Effects of the stable prostacyclin analogue iloprost on mesenteric blood flow in porcine endotoxic shock

OBJECTIVE: To determine the effects of the stable prostacyclin analog, iloprost, in a porcine model of endotoxin-induced mesenteric ischemia. DESIGN: Prospective, experimental, randomized, controlled study. SETTING: Animal research laboratory at a university medical center. INTERVENTIONS: Pigs were randomized to receive a constant infusion of iloprost (0.18 microg/kg/min) or an equivalent amount of carrier solution (normal saline) 30 mins before being infused with endotoxin (100 microg/kg over 1 hr). The infusion with iloprost or carrier solution was continued for the duration of the experiment. MEASUREMENTS AND MAIN RESULTS: Twelve pigs (six per group), weighing between 20 and 22 kg, underwent laparotomy during which a magnetic flowprobe was placed around the superior mesenteric artery and an ileal tonometer was inserted. Thirty minutes before they were infused with endotoxin, the animals were randomized to receive intravenous iloprost or normal saline. Endotoxin was infused centrally over a 60-min period. Animals received normal saline at a rate of 1.2 mL/kg/min which was begun at the start of the endotoxin infusion. Data were measured at the end of the endotoxin infusion (E60) and 1 hr later (E120). Mean arterial pressure was not affected by the dosage of iloprost used in this experiment. After resuscitation, the cardiac output returned to baseline in the iloprost-treated group but remained decreased in the control group (2.6 +/- 0.5 vs. 1.6 +/- 0.4 L/min). Superior mesenteric blood flow increased 34% above baseline levels in animals pretreated with iloprost (from 363 +/- 85 to 485 +/- 81 mL/min). The superior mesenteric PCO2 was significantly higher (53 +/- 9 vs. 40 +/- 5 torr; 7.1 +/- 1.2 vs. 5.3 +/- 0.7 kPa) and the ileal intramucosal pH was significantly lower (7.07 +/- .28 vs. 7.44 +/- .23) in the control group than in the iloprost-treated group. CONCLUSIONS: Pretreatment with intravenous iloprost effectively increased intestinal blood flow in this model of endotoxin-induced mesenteric ischemia. This action of the drug resulted in an attenuation of ileal intracellular acidosis. Since low-dose iloprost had no effect on mean arterial pressure, it may be a useful adjunct in the treatment of sepsis and septic shock.     

Glucocorticoid regulation of adrenomedullin in a rat model of endotoxic shock

Wistar rats were injected intravenously with bacterial lipopolysaccharide (LPS) and developed endotoxic shock with severe hypotension. This was accompanied by significantly elevated concentrations of adrenomedullin (AM) in the plasma and expression of high levels of AM mRNA in the lung. Pretreatment of the rats with dexamethasone (DEX) prevented hypotension caused by LPS administration, but plasma AM concentrations and AM mRNA levels in the lung remained elevated. Adrenalectomized (ADX) rats developed a more severe form of circulatory shock in response to a low-dose of LPS. This was accompanied by only a slight increase in circulating AM in the plasma. However, pretreatment of ADX rats with DEX caused substantial elevations of plasma AM concentrations and expression of AM mRNA in the lung. Our studies demonstrate that glucocorticoid upregulates the expression and secretion of AM in vivo, and endogenous glucocorticoid is required for increased AM secretion under certain conditions such as endotoxic shock.     

Effects of MK-886, a leukotriene biosynthesis inhibitor, in a rabbit model of endotoxic shock

The aim of this study was to characterise the release of calcitonin gene-related peptide (CGRP) by capsaicin, low pH and prostacyclin in terms of Ca2+ channel dependence, interactions with K(ATP) channels and the role of action potential propagation, in the isolated, perfused guinea-pig heart. The Ca2+ channel blocker omega-conotoxin reduced CGRP release evoked by 10(-7) M capsaicin, as well as CGRP release evoked by pH 7. CGRP release caused by capsaicin at low (10(-7) M) but not high (10(-6) M) concentrations was also attenuated by tetrodotoxin, indicating partial dependence on action potential propagation. CGRP release caused by prostacyclin was not altered by any of the tested drugs. The K(ATP) channel activator cromakalim and the K(ATP) channel blocker glibenclamide had no effect on CGRP release. Previous findings that low pH and capsaicin stimulate capsaicin-sensitive afferents in the isolated heart at least partly through common mechanisms are thus supported. Attenuation of capsaicin-evoked release of CGRP by tetrodotoxin suggests recruitment of additional nerve terminals by a local axon reflex.     

Pulsatile tinnitus associated with a high jugular bulb and slow venous blood flow

A case of permanent pulsatile tinnitus of the left ear in a patient with hypertriglyceridemia is reported. The combined radiological study with computed tomography, magnetic resonance imaging, and digital angiography excluded a glomus tumor and revealed an enlarged, high-position jugular bulb with slow blood flow. Causes of pulsatile tinnitus are discussed. We conclude that imaging techniques play a major role in the diagnosis of head and neck vascular abnormalities.     

Dopamine and intestinal mucosal tissue oxygenation in a porcine model of haemorrhage

Haemorrhage is associated with intestinal mucosal hypoxia and impaired gut barrier function. Dopamine increases oxygen delivery to the intestinal mucosa and may thus counteract haemorrhage-induced mucosal hypoxia. Jejunal mucosal tissue oxygen tension (mucosal PO2) and jejunal oxygen saturation of mucosal microvascular haemoglobin (mucosal HbO2) were measured in 14 anaesthetized pigs. Seven animals served as controls (group C) and seven received continuous infusion of dopamine 16 micrograms kg-1 min-1 (group D) while 45% of blood volume was removed in three equal increments. Resuscitation was performed using shed blood and fluid. Mean arterial pressure and systemic oxygen delivery decreasing significantly during haemorrhage and returned to baseline after resuscitation in both groups. Mucosal PO2 decreased from 4.4 to 1.7 kPa after haemorrhage (P < 0.01) and further to 1.5 kPa after resuscitation (P < 0.01) in group C whereas group D showed an increase from 3.9 to 5.9 kPa after the start of the dopamine infusion (P < 0.05), but no significant difference from baseline after haemorrhage (2.3 kPa) (ns) or resuscitation (3.1 kPa) (ns). Mucosal HbO2 decreased from 52 to 32% after haemorrhage (P < 0.05) and increased to near baseline (37%) (ns) after resuscitation in group C whereas group D showed no significant changes from baseline (54%) throughout the experiment. Comparison between groups showed higher mucosal PO2 and HbO2 values for group D animals after the start of the dopamine infusion (P < 0.05 each), after the first two steps of haemorrhage (P < 0.01 each) and after resuscitation (P < 0.05 each). We conclude that i.v. dopamine 16 micrograms kg-1 min-1 improved tissue oxygenation of the small intestinal mucosa during moderate haemorrhage and subsequent resuscitation.     

Liver as a focus of impaired oxygenation and cytokine production in a porcine model of endotoxicosis

OBJECTIVES: To determine whether the liver is a focus of insufficient oxygenation and whether liver is a source of tumor necrosis factor (TNF) and interleukin-6 (IL-6) in a porcine model of endotoxicosis. DESIGN: In vivo, prospective, controlled, repeated-measures, experimental study. SETTING: Experimental physiology laboratory in a university. SUBJECTS: Juvenile pigs, weighing 22 to 35 kg. INTERVENTIONS: Catheters for blood sampling were inserted into the carotid artery, portal vein, hepatic vein, and pulmonary artery of anesthetized animals. Ultrasonic flow probes were placed on the portal vein and the hepatic artery. During surgery, normal saline was infused intravenously at 25 mL/kg/hr. Following stabilization, animals were allocated randomly to one of two groups. The endotoxemic group (n = 6) received 50 mg/kg of purified Escherichia coli lipopolysaccharide infused into the external jugular vein over 1 hr. The control group (n = 6) received a sham saline infusion infused over 1 hr. Once the endotoxin or sham infusion was initiated, the rate of the intravenous saline infusion was increased to 48 mL/kg/hr for the remainder of the experiment. Measurements were obtained before the endotoxin or sham infusion, immediately after the infusion, and every 30 mins thereafter for 4 hrs. MEASUREMENTS AND MAIN RESULTS: Blood gases, lactate, and bioactive TNF and IL-6 concentrations were measured from the carotid artery, portal vein, hepatic vein, and pulmonary artery. The porcine model is characterized by systemic hypotension, pulmonary hypertension, and maintenance of cardiac output. Despite decreased hepatic oxygen delivery in endotoxemic animals (p < .02), there was no change in hepatic oxygen consumption compared with controls. Throughout the experiment, there was net hepatic consumption of lactate in both groups. There was no significant hepatic production (or consumption) of TNF or IL-6 in either group. CONCLUSIONS: In this porcine model of endotoxicosis, there is a reduction of hepatic oxygen delivery but dysoxia is not present. The liver is not a source of TNF or IL-6 in this model of endotoxicosis.     

Fibrin-film stenting in a porcine coronary injury model: efficacy and safety compared with uncoated stents

Pyogenic liver abscess is an uncommon complication of intra-abdominal or biliary tract infection and is usually a polymicrobial infection associated with high mortality and high rates of relapse. However, over the past 15 years, we have observed a new clinical syndrome in Taiwan: liver abscesses caused by a single microorganism, Klebsiella pneumoniae. We reviewed 182 cases of pyogenic liver abscess during the period September 1990 to June 1996; 160 of these cases were caused by K. pneumoniae alone, and 22 were polymicrobial. When patients with K. pneumoniae liver abscess were compared with those who had polymicrobial liver abscess, we found higher incidences of diabetes or glucose intolerance (75% vs. 4.5%) and metastatic infections (11.9% vs. 0) and lower rates of intra-abdominal abnormalities (0.6% vs. 95.5%), mortality (11.3% vs. 41%), and relapse (4.4% vs. 41%) in the former group. Liver abscess caused by K. pneumoniae is a new clinical syndrome that has emerged as an important infectious complication in diabetic patients in Taiwan.     

Can measurement of mixed venous oxygen saturation replace measurement of cardiac output in patients with advanced heart failure?

BACKGROUND: Nursing care of patients with advanced heart failure with low ejection fraction requires strict management of IV fluids. Measurement of mixed venous oxygen saturation offers advantages over measurement of cardiac output because no administration of fluid is required and data are obtained continuously. OBJECTIVES: To determine the relationship between mixed venous oxygen saturation and cardiac output in patients with advanced heart failure who have low ejection fraction and to determine if use of vasoactive medications alters the relationship between mixed venous oxygen saturation and cardiac output. METHODS: Simultaneously obtained measurements of mixed venous oxygen saturation and cardiac output were compared in 42 patients with advanced heart failure with ejection fractions of 30% or less (mean, 19.5%). RESULTS: Correlation between mixed venous oxygen saturation and cardiac output was r = 0.54 (P < .001). For subjects not receiving vasoactive medications (n = 28), r = 0.52 (P = .004); for those receiving vasoactive medications (n = 14), r = 0.57 (P = .03). CONCLUSIONS: Similar correlations in the groups receiving and not receiving vasoactive medications suggest that even with pharmacological support, changes in mixed venous oxygen saturation may not be reflected by concomitant changes in cardiac output. Measurement of mixed venous oxygen saturation should not replace measurement of cardiac output for clinical decision making in patients with advanced heart failure with low ejection fraction.     

Effects of selective nitric oxide synthase inhibitor in sheep with endotoxic shock

OBJECTIVE: To investigate the effects of S-methylisothiourea sulfate (SMT), a selective inducible nitric oxide synthase (iNOS) inhibitor, on hyperdynamic endotoxic shock sheep. METHODS: Endotoxic shock was induced by Escherichia coli endotoxin in both control (n = 8) and SMT groups (n = 8). SMT was given intravenously. Hemodynamic data, oxygen delivery derived parameters and intramucosal pH (pHi) were measured. RESULTS: The control group had a hyperdynamic state, similar to that of human septic shock. In the SMT group, blood pressure was maintained at baseline, and cardiac index (CI) was lower than that in the control group (P < 0.05). Oxygen extraction ratio (O2 ext) was increased up to 40% +/- 5% and was much higher than that of the control group (P < 0.01). Pulmonary artery pressure (PAP) was higher than that of the control group (P < 0.01), and pHi decreased gradually similarly to the control group. CONCLUSION: SMT restored the blood pressure and increased O2 extespecially in the gut, but decreased CI and oxygen delivery and increased PAP. So over inhibition of iNOS should be cautiously considered.     

Measurement of cerebral oxyhaemoglobin saturation and jugular blood flow in term healthy newborn infants by near-infrared spectroscopy and jugular venous occlusion

Data of cerebral haemodynamics and oxygenation are important for optimal treatment and prognosis in neonatal intensive care. Mostly premature and asphyxiated infants have been examined, but near-infrared spectroscopy (NIRS) allows estimations in healthy term newborns. In this study, cerebral venous saturation (CVsO2) and jugular blood flow (JBF) was estimated in 11 healthy term newborns. Mean CVsO2 was 64.12 +/- 4.6%, which conform with expectations. Mean JBF was only 6.1 ml/100 g/min, which is unacceptably low compared to earlier published data. We discuss physiological and methodological aspects and conclude that the combination of NIRS and venous occlusion appears to be a reliable method for estimation of CVsO2 in normally healthy newborns, whereas the reason for the failure of the method for estimation of JBF is unclear.     

Effects of a new platelet-activating factor antagonist, UR-12670, on several endotoxic shock markers in rats

Chemical and pharmaceutical research have provided physicians with an array of drugs that have beneficial effects on a variety of diseases. Such drugs, however, mostly help in controlling the manifestations of the pathological condition but do not permanently modify the underlying cause. Hence the necessity of new forms of therapy that change drastically the current approach to medical treatment. Gene therapy, with its potential to correct the malfunctioning genes at the origin of variety of diseases, seems to fulfill the requirements of this therapeutic "revolution". The feasibility of such an approach is underscored by the improved knowledge of the molecular mechanism and/or gene defects at the origin of acquired diseases widely spread in the population, and of more rare congenital conditions. The technical advances in molecular biology and genetic engineering achieved in the last ten years, offer the tools necessary to implement such therapeutic interventions. Here we present the approaches currently employed for gene therapy in the context of recent clinical trials. The scientific, ethical and economical implications deriving from a prospective routine use of gene therapy in the clinical setting are discussed.     

Covariate measurement error and the estimation of random effect parameters in a mixed model for longitudinal data

We explore the effects of measurement error in a time-varying covariate for a mixed model applied to a longitudinal study of plasma levels and dietary intake of beta-carotene. We derive a simple expression for the bias of large sample estimates of the variance of random effects in a longitudinal model for plasma levels when dietary intake is treated as a time-varying covariate subject to measurement error. In general, estimates for these variances made without consideration of measurement error are biased positively, unlike estimates for the slope coefficients which tend to be 'attenuated'. If we can assume that the residuals from a longitudinal fit for the time-varying covariate behave like measurement errors, we can estimate the original parameters without the need for additional validation or reliability studies. We propose a method to test this assumption and show that the assumption is reasonable for the example data. We then use a likelihood-based method of estimation that involves a simple extension of existing methods for fitting mixed models. Simulations illustrate the properties estimators.     

Parellel blood circulation with oxygenation of blood in severe poisoning with carbon monoxide fumes

The authors present an analysis of treatment in 141 patients with acute carboxyhemoglobinemia, in 110 of them severe intoxication was noted. All these patients were treated taking into account the degree of intoxication, the period of time elapsed since the moment of the intoxication till the onset of therapy, and the presence of biochemical shifts in blood. In 31 patients being in an extremely poor comatous state with considerable disorders in gas balance, persistant hemodynamic disturbances and manifest humoral shifts a parallel perfusion with extracorporeal oxygenation of blood was performed with medical drug therapy in the background. The immediate effect was found to be quite favourable, however, 19 patients died in different terms as a result of subsequent complications, most frequently due to pneumonia and meningoencephalitis.     

Home blood pressure measurement has a stronger predictive power for mortality than does screening blood pressure measurement: a population-based observation in Ohasama, Japan

OBJECTIVE: To compare the predictive powers of self-measurement of blood pressure at home (home blood pressure measurement) and casual (screening) blood pressure measurement for mortality. DESIGN: A prospective cohort study. SUBJECTS AND METHODS: We obtained home and screening blood pressure measurements for 1789 subjects aged > or = 40 years who were followed up for a mean of 6.6 years. The prognostic significance of blood pressure for mortality was determined by the Cox proportional hazards regression model adjusted for age, sex, smoking status, past history of cardiovascular disease, and the use of antihypertensive medication. RESULTS: When the home blood pressure values and the screening blood pressure values were simultaneously incorporated into the Cox model as continuous variables, only the average of multiple (taken more than three times) home systolic blood pressure values was significantly and strongly related to the cardiovascular mortality risk. The average of the two initial home blood pressure values was also better related to the mortality risk than were the screening blood pressure values. CONCLUSIONS: Home blood pressure measurement had a stronger predictive power for mortality than did screening blood pressure measurement for a general population. This appears to be the first study in which the prognostic significances of home and screening blood pressure measurements have been compared.