining 23, 5 were given combination treatment with methylprednisolone, naloxone, ketanserin, promethazine, C1 esterase inhibitor, antithrombin III and aprotinin; 7 were given methylprednisolone only; 6 were given the three protease inhibitors (C1 esterase inhibitor, antithrombin III and aprotinin); and 5 were given naloxone, ketanserin and promethazine. MAIN OUTCOME MEASURES: Assessment of haemodynamic, proteolytic, and cellular effects of endotoxaemia. RESULTS: Only the combination treatment totally blocked all the effects of the infusion of endotoxin. CONCLUSION: As endotoxin affects several mediators, combination treatment is necessary to block all its deleterious effects in pigs.

Plasma kallikrein generation in endotoxemia is abolished by ultra high doses of methyl-prednisolone: in vivo studies in a pig model.

Thirty-one healthy young pigs were studied to evaluate the effects of methylprednisolone sodium succinate (MP) on cellular, proteolytic, and hemodynamic parameters in normal and endotoxin-exposed animals. Fourteen animals served as controls, whereas 17 test animals received a continuous infusion of endotoxin, 0.01 mg/kg/3hr. Seven of the test animals and seven of the control group received a total of 200 mg/kg body weight over 5 hr of MP, 100 mg/kg as pretreatment before the endotoxin infusion was started. The administration of MP to control animals did not cause changes in the plasma kallikrein-kinin system, as determined with chromogenic peptide substrate assays. Only temporary effects, which normalized during the observation period, were seen in hemodynamic parameters. The pretreatment with MP significantly counteracted the increases in plasma kallikrein activity (KK) and the decreases in functional kallikrein inhibition capacity (KKI) seen after endotoxin infusion in untreated animals. Marked reductions in the number of circulating leukocytes and platelets were observed in untreated endotoxemia, together with increases in hematocrit. Furthermore, increases in pulmonary vascular resistance (PVR) and decreases in cardiac output (CO), left ventricular stroke work (LVSW), and mixed venous oxygen saturation (SvO2) ensued. The changes in circulating cells, PVR, and SvO2 were significantly counteracted by MP treatment, whereas changes in hematocrit, CO, and LVSW were only moderately improved.

[Diaphragmatic injuries]. / Diafragmaskader.

Diaphragmatic injuries are serious, since they can lead to herniation of abdominal organs into the thorax. The injury is simple to treat when diagnosed early. The operation can then be performed with direct suturing. Concomitant injuries are common, however, and complicate diagnosis and treatment in an acute situation. During the period 1980-90, 30 patients with diaphragmatic injuries where treated in Ullevål hospital, 18 after closed and 12 after penetrating trauma. 28 of the 30 patients also had associated injuries. In four patients the diagnosis was initially missed. The majority of the patients were treated by laparotomy. Four patients died during the primary admission to the hospital, one of them suddenly in delirium tremens, two from massive bleeding from a pelvic fracture and one from septicemia and multiorgan failure. One patient died four years later from pneumococcal septicemia. No patient died because of the diaphragmatic injury, and traumatic diaphragmatic hernia due to earlier injuries was not registered during the study period.

[Study and diagnosis of pancreatic cancer]. / Utredning og diagnose av cancer pancreatis.

The most common initial symptom was abdominal pain. Other frequent debut symptoms were loss of weight and jaundice. ERCP and PTC were found to be the best diagnostic procedures. CT or ultrasonography were normal in 10-20% of the patients. Nearly all tumors of the pancreas were found by the ERCP procedure. We also used angiography to evaluate operability of the pancreas tumor. Angiography was found to be a very uncertain diagnostic procedure, however, and we have now decided not to use angiography in the future evaluation of patients with cancer of the pancreas.

[Abdominal injuries after blunt trauma]. / Abdominalskade etter stumpt traume.

We present a series of 331 patients admitted to hospital in 1980-87 with abdominal injuries after blunt trauma. The patients included 230 males and 101 females. The median age was 29 years. More than half of the patients were injured in traffic accidents. 11% were transferred to our Trauma Center from other hospitals, median five hours after the accident. A doctor-manned helicopter transported 52 patients (18%) directly to our hospital. 70% had extra-abdominal injuries as well. A minimum of 20% were intoxicated by alcohol and/or drugs. Severe injuries (AIS greater than 3) were present in 46%. 168 patients underwent laparotomy, in 56% within two hours of admission. In 27 of the 168 laparotomized patients (16%) no intraabdominal injury was encountered that needed repair.

[Pancreatic cancer. Treatment and results]. / Cancer pancreatis. Behandling og resultater.

Between 1980 and 1989, 151 patients were treated for adenocarcinoma of the pancreas. One fifth of the patients underwent radical surgery whereas 1/3 had a palliative operation. Leakage from the pancreatico-duodenal anastomosis, constructed with a mucosa to mucosa technique, did not occur in patients operated with pancreatico-duodenal resection (n = 19). The postoperative lethality in this group was 5%. Median overall survival time was four months, after a radical operation 11.5 months and after a palliative operation five months. Five patients with cancer of the papillary region had a median survival time of 40 months and four patients are still alive.

[Use of resources in the treatment of pancreatic cancer]. / Ressursbruk ved behandling av cancer pancreatis.

We calculated the costs of surgery for pancreatic cancer in 151 patients treated for carcinoma of the pancreas at Ullevål sykehus, University of Oslo, during the period 1980-89. The costs of the diagnostic process and the hospital stay were calculated separately. We found that radical surgery cost about NOK 80,000 more than a palliative operation. The median survival time after radical operation was only 11 months, compared with five months after palliative surgery. We are discussing the price of the surgery in relation to the results. We stress the importance of restrictive selection criteria for radical surgery of pancreatic cancer and conclude that the higher cost of radical surgery as compared with palliative procedures is acceptable.

[Grading and prognosis of blunt abdominal injuries]. / Gradering og prognostikk ved stumpe abdominalskader.

From 1 January 1980 to 31 December 1987, 297 patients were admitted to Ullevål Hospital, Dept. of Surgery, with abdominal injury after blunt trauma. The Injury Severity Score (ISS) was determined in retrospect, and correlated to mortality, morbidity and use of resources. 50 patients (16.8%) died. Mortality increased with increasing ISS, until ISS was above 34. In this group, mortality was 75%. In the survivors, hospital costs (days in the hospital, in the intensive care unit, on mechanical respiration, and number of blood units transfused) increased with increasing ISS. The likelihood of developing septicaemia adult respiratory distress syndrome (ARDS) or multiple organ failure also increased with increasing ISS. Those who died were older and had a higher ISS than the survivors. In patients over 55 years old, the mortality increased significantly. The ISS is well suited for identification of seriously injured patients after blunt abdominal trauma. The ISS can be used to predict mortality, morbidity and cost of treatment in groups of patients.

[Delayed surgery in blunt abdominal trauma]. / Forsinket operasjon ved stumpe buktraumer.

Abdominal organ injuries caused by blunt trauma are notoriously difficult to diagnose, and for this reason an operation may be dangerously delayed. 426 abdominal organ injuries were registered in a series of 331 patients admitted after blunt abdominal trauma. 151 of these patients had 199 abdominal organ injuries which required surgical repair. In 31 patients (20%) with 44 organ injuries, operation was delayed for more than six hours after admission, in most cases because of missed diagnosis. One of these patients died as a result. Hollow viscus injuries were the most commonly missed. In addition to repeated clinical evaluation, peritoneal lavage, repeated if necessary, and diagnostic imaging must be used as valuable tools of diagnosis, especially in comatous patients, in patients with multiple injuries, and in intoxicated patients.

Methylprednisolone induces activation of the contact system in a dose-dependent manner. An in vitro study.

The effect of methylprednisolone sodium succinate (MP) on the contact system of plasma was studied in human citrated pool plasma. Contact activation was demonstrated by the presence of plasma kallikrein (KK) activity and activated Hageman factor (FXIIa) and/or KK in complex with C1 inhibitor (C1inh), detected by chromogenic peptide substrates or radioimmunoassays, using monoclonal antibodies directed to neodeterminants exposed on complexed C1inh, respectively. When plasma and different doses of MP were incubated for a period of 24 hours, the highest dose of MP (10 mg/ml) gave rapid and marked increases in KK activities and concentrations of C1inh complexes. MP at 5 mg/ml plasma also induced activation of the contact system, although this activation was less pronounced. Even the lower dose of MP (1 mg/ml), which is equivalent to doses used in humans, increased plasma concentrations of KK-C1inh complexes. In conclusion, this in vitro study shows that MP in a dose-dependent way activates the contact system of plasma.

Studies on components of the contact phase system in patients with advanced gastrointestinal cancer.

The authors have studied components of the contact system in plasma obtained from patients with advanced gastrointestinal cancer. Plasma samples from 118 healthy blood donors served as controls. Plasma prekallikrein (PKK) values, evaluated by chromogenic peptide substrate technique, were significantly decreased in patients with cancer compared with healthy blood donors. High molecular weight kininogen (HMwK) and Hageman factor (FXII) values, assayed by immunochemical techniques, were also decreased in the patients with cancer. The changes of contact factors were most pronounced in patients with liver metastasis. The most striking observation in our study, however, was the elevated inhibitor values in patients with cancer. Alpha-2-macroglobulin (alpha 2-M) and C1 inhibitor (C1INH) values, determined both by functional and immunochemical techniques, were markedly increased in patients with cancer. In conclusion, this study shows that patients with intestinal cancer have reduced values of contact factors and markedly elevated inhibitor values which indicate that development of malignant tumors in the gastrointestinal tract is associated with changes in the contact system of plasma.

[Penetrating abdominal injuries]. / Penetrerende abdominalskader.

We have reviewed the medical records of 111 patients treated for abdominal stab wounds during the period 1980-87. Our two hospitals serve a catchment area of about 450,000 people. Exploratory laparotomy was performed in 89 patients with suspected peritoneal penetration. In 16 patients the laparotomy was negative, and in 15 patients only minor injuries were noted. There were no serious complications in these 31 patients. Twenty-seven patients had thoracic wounds below the fourth intercostal space, 15 with intraabdominal injuries. The most common injuries were lacerations of the liver, the small bowel and the diaphragm. The mortality in the series was 2%. Stab wounds are infrequent in Norway, and most surgeons have limited experience of such injuries. We discuss whether to employ immediate exploratory laparotomy or selective management when the peritoneum has been penetrated. When there is no evidence of evisceration or omental protrusion, local exploration of the wound should be performed in order to confirm or exclude peritoneal penetration. Injury to the diaphragm and intraabdominal viscera should always be suspected in thoracic stab wounds below the fourth intercostal space.

[Diagnostic peritoneal lavage in blunt abdominal trauma]. / Diagnostisk peritoneal skylling ved stumpe abdominaltraumer.

Peritoneal lavage was performed in 142 of 331 patients submitted to hospital after blunt abdominal trauma. The lavage catheter was introduced through a short infra-umbilical longitudinal incision with surgically controlled access to the peritoneal cavity. First time lavage was positive in 58 out of 68 patients in demand of laparotomy, and after repeated lavages in 66 of 68. In 12 patients there was a false positive lavage. The sensitivity was 97% and the specificity 84%. Negative lavage strongly indicates that laparotomy is not necessary. A positive test as an indication for laparotomy should be regarded with reservation. The method is simple to perform and represents a valuable supplement to clinical evaluation in patients with blunt abdominal trauma.

Pulmonary function and energy expenditure after marked weight loss in obese women: observations before and one year after gastric banding.

Pulmonary function and pulmonary gas exchange at rest, and during and after a standard exercise load of 500 kpm in 1 min on bicycle ergometer were studied in 34 women with severe, uncomplicated obesity, aged 37.8 (20-59) years, before and 1 year after gastric banding, resulting in a weight loss from 113.2 (84-156) to 81.7 (60-110) kg. Following the weight loss, TLC and VC rose from 93 and 94 per cent of expected to 98 and 101 per cent, respectively. FRC, ERV and FRC/TLC rose more markedly from 77, 64 and 83 per cent to 98, 109 and 99 per cent. IC fell from 108 to 99 per cent. RV and RV/TLV remained unchanged. FEV1.0 rose from 97 to 103 per cent, while MVV rose from 102 to 112 per cent, i.e. above normal. TLCO and PaCO2 remained unchanged, at 90 and 95 per cent, whereas PaO2 rose from 86 to 91 per cent. Resting O2 intake (VO2) decreased from 147 to 115 per cent of the expected for normal weight women, while VO2/BSA decreased from 113 to 99 per cent, the changes being greater than expected from commonly used formulas for prediction of metabolic rate. O2 cost of work (EO2) decreased from 142 to 105 per cent. Resting ventilation (V) declined from 136 to 113 per cent, while ventilatory cost of work (EV) decreased from 142 to 105 per cent. CO2 recovery time after work (CO2RT) decreased from 121 to 100 per cent, while the ratios CO2RT to EO2 and to extra CO2 output of work (ECO2) rose slightly. Thus, the loss of weight led to increased filling of the lungs, improved dynamic function, reduced ventilation/perfusion disturbances and greater than expected reduction of energy expenditure, both at rest and exercise. In the obese state there was no evidence of alveolar hypoventilation or impaired ventilatory control. The beneficial effect of weight reduction on the exertional dyspnea included a combination of marked reduction of ventilatory demands and moderate rise in ventilatory capacity.

Methylprednisolone in high doses gives different effects on the early and the late part of complement.

The effects of methylprednisolone (MP) on endotoxin-induced activation of complement were studied in citrated pool plasma. Complement activation was tested in two immunoassays: one evaluating C3 activation fragments (C3act) and the other the terminal complement complex (TCC). These components are indicators of initial and terminal complement activation, respectively. Plasma samples were obtained at 1, 2, 4 and 6 h of incubation. Plasma containing endotoxin (2.10(9) ng/l) without MP revealed a marked increase of both C3act and TCC after 1 h. MP in high doses (10 mg/ml) gave an additive effect on activation of the initial part of the complement cascade compared to test plasma containing only endotoxin. In contrast, endotoxin-induced activation of the terminal part of the complement cascade was inhibited by the same dose of MP. The influence of lower doses of MP (0.1 and 1 mg/ml) on endotoxin-induced activation of complement was insignificant. Interestingly, MP without endotoxin induced activation of the initial part of complement. In test plasmas containing 5 and 10 mg/ml of MP (without endotoxin) marked increases of C3act values were seen. Despite this obvious activation of the early part of complement, only insignificant changes were found in TCC values. Test plasmas containing 0.1 and 1 mg/ml of MP revealed only minor changes in both C3act and TCC. In conclusion, the present study shows that high doses of MP activate the initial part of complement and that the endotoxin-induced activation of this cascade system was facilitated by MP. The terminal part of complement was, on the other hand, inhibited by high doses of MP.