Early life origins of chronic obstructive pulmonary disease.

BACKGROUND: Early life development may influence subsequent respiratory morbidity. The impact of factors determined in childhood on adult lung function, decline in lung function and chronic obstructive pulmonary disease (COPD) was investigated. METHODS: European Community Respiratory Health Survey participants aged 20-45 years randomly selected from general populations in 29 centres underwent spirometry in 1991-3 (n = 13 359) and 9 years later (n = 7738). Associations of early life factors with adult forced expiratory volume in 1 s (FEV(1)), FEV(1) decline and COPD (FEV(1)/FVC ratio <70% and FEV(1) <80% predicted) were analysed with generalised estimating equation models and random effects linear models. RESULTS: Maternal asthma, paternal asthma, childhood asthma, maternal smoking and childhood respiratory infections were significantly associated with lower FEV(1) and defined as "childhood disadvantage factors"; 40% had one or more childhood disadvantage factors which were associated with lower FEV(1) (men: adjusted difference 95 ml (95% CI 67 to 124); women: adjusted difference 60 ml (95% CI 40 to 80)). FEV(1) decreased with increasing number of childhood disadvantage factors (> or =3 factors, men: 274 ml (95% CI 154 to 395), women: 208 ml (95% CI 124 to 292)). Childhood disadvantage was associated with a larger FEV(1) decline (1 factor: 2.0 ml (95% CI 0.4 to 3.6) per year; 2 factors: 3.8 ml (95% CI 1.0 to 6.6); > or =3 factors: 2.2 ml (95% CI -4.8 to 9.2)). COPD increased with increasing childhood disadvantage (1 factor, men: OR 1.7 (95% CI 1.1 to 2.6), women: OR 1.6 (95% CI 1.01 to 2.6); > or =3 factors, men: OR 6.3 (95% CI 2.4 to 17), women: OR 7.2 (95% CI 2.8 to 19)). These findings were consistent between centres and when subjects with asthma were excluded. CONCLUSIONS: People with early life disadvantage have permanently lower lung function, no catch-up with age but a slightly larger decline in lung function and a substantially increased COPD risk. The impact of childhood disadvantage was as large as that of heavy smoking. Increased focus on the early life environment may contribute to the prevention of COPD.

Survival after peptic ulcer perforation: a time trend analysis.

The survival of 1098 patients with ulcer perforation in Norway during the period 1952-1990 was compared with expected survival. Cox regression models incorporating population mortality rates, were used to analyse effects of sex, age, year of birth, and year at risk on excess mortality. Survival was lower in patients than in the general population through a follow-up period of 38 years. Relative survival was lower in women as compared to men, due to more delayed treatment. Long-term survival was lower after praepyloric perforations than after the other perforation types. Relative survival was higher in patients treated 1952-1970 than in those treated more recently. However, adjustment for year of birth revealed a decline in short-term mortality with calendar time, which is in accordance with improved management during the study period. Relative mortality, particularly long-term mortality, was higher in younger birth cohorts, suggesting a shift towards more serious etiologies.

Gastric carcinogenesis in rats given hypertonic salt at different times before a single dose of N-methyl-N'-nitro-N-nitrosoguanidine.

A 1-ml dose of 4.5 M NaCl was given intragastrically to male Wistar rats at 10 min, 1 h, 4 h, 12 h, 24 h or 48 h before a single intragastric dose of 250 mg/kg N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). After 52 weeks the incidence of forestomach squamous cell carcinoma was 21% in control animals receiving MNNG alone. The cancer incidence in the forestomach varied with the time elapsed between application of NaCl and MNNG, and was significantly increased in animals pretreated with NaCl 4 h (43%), 12 h (54%) and 24 h (41%) before MNNG. These results show that salt has a cocarcinogenic effect on initiation of forestomach carcinogenesis in rats, and that this effect depends on the time interval between pretreatment with NaCl and application of MNNG. Gastric adenocarcinomas occurred more frequently in the antrum (78%) than in the corpus (22%). The incidence of gastric adenocarcinoma in animals pretreated with salt before application of MNNG (11%-22%) was not significantly influenced by the time elapsed between pretreatment with salt and application of MNNG, and did not differ from animals receiving MNNG alone (18%). The lack of a cocarcinogenic effect of NaCl on glandular gastric carcinogenesis might be due to the use of dimethyl/sulfoxide as solvent for MNNG.

Effect of salt on cell proliferation and N-methyl-N'-nitro-N-nitrosoguanidine penetration to proliferative cells in the forestomach of rats.

We have studied the effect of intragastric instillation of 4.5 M NaCl on cell proliferation and carcinogen penetration into the forestomach of Wistar rats at different time intervals after salt exposure. Cells in the S-phase were labelled by incorporation of bromodeoxyuridine and located after immunohistochemistry. N-[3H]Methyl-N'-nitro-N-nitrosoguanidine ([3H]MNNG) was used as the carcinogen and penetration of [3H]MNNG to proliferative cells was determined by autoradiography. The number of cells in S-phase per millimetre epithelium length 12 h and 24 h after salt exposure (32.2 +/- 11.9 and 20.6 +/- 7.4) was significantly higher than in the control animals (9.4 +/- 3.6). No increase in cell proliferation occurred during the first 2 h after salt exposure. Microscopy also revealed oedema in the lamina propia. The forestomach blood flow was not influenced by the application of hypertonic saline. [3H]MNNG at a concentration of 40 micrograms/ml did not penetrate to the proliferative cells in the forestomach and no effect of salt pretreatment on carcinogen penetration was seen. The low penetration of [3H]MNNG to proliferative cells in the forestomach epithelium may explain why this concentration of MNNG given in drinking water over several weeks usually does not induce squamous cell carcinomas in the forestomach. The previously observed cocarcinogenic effect of salt on squamous cell cercinogenesis in the upper gastrointestinal tract could be due to the observed increase in cell proliferation after salt exposure.

Proximal gastric vagotomy for peptic ulcer disease: follow-up of 483 patients for 3 to 14 years.

During the years 1972 to 1986, proximal gastric vagotomy was performed in 483 patients for management of duodenal, pyloric, or prepyloric ulcers. In 25 patients a drainage procedure was added because of pyloric stenosis. The operations were performed by 64 surgeons, most of whom were junior residents. After surgery four patients had lesser curve necrosis; one of the patients died. The 14-year cumulative ulcer recurrence rate was similar (about 13%) in patients treated for duodenal and pyloric/prepyloric ulcers. The cumulative recurrence rate was significantly higher in women (17%) than in men (12%). Twenty-three percent of female patients and 16% of male patients were considered Visick grade 4. Moderate dumping occurred in 29% and diarrhea in 7% of the patients. The diarrhea was moderate except in one patient who had disabling diarrhea. Women had more frequent nausea, epigastric fullness after meals, and food intolerance than men. Basal acid output, pentagastrin-stimulated peak acid output, and insulin-stimulated peak acid output were not found to be reliable tests for evaluating the completeness of vagotomy or predicting ulcer recurrence.

Effect of luminal pH and nutrient bicarbonate concentration on restitution after gastric surface cell injury.

Frog fundic mucosas whose surface layers were severely injured by exposure to 1 M NaCl for 10 minutes in an Ussing chamber uniformly recovered both physiologically and anatomically within 4 to 6 hours. The purpose of the present study was to examine the effects of luminal H+ and nutrient HCO-3 concentrations on this process of reconstitution. With 18 mM HCO-3, return of the transmucosal potential difference, tissue electrical resistance, and short-circuit current toward normal and anatomic recovery occurred at luminal pH of 7.4, 5.0, and 4.0 but not at 3.0. An inhibitor of pepsin did not favorably affect the outcome of luminal pH 3.0, but a nutrient HCO-3 concentration of 47.8 mM completely prevented the adverse effects of luminal pH 3.0. Reconstitution of epithelial integrity did not occur in the absence of HCO-3 at luminal pH 4.0. Thus, low luminal pH inhibits and high nutrient HCO-3 concentration supports the epithelial restitution after mucosal damage caused by hyperosmolar NaCl.

Comparison of different methods for measuring intra-abdominal pressure.

OBJECTIVE: Intra-abdominal pressure (IAP) can be measured in different ways but is usually measured indirectly via the urinary bladder. The aim of the study was to: 1) compare urinary bladder pressure, femoral vein pressure, and inferior caval vein pressure with IAP at different levels of IAP; and 2) try to find an optimal amount of fluid to be instilled into the urinary bladder before measurement of the bladder pressure, and to compare changes in blood flow in the femoral vein with that in the caval vein at different pressure levels. DESIGN: Experimental study. SETTING: Animal research laboratory. SUBJECTS: Eight domestic swine of both sexes, weighing 30.6+/-2.9 kg (mean+/-SD). INTERVENTIONS: Catheters connected to pressure transducers were placed into the urinary bladder, the inferior caval vein, the femoral vein, and the superior caval vein. Transit time flow probes were placed around the inferior caval vein and the femoral vein. After a stabilizing period, the abdominal pressure was increased stepwise by instillation of Ringer's solution into the abdomen and then decreased. Thereafter, we instilled fluid into the bladder at an IAP of 8 mmHg and at 20 mmHg and measured the amount of fluid needed to elevate the intra-vesical pressure by 2 mmHg. RESULTS: The pressures recorded in the urinary bladder, the inferior caval vein, and the femoral vein reflected the pressure in the abdominal cavity very well. The fluid volume needed to increase the bladder pressure by 2 mmHg was significantly lower at 20 mmHg IAP than at 8 mmHg. Blood flow in the femoral vein and the inferior caval vein showed a similar pattern and decreased when the intra-abdominal pressure increased. CONCLUSIONS: In our porcine model, and increasing the IAP by means of instillation of Ringer's solution, a reliable estimation of the IAP was obtained by measuring the pressure in the urinary bladder, the femoral vein or the inferior caval vein. The IAP estimated indirectly as the urinary bladder pressure is affected by the amount of fluid in the bladder, which should not exceed 10-15 ml. The decrease in femoral vein blood flow reflects the changes in inferior caval vein flow during increased IAP.

Role of angiotensin II under prolonged increased intraabdominal pressure (IAP) in pigs.

BACKGROUND: The aim of the study was to investigate the effect of the angiotensin II receptor antagonist losartan on renal hemodynamics and diuresis in pigs with increased intraabdominal pressure (IAP). METHODS: The IAP was maintained at 30 mmHg for 3 h by intraperitoneal instillation of Ringer's solution. Ten animals were treated with losartan; another 10 animals served as controls. Renal blood flow, hormones in renal vein blood, and diuresis were measured. RESULTS: In control animals, the renal vascular resistance increased renal blood flow remained constant, the blood concentration of aldosterone increased and the diuresis decreased during increased IAP. Losartan prevented the increase in vascular resistance and improved renal blood flow under increased IAP. It also prevented the rise in aldosterone concentration and increased the urine output to baseline level. CONCLUSION: Our results suggest that the renal vasoconstriction associated with increased IAP is due to increased production of angiotensin II. The oliguria associated with increased IAP is probably due, at least partly, to increased reabsorbtion of sodium and water in the renal tubuli caused by increased tissue concentration of aldosterone.

Effects of the aldosterone receptor antagonist potassium canrenoate on renal blood flow and urinary output during prolonged increased intraabdominal pressure (IAP) in pigs.

BACKGROUND: Increased intraabdominal pressure can be found after major abdominal trauma and necrotizing pancreatitis and is used during laparoscopic surgery. The purpose of this study was to investigate the effect of the aldosterone receptor antagonist (potassium canrenoate) on renal hemodynamics and urinary output in pigs during increased intraabdominal pressure (IAP). METHODS: The IAP was kept at 30 mmHg for 3 h by instillation of Ringer's solution into the peritoneal cavity. Eight animals were treated with potassium canrenoate and eight animals served as controls. Renal blood flow, hormones in femoral artery blood, and the urinary output were measured. RESULTS: The administration of potassium canrenoate was followed by increased aldosterone concentrations in arterial blood, increased blood concentration of potassium, and increased concentration of sodium in the urine, indicating satisfactory inhibition of aldosterone. Potassium canrenoate did not cause changes in cardiac output and arterial pressure. It did not affect the renal vascular resistance that increased at an IAP of 30 mmHg, or the renal blood flow that remained constant during the experiments. The group treated with potassium canrenoate had higher mean urinary output than the controls, but the difference was not significant. CONCLUSION: Increased IAP in pigs is associated with markedly reduced urinary output and increased serum concentrations of aldosterone. Although the urinary output did not increase significantly, the increased sodium concentration in the urine of canrenoate-treated animals suggests that the high blood level of aldosterone contributes to the oliguria under increased IAP.

Effects of prolonged increased intra-abdominal pressure on gastrointestinal blood flow in pigs.

BACKGROUND: The aim of the study was to investigate the effects of prolonged intra-abdominal pressure on systemic hemodynamics and gastrointestinal blood circulation. METHODS: The intra-abdominal pressure in anesthetized pigs was elevated to 20 mmHg (7 animals), 30 mmHg (7 animals), and 40 mmHg (4 animals), respectively. These pressures were maintained for 3 h by intra-abdominal infusion of Ringer's solution. A control group of seven animals had normal intra-abdominal pressure (IAP). Transit time flowmetry and colored microspheres were used to measure blood flow. RESULTS: An IAP of 20 mmHg did not cause significant changes in systemic hemodynamics or tissue blood flow. An IAP of 30 mmHg caused reduced blood flow in the portal vein, gastric mucosa, small bowel mucosa, pancreas, spleen, and liver. Serum lactate increased in animals with an IAP of 30 mmHg, but microscopy did not disclose mucosal damage in the stomach or small bowel. An IAP of 40 mmHg was followed by severe circulatory changes. CONCLUSIONS: Prolonged IAP at 20 mmHg did not cause changes in general hemodynamics or gastrointestinal blood flow. Prolonged IAP at 30 mmHg caused reduced portal venous blood flow and reduced tissue flow in various abdominal organs, but no mucosal injury. A prolonged IAP of 40 mmHg represented a dangerous trauma to the animals.

Role of histamine in regulation of blood flow in the injured gastric mucosa of the cat.

Superficial mucosal damage caused by a mild irritant (2 M NaCl) results in release of histamine and probably prostaglandins giving increased GMBF. This hyperemic response contributes to protect the mucosa during the early phase of repair after damage by supplying the mucosa with bicarbonate and by eliminating back diffusing acid and other toxic substances such as ethanol. We conclude that histamine plays an important role in the blood flow regulation in the stomach.

Acute gastric mucosal lesions, haemodynamic and microcirculatory changes in the thermally injured rat.

Early postburn changes in central haemodynamics, organ blood flow distribution and morphology of the gastric mucosa were studied using a standarized thermal skin injury model. Organ blood flow and cardiac output were determined using radioactive microspheres. In the control animals no marked changes in cardiac output or organ blood flow were observed, and the gastric mucosa remained essentially undamaged. After burn injury and no fluid resuscitation, cardiac output decreased by 78 per cent, and blood flow to the stomach, pancreas, spleen, muscle, skin and kidneys also decreased markedly and to about the same degree as the cardiac output, however the adrenal flow remained roughly unchanged at the baseline level. Gross and microscopic lesions developed in the stomach, especially in the corpus. In animals given fluid resuscitation after burn injury cardiac output decreased by 38 per cent during the experiment, but blood flow in the stomach, brain, kidneys and spleen remained fairly constant, while pancreatic and muscle blood flow decreased and adrenal blood flow increased markedly. The gastric mucosa showed only minor microscopic, but no macroscopic lesions at the end of the experiment. The results indicate that acute thermal skin injury induces profound changes in central haemodynamics and organ blood flow which can, however, largely be overcome by adequate fluid resuscitation. The data also suggest that, as in other examples of 'stress ulceration', impaired mucosal blood flow may underlie the stress ulceration which complicates severe burns.

Delay in operative treatment among patients with small bowel obstruction.

BACKGROUND AND AIMS: Delay in operative treatment for small bowel obstruction (SBO) has been shown to affect outcome adversely. The objective of this study was to detect time trends in treatment delay for patients with SBO during the study period 1961 to 1995 and to investigate factors influencing and factors affected by delay. MATERIALS AND METHODS: The records of 815 patients with 921 operations for SBO from 1961-1995 were studied. Patients with large bowel obstruction, paralytic ileus and SBO caused by abdominal cancer or intussusception were excluded. Data were analysed with descriptive statistics and multiple linear regression analyses. RESULTS: Old age and female sex were associated with increased treatment delay. Delay in hospital increased from 5 hours (median) in the 1960'ies to 16 hours (median) in the 1990'ies. Treatment delay correlated significantly with postoperative morbidity and hospital stay. Mortality increased after prolonged treatment delay in SBO caused by hernias whereas no significant increase in mortality was observed among adhesive obstructions. CONCLUSIONS: Hospital delay increased throughout the study period. Old patients and women had a longer median treatment delay than did young ones and men. Treatment delay led to an increase in postoperative morbidity and hospital stay after surgery for SBO.

Acute erosions of the gastric mucosa in burned rats: effect of gastric acidity and fluid replacement.

Early changes in the morphology of the gastric mucosa after the skin had been burned were studied using a standardised model in rats. A full thickness burn was inflicted by exposing about 20% of the total body surface area to hot water (99 degrees C) for 10 s. Intragastric acidity was kept at pH 1.0 or pH 7.4 in six experimental groups of eight rats. Rats were subjected to burns with the stomach irrigated at pH 1.0 or pH 7.4. Parallel groups received fluid replacement with a solution of human albumin, and two uninjured groups served as controls. Lesions of the gastric mucosa were measured by planimetry of photographs, and light microscopy was used for histological examination. At an intragastric pH of 1.0, the burned rats developed mucosal erosions covering an average of 13% of the total glandular mucosa; the remaining groups had only minimal mucosal lesions. Erosions of the gastric mucosa after the skin had been burned could be prevented in two ways--either by establishing an alkaline (pH 7.4) milieu in the gastric lumen, or by replacing sufficient fluid to maintain aortic blood pressure at the pre-experiment level. Fluid replacement prevented mucosal erosions even if the intragastric pH was kept at 1.0. Thus both luminal acidity and local tissue blood flow are possible mechanisms for gastric epithelial damage following burns of the skin.

Evaluation of the microsphere-method for determination of cardiac output.

Cardiac output was determined by means of radioactive microspheres, 15 +/- 5 microns in diameter. Blood flow in the ascending aorta was measured by an electromagnetic flowmeter. In eight cats thirty-eight simultaneous measurements were made of cardiac output and aortic flow. The observations correlated well (r = 0.89), with a mean difference of 5.2%, probably corresponding to coronary blood flow. Continuous flow recordings showed no alterations in aortic flow during the injections of microspheres; arterial blood pressure and heart rate remained unchanged even after six injections, each consisting of about 2 x 10(5) spheres per kg body weight. Tests for shunting of microspheres were performed and revealed shunt fractions in the systemic circulation of about 8%, with no significant shunting through the lungs. The microsphere method for determining cardiac output is thought to be an accurate method, suitable for small and medium sized animals.

Gastric ulceration associated with experimental vascular occlusion.

The left gastric artery was cannulated in 17 cats, and a single dose of microspheres was injected into the artery, after which it was ligated. Microspheres with diameters of 8-10 micrometer induced gastric mucosal erosions that healed within 1-2 weeks. Microscopic examination revealed that there were few microspheres in the submucosa, more in the muscularis and large numbers in the glandular layer. The muscularis mucosae was intact. After injection of 50 +/- 5 micrometer spheres a large gastric ulcer developed. The ulcers healed after 4 weeks. Microscopically, the ulcer penetrated through the muscularis mucosae, and many microspheres were seen in the submucosa and serosa beneath the ulcer.

The role of blood flow in gastric mucosal defence, damage and healing.

Blood flow plays an important role in protection of normal gastric mucosa and in the protection and healing of damaged mucosa. Blood flow contributes to protection by supplying the mucosa with oxygen and HCO3-, and by removing H+ and toxic agents diffusing from the lumen into the mucosa. Low mucosal blood flow predisposes to injury, whereas high blood flow protects against injurious agents. Superficial mucosal damage is followed by increased blood flow which supports the healing process and prevents superficial lesions from developing into deep ones. The hypermic response increases the supply of HCO3- to the mucosa and increases the resistance of the injured mucosa against back diffusing H+ and aggressive drugs such as ethanol (adaptive protection). Mucosal ischemia contributes to gastric ulceration in various clinical conditions such as hemorrhagic shock, stress, aorta aneurysm and after proximal gastric vagotomy. Blood vessels are damaged in gastric ulcers. During ulcer healing blood flow returns to normal. Stimulated or inhibited angiogenesis in the granulation tissue effects the healing of a gastric ulcer.

Blood flow distribution in the stomach of cats with gastric ulcer.

Ulcer was induced in the anterior wall of the antrum by a subserous injection of 0.3 ml of a 20% acetic acid solution. Carbonized microspheres 15 plus or minus 5 mu in diameter and labelled with 169Yb were used to measure blood flow in different regions and layers of the stomach. Approximately 2-3 million microspheres were injected into the left ventricle of the heart. Simultaneously a blood sample was drawn from the distal aorta at a flow of 1 ml/min. Standardized tissue samples were punched from the lesser curvature and the anterior and posterior walls of the antrum, corpus, and fundus. In each sample the mucosa was separated from the muscularis. The radioactivity of the blood and tissue samples was determined, and the blood flow was calculated for each tissue sample. Three groups of animals were examined: 1) anaesthetized control animals, 2) animals laparotomized one week before examination, 3) animals with a one-week ulcer. In the control animals the blood flow was found to be the same in corresponding regions of the anterior and posterior walls of the stomach. The flow was slightly lower in the antrum than the fundus. The flow was similar in the different regions of the muscularis. The muscularis flow was markedly lower than the mucosa flow. In the laparotomized animals the blood flow was found to be increased in the muscularis of the corpus. In the ulcer animals the mucosa flow was increased in the anterior wall of the antrum, and the muscularis flow was increased in the antrum and the anterior wall of the corpus.

[Use of growth hormone during catabolic state in a patient in postoperative intensive care]. / Bruk av veksthormon ved katabol tilstand hos en kirurgisk intensivpasient.

Patients in the intensive care unit often enter a catabolic state with significant protein loss, which may increase postoperative complications. Nutritional support alone usually does not reverse a catabolic state and thereby induce a positive protein balance. Recent studies suggest that recombinant human growth hormone (rhGH) stimulates protein synthesis and improves protein balance in critically ill patients. An increase in the level of growth hormone often fails to occur in critical illness and injury. We describe the case of a man aged 45 years who underwent laparoscopic fundoplasty for hiatus hernia repair. Because of complications, including perforation of the oesophagus, he entered a sustained catabolic state with negative protein balance and a weight loss approaching 20%. Therefore, on the 29th day after operation we started treatment with rhGH, Norditropin 24 IE/day im. The protein balance became positive three days later. This parameter maintained positive, also after the growth hormone therapy was discontinued 12 days later. The further course was uneventful and the patient was transferred to his local hospital 51 days after the fundoplasty. His condition was improving steadily.