Clinical impact of chronic substance abuse in a Norwegian ICU-population.

BACKGROUND: The clinical impact of chronic substance abuse of alcohol and drugs-referred to as substance use disorders (SUD)-is often overlooked in the intensive care (ICU) setting. The aims of the present study were to identify patients with SUD-regardless of cause of admission-in a mixed Norwegian ICU-population, and to compare patients with and without SUD with regard to clinical characteristics and mortality. METHODS: Cross-sectional prospective study of a mixed medical and surgical ICU-population aged ≥18 years in Oslo, Norway. Data were collected consecutively, using a questionnaire including the AUDIT-C test, medical records and toxicology results. Patients classified with SUD were divided into the subgroups alcohol use disorders (AUD) and drug use disorders (DUD). RESULTS: Overall, 222 (26%) of the 861 patients included were classified with SUD; 137 (16%) with AUD and 85 (10%) with DUD. 130/222 (59%) of the SUD-patients had substance abuse-related cause of ICU-admission. Compared to non-SUD patients, DUD-patients were younger (median age 42 vs 65 years) and had lower SAPS II scores (41 vs 46), while AUD-patients had higher SOFA scores (8.0 vs 7.3). Overall, age-adjusted logistic regression analysis showed similar hospital mortality for SUD-patients and non-SUD patients, but AUD was associated with increased mortality among medical patients and in patients with sepsis (OR 1.7 (95% CI 1.0-2.8), and OR 2.6 (95% CI 1.1-6.2)). CONCLUSION: One in four ICU-patients had SUD regardless of cause of admission. Alcohol use disorder was associated with increased mortality in medical patients and in patients with sepsis.

Impact of acute kidney injury on patient outcome in out-of-hospital cardiac arrest: a prospective observational study.

BACKGROUND: Kidney disease after out-of-hospital cardiac arrest (OHCA) is incompletely described. We examined the occurrence of acute kidney injury (AKI) in OHCA patients and impact of AKI, with or without renal replacement therapy (RRT), on 6-month mortality and neurological outcome. METHODS: Prospective study at Oslo University Hospital, Oslo, Norway. Adult resuscitated comatose OHCA patients treated with targeted temperature management at 33°C for 24 h were included. AKI and chronic kidney disease (CKD) were classified according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines. Main outcomes were 6-month mortality and good neurological outcome defined as Cerebral Performance Category 1-2. RESULTS: Among 245 included patients (84% males, mean age 61 years), 11 (4%) had previously known CKD and 112 (46%) developed AKI. Overall 6-month outcome revealed that 112 (46%) died and 123 (50%) had good neurological outcome. Compared with no kidney disease, the presence of AKI was significantly associated with 6-month mortality (odds ratio (OR) 3.17, 95% confidence interval (CI) 1.95-5.43, P < 0.001) and good neurological outcome (OR 0.28, 95% CI 0.16-0.48, P < 0.001). Six-month mortality (50 vs. 61%, P = 0.401) and frequency of good neurological outcome (44 vs. 35%, P = 0.417) were not statistically different in AKI patients with or without RRT, also after excluding patients where RRT was withheld due to futility. CONCLUSIONS: Kidney disease occurred in about half of patients successfully resuscitated from OHCA. Presence of AKI, but not RRT, was associated with unfavourable 6-month outcome.

Markers of thrombin generation are associated with myocardial necrosis and left ventricular impairment in patients with ST-elevation myocardial infarction.

INTRODUCTION: Platelet activation, thrombin generation and fibrin formation play important roles in intracoronary thrombus formation, which may lead to acute myocardial infarction. We investigated whether the prothrombotic markers D-dimer, pro-thrombin fragment 1 + 2 (F1 + 2) and endogenous thrombin potential (ETP) are associated with myocardial necrosis assessed by Troponin T (TnT), and left ventricular impairment assessed by left ventricular ejection fraction (LVEF) and N-terminal pro b-type natriuretic peptide (NT-proBNP). MATERIALS/METHODS: Patients (n = 987) with ST-elevation mycardial infarction (STEMI) were included. Blood samples were drawn at a median time of 24 h after onset of symptoms. RESULTS: Statistically significant correlations were found between both peak TnT and D-dimer (p < 0.001) and F1 + 2 (p < 0.001), and between NT-proBNP and D-dimer (p = 0.001) and F1 + 2 (p < 0.001). When dividing TnT and NT-proBNP levels into quartiles there were significant trends for increased levels of both markers across quartiles (all p < 0.001) D-dimer remained significantly associated with NT-proBNP after adjustments for covariates (p = 0.001) whereas the association between NTproBNP and F1 + 2 was no longer statistically significant (p = 0.324). A significant inverse correlation was found between LVEF and D-dimer (p < 0.001) and F1 + 2 (p = 0.013). When dichotomizing LVEF levels at 40 %, we observed significantly higher levels of both D-dimer (p < 0.001) and F1 + 2 (p = 0.016) in the group with low EF (n = 147). SUMMARY/CONCLUSION: In our cohort of STEMI patients we demonstrated that levels of D-dimer and F1 + 2 were significantly associated with myocardial necrosis as assessed by peak TnT. High levels of these coagulation markers in patients with low LVEF and high NTproBNP may indicate a hypercoagulable state in patients with impaired myocardial function.

Inhibition of phosphodiesterase-3 by levosimendan is sufficient to account for its inotropic effect in failing human heart.

BACKGROUND AND PURPOSE: Levosimendan is known as a calcium sensitizer, although it is also known to inhibit PDE3. We aimed to isolate each component and estimate their contribution to the increased cardiac contractility induced by levosimendan. EXPERIMENTAL APPROACH: Contractile force was measured in electrically stimulated ventricular strips from explanted failing human hearts and left ventricular strips from normal male Wistar rats. PDE activity was measured in a two-step PDE activity assay on failing human ventricle. KEY RESULTS: Levosimendan exerted a positive inotropic effect (PIE) reaching maximum at 10(-5) M in ventricular strips from failing human hearts. In the presence of the selective PDE3 inhibitor cilostamide, the PIE of levosimendan was abolished. During treatment with a PDE4 inhibitor and a supra-threshold concentration of isoprenaline, levosimendan generated an amplified inotropic response. This effect was reversed by ß-adrenoceptor blockade and undetectable in strips pretreated with cilostamide. Levosimendan (10(-6) M) increased the potency of ß-adrenoceptor agonists by 0.5 log units in failing human myocardium, but not in the presence of cilostamide. Every inotropic response to levosimendan was associated with a lusitropic response. Levosimendan did not affect the concentration-response curve to calcium in rat ventricular strips, in contrast to the effects of a known calcium sensitizer, EMD57033 [5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one]. PDE activity assays confirmed that levosimendan inhibited PDE3 as effectively as cilostamide. CONCLUSIONS AND IMPLICATIONS: Our results indicate that the PDE3-inhibitory property of levosimendan was enough to account for its inotropic effect, leaving a minor, if any, effect to a calcium-sensitizing component.

Elevated levels of PAI-1 activity and t-PA antigen are associated with newly diagnosed abnormal glucose regulation in patients with ST-elevation myocardial infarction.

BACKGROUND: Both Type 2 diabetes and cardiovascular disease have been associated with enhanced coagulation and suppressed fibrinolysis. OBJECTIVES: To investigate a possible relationship between selected hemostatic variables and abnormal glucose regulation (AGR) in patients with acute ST-elevation myocardial infarction (STEMI) without known diabetes and to study changes in selected hemostatic variables from baseline to follow-up in STEMI patients with or without AGR. METHODS: Plasminogen activator inhibitor-1 (PAI-1) activity, tissue plasminogen activator (t-PA) antigen, prothrombin fragment 1+2 (F(1+2)) and von Willebrand factor (vWF) were measured in fasting blood samples from 199 STEMI patients 16.5 h (median time) after admission and 3 months later. All patients were classified into normal glucose regulation (NGR) or AGR based on an oral glucose tolerance test at follow-up, according to the WHO criteria. RESULTS: High PAI-1 activity (≥ 75th percentile) measured in-hospital was associated with AGR (n = 49) with an adjusted odds ratio of 2.2 (95% confidence interval, 1.1, 4.4). In addition, high levels of t-PA antigen (≥ 75th percentile) were associated with AGR (adjusted odds ratio, 3.5; 95% confidence inteval, 1.5, 8.2), but only in men. Changes in the levels of F(1+2) were significantly more pronounced in patients with AGR compared with NGR (adjusted P = 0.04). CONCLUSION: Elevated levels of PAI-1 activity and t-PA antigen measured in-hospital in STEMI patients were associated with AGR classified at 3-month follow-up. Additionally, changes in the levels of F(1+2) were more pronounced in patients with AGR compared with NGR. The data suggest an enhanced prothrombotic state after an acute STEMI in patients with AGR without known diabetes.

Angiotensin II activates a bumetanide sensitive increase in 86RB+ efflux in the rat heart.

We previously reported that alpha-adrenoceptor (AR) stimulation of the isolated perfused rat heart increased the efflux of 42K+ and the K+ analogue 86Rb+. The main part of this increase was bumetanide sensitive, indicating an activation of the Na+/K+/2Cl- cotransporter. The purpose of the present study was to investigate the effects of angiotensin II (1-100 nmol/l) and the protein kinase C (PKC) activator PMA (phorbol-12-myristate-13-acetate, 1-1000 nmol/l) on 86Rb+ efflux from isolated rat hearts and to compare the effects with the effect of the alpha1- AR agonist phenylephrine (30 micromol/l) in the presence of a beta-AR antagonist. Phenylephrine increased the 86Rb+ efflux rate by 47+/-4.1% (n=5, p<0.001). Angiotensin II induced a maximal increase in 86Rb+ efflux rate of 13+/-1.6% (n=12, p<0.0001). The effect of angiotensin II was totally eliminated by bumetanide (50 micromol/l). PMA decreased the 86Rb+ efflux rate by 23+/-7.0 % (n=7, p=0.02) and this effect of PMA was not sensitive to bumetanide. Pre-treatment of the hearts with PMA for 30 min did not influence the response to phenylephrine. In conclusion, angiotensin II stimulation, but not PKC activation by PMA increased the 86Rb+ efflux rate in isolated rat hearts, but the effect was smaller than that of alpha1- AR stimulation. The effect of angiotensin II was completely abolished by bumetanide indicating an activation of the Na+/K+/2Cl- -cotransporter.

Alpha1-adrenergic activation of myocardial Na-K-2Cl cotransport involving mitogen-activated protein kinase.

The translocation mechanisms involved in the alpha1-adrenoceptor-stimulated efflux of the potassium analog 86Rb+ were studied in isolated rat hearts. Phenylephrine (in the presence of a beta-blocker) increased the efflux of 86Rb+ and 42K+, and the Na-K-2Cl (or K-Cl) cotransport inhibitor bumetanide reduced the response by 42 +/- 11%. Furosemide inhibited the response with a lower potency than that of bumetanide. The bumetanide-insensitive efflux was largely sensitive to the K+ channel inhibitor 4-aminopyridine. Inhibitors of the Na+/H+ exchanger or the Na+-K+ pump had no effect on the increased 86Rb+ efflux. The activation of the Na-K-2Cl cotransporter was dependent on the extracellular signal-regulated kinase (ERK) subgroup of the mitogen-activated protein (MAP) kinase family. Phenylephrine stimulation increased ERK activity 3.4-fold. PD-98059, an inhibitor of the ERK cascade, reduced both the increased 86Rb+ efflux and ERK activity. Specific inhibitors of protein kinase C and Ca2+/calmodulin-dependent kinase II had no effect. In conclusion, alpha1-adrenoceptor stimulation increases 86Rb+ efflux from the rat heart via K+ channels and a Na-K-2Cl cotransporter. Activation of the Na-K-2Cl cotransporter is apparently dependent on the MAP kinase pathway.

Receptor subtypes involved in the alpha1-adrenoceptor mediated increase in 86Rb+ efflux from the rat heart.

The aim of this study was to determine the involvement of the different alpha1-adrenoceptor subtypes in the alpha1-adrenoceptor mediated increase in 86Rb+ efflux from rat hearts. Isolated hearts were perfused in the presence of a beta-adrenoceptor antagonist (1 microM timolol). After loading with 86Rb+, the efflux was measured during alpha1-adrenoceptor stimulation by phenylephrine (30 microM). Phenylephrine increased the 86Rb+ efflux by about 30%. Pretreatment with the preferentially alpha1B-adrenoceptor inhibitor chloroethylclonidine (CEC), reduced the response to phenylephrine by about 50%. The preferential alpha1D-adrenoceptor inhibitor BMY 7378 inhibited the response to phenylephrine by 35%, with a pKI=8.4 (95% C.I. 8.2-8.6). The response was sensitive to the preferential alpha1A-adrenoceptor inhibitors (+)niguldipine, 5-methylurapidil (5-MU) and WB-4101 at relatively high concentrations, and 5-MU inhibited the response with a pKI=7.7 (95% C.I. 7.2-8.0) in CEC pretreated hearts. In conclusion, the phenylephrine stimulated increase in 86Rb+ efflux in the rat heart is not specifically linked to only one of the alpha1-adrenoceptor subtypes, but involves the alpha1B- and the alpha1D-adrenoceptor subtypes, and probably the alpha1A-adrenoceptor subtype as well.

Alpha 1-adrenoceptor mediated activation of Na/K/2Cl cotransport and K+ channels in the rat heart involves different receptor subtypes.

Involvement of receptor subtypes in the alpha 1-adrenoceptor mediated activation of Na/K/2Cl-cotransport and K+ channels was studied in isolated perfused spontaneously beating rat hearts stimulated by phenylephrine (30 mumol/l) in the presence of a beta-adrenoceptor antagonist (1 mumol/l timolol). The effects of alpha 1-adrenoceptor stimulation on K+ translocation mechanisms were studied by measuring the efflux of 86Rb+ (a potassium analogue). The effects of 50 mumol/l bumetanide (Na/K/2Cl-cotransport inhibitor) and 0.1-0.3 mmol/l 4-aminopyridine (inhibitor of K+ channels) were studied in the presence of alpha 1-adrenoceptor subtype selective antagonists. Bumetanide reduced the alpha 1-adrenoceptor mediated increase in 86Rb+ efflux by 53 +/- 16.4% (n = 14, P < 0.001) in hearts pretreated with the preferentially alpha 1B-adrenoceptor antagonist chloroethylclonidine (CEC, 10 mumol/l), and by 35 +/- 7.3% (n = 15, P < 0.001) in the presence of the preferentially alpha 1D-adrenoceptor antagonist BMY 7378 (1 mumol/l). In the presence of the preferentially alpha 1A-adrenoceptor antagonist 5-methylurapidil (10 mumol/l), however, bumetanide had no effect on the response to phenylephrine. 4-Aminopyridine reduced the phenylephrine stimulated 86Rb+ efflux in the presence of 5-methylurapidil, but the effect of the K(+)-channel blocker was eliminated in CEC treated hearts. Thus the effects of the two translocation inhibitors were influenced differently by the two subtype selective antagonists, showing that alpha 1-adrenoceptor stimulation activates a bumetanide sensitive Na/K/2Cl-cotransport mechanism in the rat heart mainly through the alpha 1A-receptor subtype while the 4-aminopyridine sensitive K+ channels, are mainly activated by the alpha 1B-adrenoceptor subtype.

Concentration-response relationship of alpha 1-adrenoceptor-stimulated increase of 86Rb+ efflux in rat heart.

UNLABELLED: The aim of the present study was to establish a concentration-response relationship for the alpha 1-adrenoceptor mediated increase of 86Rb+ efflux, and to characterize the sensitivity of this response to the selective alpha 1-adrenoceptor antagonist prazosin. Isolated rat hearts were perfused retrogradely at constant flow and at 31 degrees. Timolol (10(-6) mol/l) was used to block beta-adrenoceptors. After a loading period with 86Rb+ and 55 min. washout, the hearts were exposed to phenylephrine in a concentration range from 3 x 10(-8) mol/l to 10(-4) mol/l. Control experiments comparing the effects of alpha 1-adrenoceptor stimulation on 86Rb+ efflux and 42K+ efflux were performed. alpha 1-Adrenoceptor stimulation increased the 86Rb+ efflux with a pD2 = 6.35 +/- 0.20 (mean +/- S.E.M). The maximal response to phenylephrine was 22.5 +/- 2.0% (mean +/- S.E.M.) of the control values. The concentration-response curve was shifted to higher concentration of agonist in the presence of the alpha 1-adrenoceptor antagonist prazosin (3 x 10(10) mol/l). The calculated inhibition constant for prazosin was 6.1 x 10(-11) mol/l. 86Rb+ was found to be a suitable K+ analogue in the study of relative changes in K+ efflux although the basal efflux kinetics were different for the two isotopes. CONCLUSION: Phenylephrine increased the 86+b+ efflux concentration-dependently. A high sensitivity to prazosin confirmed the involvement of the alpha 1-adrenoceptor population.

Life threatening intoxication with sodium valproate.

Two female epileptics, 19 and 27 years old, were admitted after ingestion of an overdose of sodium valproate. The patients were comatose for 6 and 7 days and required mechanical ventilation for 7 and 10 days. Both patients were in deep coma for several days after serum concentrations had dropped into the therapeutic range. Serum concentrations of sodium valproate were 3348 mumol/L (482 mg/mL) in one patient and more than 10,000 mumol/L (1440 mg/mL) in the other. Drug elimination followed first order kinetics, and the plasma half-lives of sodium valproate were 19 and 20 hours, respectively. Their anemia, leucopenia and thrombocytopenia required transfusion. Liver enzymes were only moderately elevated, but one of the patients developed acute pancreatitis. There were no apparent sequelae two weeks after discharge from the hospital.