Biomedical subjects

A B Johan Groeneveld

Publications and source records attributed to A B Johan Groeneveld.

9 recordsLinked to original sources

PubMed2003

Endotoxin impairs endothelium-dependent vasodilation more in the coronary and renal arteries than in other arteries of the rat.

Endotoxemia may result in endothelial dysfunction, and some vascular beds may be affected more than others. To test this hypothesis, we studied, in vitro, the reactivity of isolated rat coronary, renal, superior mesenteric, and hepatic arteries exposed to endotoxin (E. coli, 50 microg. mL(-1)) or saline for 2 h at 37 degrees C. Vascular smooth muscle function was tested using 125 mM KCl, the vasoconstrictors norepinephrine (NE), and the thromboxane analog U46619 (coronary artery). Endothelium-dependent vasorelaxation was tested with acetylcholine (ACh) in preconstricted vessels. Although differing between vessel types, the smooth muscle contractile responses were not affected by endotoxin, either in the presence or absence of L-arginine. Endotoxin impaired the response to ACh in rat coronary arteries (92.7 +/- 4.6% vasodilation in control and 41.3 +/- 11.6% in endotoxin-exposed segments) and in renal arteries (66.7 +/- 5.2% vasodilation in control and 43.2 +/- 4.9% in endotoxin-exposed segments), so that there was a mean 55% decrease vs controls in coronary and a mean 35% decrease in renal arteries. Endotoxin did not affect superior mesenteric and hepatic arteries. Brief endotoxin exposure of isolated rat arteries may thus inactivate endothelial NO synthase, independent of iNOS. The increase in heterogeneity among endothelium-dependent vasodilation after endotoxin may help to explain early blood flow maldistribution in endotoxin shock.

Animals↗

PubMed2003

Elevated nucleosome levels in systemic inflammation and sepsis.

OBJECTIVE: Multiple organ dysfunction syndrome is a frequent complication of severe sepsis and septic shock and has a high mortality. We hypothesized that extensive apoptosis of cells might constitute the cellular basis for this complication. DESIGN: Retrospective study. SETTING: Medical and surgical wards or intensive care units of two university hospitals. PATIENTS: Fourteen patients with fever, 15 with systemic inflammatory response syndrome, 32 with severe sepsis, and eight with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed circulating levels of nucleosomes, specific markers released by cells during the later stages of apoptosis, with a previously described enzyme-linked immunosorbent assay in these 69 patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock. Severity of multiple organ dysfunction syndrome was assessed with sepsis scores, and clinical and laboratory variables. Elevated nucleosome levels were found in 64%, 60%, 94%, and 100% of patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock, respectively. These levels were significantly higher in patients with septic shock as compared with patients with severe sepsis, systemic inflammatory response syndrome, or fever, and in nonsurvivors as compared with survivors. In patients with advanced multiple organ dysfunction syndrome, nucleosome levels correlated with cytokine plasma levels as well as with variables predictive for outcome. CONCLUSIONS: Patients with severe sepsis and septic shock have elevated plasma levels of nucleosomes. We suggest that apoptosis, probably resulting from exposure of cells to excessive amounts of inflammatory mediators, might by involved in the pathogenesis of multiple organ dysfunction syndrome.

Adult↗

PubMed2002

Cold storage sensitizes rat femoral artery to an endotoxin-induced decrease in endothelium-dependent relaxation.

Cold-stored arteries, tissues or organs are transferred in vascular, reconstructive and transplantation surgery. The function of transferred vessels and tissues diminishes when infection complicates transplantation, thereby contributing to morbidity. To evaluate the mechanisms involved, the effects of cold storage on basal vascular reactivity and the sensitivity to the vascular effects of endotoxin were tested in isolated rat femoral artery segments. A crossover design was followed, so that prior to cold storage 4 vessels were incubated for 2 h at 37 degrees C with endotoxin (Escherichia coli 0127:B8, 50 microg mL(-1)) in Krebs solution and 4 with Krebs solution only, while, after cold storage, segments from the former vessels were incubated with Krebs solution only and segments from the latter with endotoxin in Krebs solution. Vascular reactivity was tested in a wire myograph by the addition of depolarizing 125 mM KCl or norepinephrine (NE) as well as the endothelium-dependent vasodilator acetylcholine (ACh) and endothelium-independent vasodilator sodium nitroprusside (SNP). Cold storage did not affect vascular reactivity in the absence of endotoxin. Endotoxin decreased maximum response to NE prior to storage and sensitivity to SNP prior to and after cold storage. After cold storage, endotoxin decreased relaxation to ACh and increased vasoconstriction in response to KCl and NE (P < 0.05). We conclude that cold storage does not alter endothelial and smooth muscle function but sensitizes rat femoral artery to an endotoxin-induced decrease in endothelium-dependent relaxation and thereby to an increase in vasoconstrictor responses, whereas endotoxin alone only decreases receptor-dependent vasoconstrictor responses and sensitivity to NO donors. This may explain in part the detrimental effect of infection on function of cold-stored arterial grafts and tissue/organ transfers.

Acetylcholine↗

PubMed2002

Hypoproteinemia as a marker of acute respiratory distress syndrome in critically ill patients with pulmonary edema.

OBJECTIVE: To assess the value of serum protein levels for differentiating permeability pulmonary edema in the course of acute respiratory distress syndrome (ARDS) from cardiogenic pulmonary edema (CPE). DESIGN AND SETTING: Observational cohort study in intensive care units of 720-bed university hospital. PATIENTS: Twenty-four consecutive patients with clinical evidence of edema, 11 fulfilling the consensus definition of ARDS, 7 having sepsis, 5 with all ARDS consensus criteria and sepsis but a pulmonary capillary wedge pressure above 18 mmHg (mixed), and 8 with CPE. All patients except for one with CPE were mechanically ventilated. MEASUREMENTS AND RESULTS: Radionuclide assessments of pulmonary microvascular protein (transferrin) permeability (pulmonary leak index, PLI) were carried out and serum protein levels determined at admission and for ARDS/mixed patients, at recovery, defined by a decrease in positive end-expiratory pressure to 0 cmH2O. At admission the PLI was higher in ARDS/mixed than in CPE patients. The total protein and transferrin levels were lower in the former. The area under the curve of the receiver operating characteristic for diagnosing ARDS (vs. CPE) was 0.98 for transferrin (cutoff value 1.5 g/l), 0.95 for total protein (cutoff value 59 g/l) and 0.80 for albumin (cutoff value 24 g/l) levels. In various clinical diagnostic groups the transferrin level approached the PLI in diagnostic value. At recovery the PLI had decreased and serum protein levels increased. CONCLUSIONS: The data suggest that hypoproteinemia is a marker of ARDS. This may partially reflect increased permeability in the lungs, systemically, or both.

Adult↗

PubMed2002

Insulin: a wonder drug in the critically ill?

Stress hyperglycaemia is a common event in acute critical illness. There is increasing evidence that maintaining normoglycaemia and treatment with insulin (or with glucose-insulin-potassium [GIK]), even in non-diabetic persons, is helpful in limiting organ damage after myocardial infarction, stroke, traumatic brain injury and other conditions, even though the conditions may be accompanied by insulin resistance. A landmark study now suggests that maintaining normoglycaemia with intensive insulin treatment in a heterogeneous population of critically ill patients decreases morbidity and mortality. The potential mechanisms that underlie such a beneficial effect are discussed.

Animals↗

PubMed2002

Vascular pharmacology of acute lung injury and acute respiratory distress syndrome.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) following sepsis, major trauma and surgery are leading causes of respiratory insufficiency, warranting artificial ventilation in the intensive care unit. It is caused by an inflammatory reaction in the lung upon exogenous or endogenous etiologies eliciting proinflammatory factors, and results in increased alveolocapillary permeability and protein-rich alveolar edema. The interstitial and alveolar inflammation and edema alter ventilation perfusion matching, gas exchange and mechanical properties of the lung. The current therapy of the condition is supportive, paying careful attention to fluid balance, relieving the increased work of breathing and improving gas exchange by mechanical ventilation, but in vitro, animal and some clinical research is done to evaluate the value of anti-inflammatory therapies on morbidity and outcome, including inflammatory cell-stabilizing corticosteroids, xanthine derivates, prostanoids and inhibitors, O(2) radical scavenging factors such as N-acetylcysteine, surfactant replacement, vasodilators including inhaled nitric oxide, vasoconstrictors such as almitrine, and others. None of these compounds has been proven to benefit survival in patients, however, even though carrying a physiologic benefit, except perhaps for steroids that may improve outcome in the later stage of ARDS. This partly relates to the difficulty to assess the lung injury at the bedside, to the multifactorial pathogenesis and the severity of comorbidity, adversely affecting survival.

Animals↗

PubMed2002

Correlation between midazolam and lignocaine pharmacokinetics and MEGX formation in healthy volunteers.

AIMS: The objectives of the present investigation were: (a) to determine the correlation between lignocaine and midazolam pharmacokinetics following intravenous administration in healthy volunteers, (b) to determine the effects of treatment with an inhibitor of CYP3A4 (erythromycin) on this correlation and (c) to assess the precision of the MEGX-test as a sole predictor of lignocaine and midazolam pharmacokinetics. METHODS: The study was conducted in four male and four female healthy volunteers, aged between 21 and 26 years, who received 1 mg kg-1 lignocaine HCl i.v. on days 1, 3, 5, 9 and 10 of the investigation. On days 5 and 10 they also received midazolam, 0.075 mg kg-1 i.v. and from days 6-10 they took erythromycin 500 mg orally, four times daily. Following administration of lignocaine and midazolam, frequent venous blood samples were obtained for determination of the concentrations of lignocaine, MEGX and midazolam. RESULTS: In the absence of erythromycin a statistically significant linear correlation was observed between the clearance of lignocaine and midazolam (CL(midazolam)= 0.41 x CL(lignocaine)+ 1.2; r(2) = 0.857; P < 0.001). Erythromycin cotreatment resulted in a loss of the correlation between the two clearances (r(2) = 0.39; P = 0.1). Erythromycin caused a statistically significant reduction in midazolam clearance from the original value of 3.8 to 2.5 (95% CI for the difference -2.27, -0.35) ml kg-1 min-1. Interestingly there was no significant change in the clearance of lignocaine (6.4 vs 5.8 (95% CI for the difference -2.74, -1.51) ml kg-1 min-1). Furthermore no correlation at all was observed between the MEGX-test and lignocaine or midazolam clearances. Considering the data on day 1, 3 and 5 the intra-individual coefficient of variation in the MEGX-test was 45.3% at 15 min and 23.5% at 30 min, respectively. CONCLUSIONS: It is concluded that there is a significant correlation between lignocaine and midazolam clearances but this correlation is lost after CYP3A4 inhibition by erythromycin. The MEGX-test is of no value in assessing intra- and inter-individual variability in midazolam clearance.

Adult↗

PubMed2002

Tumor necrosis factor-alpha impairs endothelium-dependent relaxation of rat renal arteries, independent of tyrosine kinase.

We hypothesized that tumor necrosis factor-alpha (TNF-alpha) mimics endotoxin in attenuating endothelium-dependent vasodilation and smooth muscle constriction of rat renal arteries, and that tyrosine kinase is involved. Isolated rat renal arteries (n =6 per group), pretreated for 2 h by genistein (4',5,7-trihydroxyisoflavone, 10 microg/mL, a tyrosine kinase inhibitor) or vehicle, were exposed for 2 h to recombinant human (rh) TNF-alpha (100 ng/mL) or vehicle. rhTNF-alpha attenuated (P < 0.05) the constriction response to depolarizing 125 mM KCl (952.6+/-125.3 mg/mm vs. 1191.4+/-136.8 mg/mm in rhTNF-alpha-exposed and control segments, respectively), but did not affect the constriction response to norepinephrine (NE, 0.01-10 microM). Genistein did not affect the constriction response to KCl. The concentration-response relation to NE in genistein-pretreated control segments showed (P < 0.05) a rightward shift, while the maximum constriction was not affected. Genistein did not prevent a reduction (P < 0.05) by rhTNF-alpha in the maximum response to NE (721.7+/-42.4 mg/mm vs. 999.8+/-84.4 mg/mm in controls). The endothelium-dependent relaxation induced by (acetyl choline) ACh (0.001-1.0 microM) was attenuated (P < 0.05) by rhTNF-alpha (39.4%+/-6.7% and 77.4%+/-10.0% in rhTNF-alpha-exposed and control segments, respectively). The reduction (P < 0.05) in maximum ACh-induced relaxation after exposure to rhTNF-alpha was not affected by genistein (44.6%+/-3.4% and 70.8% x 2.2% in genistein-pretreated rhTNF-alpha-exposed and control segments, respectively). Hence, the attenuated endothelium-dependent relaxation and smooth muscle constriction of rat renal arteries following short-term rhTNF-alpha exposure, mimicking the effect of endotoxin, does not involve the activity of tyrosine kinase. The latter may be involved in pharmacomechanical coupling, by increasing Ca2+ sensitivity, but less in the electromechanical coupling of smooth muscle constriction.

Acetylcholine↗

PubMed2001

Early inhibition of activated fibrinolysis predicts microbial infection, shock and mortality in febrile medical patients.

To evaluate the contribution of an imbalance between coagulation activation and fibinolysis activation and inhibition to morbidity and mortality in sepsis, we determined in medical hospitalized patients at inclusion (day 0) for fever (temperature above 38.0 degrees C axillary or 38.3 degrees C rectally), and daily thereafter for two days, circulating thrombin-antithrombin III (TAT) complexes, plasmin-alpha2-antiplasmin (PAP) complexes (day 0 only), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and interleukin (IL)-6, the latter as a marker of the inflammatory host response. Study variables were 1) positive microbiological results for specimens from local sites associated with a clinical infection, positive blood cultures (including parasitemia) or both, within 7 days after inclusion, 2) development of shock, i.e. systolic blood pressure <90 mmHg or a reduction of 40 mmHg from baseline within 7 days after inclusion, and 3) death related to febrile illness within 28 days after inclusion. The peak plasma levels of TAT complexes were elevated in 44% and the PAP complexes in all patients. The t-PA and PAI-1 levels were elevated in 74 and 94% of patients, respectively. Values for TAT and PAP did not differ among subgroups, while peak t-PA and IL-6 levels were higher in patients with positive microbiological results, developing shock or ultimately dying than in those without the complications (p<0.005). Peak PAI-1 levels were elevated in patients developing shock and ultimate death versus those with an uncomplicated course (p <0.05). Peak IL-6 related to PAI-1 and t-PA levels, which interrelated. Patients with elevated TAT levels had increased plasma levels of IL-6, PAP, PAI-1 and t-PA versus those with normal TAT (p <0.05). Our data indicate that inhibition of activated fibrinolysis, which may partly depend on both cytokinemia and activation of coagulation, predicts microbial infection, septic shock and mortality of febrile medical patients. This suggests an early pathogenic role of inhibition of activated fibrinolysis in the downhill course of serious microbial infection.

Adolescent↗