Biomedical subjects

Eric Bellissant

Publications and source records attributed to Eric Bellissant.

17 recordsLinked to original sources

PubMed2006

Direct effects of 3 combinations of enalapril, metoprolol, and spironolactone on cardiac remodeling in dilated cardiomyopathic hamsters.

BACKGROUND: In congestive heart failure, enalapril (E), metoprolol (M), and spironolactone (S) improve survival. Their direct effects on cardiac remodeling, when administered in combination, remain to be assessed. METHODS AND RESULTS: One hundred and five cardiomyopathic hamsters were divided into 5 groups (control, E, E-M, E-S, E-M-S) and treated from 150 to 240 days of age (E: 3 mg/kg, M: 1 mg/kg, S: 20 mg/kg). Cardiac and systemic hemodynamics, and cardiac remodeling were investigated. There was no difference between groups on blood pressure. Compared with C, both S-treated groups significantly increased cardiac index (E-S: +49%; E-M-S: +46%). Compared with C, E significantly decreased left ventricular (LV) cavity area (-10%). Compared with E, all combinations significantly decreased LV cavity area (E-M: -13%, E-S: -22%, E-M-S: -19%) and right ventricular (RV) collagen density (E-M: -18%, E-S: -30%, E-M-S: -34%), and the tri-therapy significantly decreased LV collagen density (-18%). Compared with bi-therapies, the tri-therapy significantly decreased LV (-19% vs. E-M, -16% vs. E-S) and RV (-20% vs. E-M) collagen densities. CONCLUSION: At subdepressor doses, both bi-therapies induced similar effects on myocardial remodeling, enhancing the effects of E on LV cavity area and reducing RV collagen density. Compared with bi-therapies, the tri-therapy induced additional effects on LV and RV collagen densities.

Adrenergic beta-Antagonists↗

PubMed2006

Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome.

OBJECTIVE: We investigated the efficacy of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome (ARDS) by post hoc analysis of a previously completed clinical trial. DESIGN: Retrospective analysis of a placebo-controlled, randomized, double-blind trial of low doses of corticosteroids in septic shock. SETTING: Nineteen intensive care units in France. PATIENTS: Among the 300 septic shock patients enrolled, we selected those meeting standard criteria for ARDS at inclusion. INTERVENTIONS: Seven-day treatment with 50 mg of hydrocortisone every 6 hrs and 50 microg of 9-alpha-fludrocortisone once a day. MEASUREMENTS AND MAIN RESULTS: There were 177 patients with ARDS (placebo, n = 92; corticosteroids, n = 85) including 129 (placebo, n = 67; corticosteroids, n = 62) nonresponders and 48 (placebo, n = 25; corticosteroids, n = 23) responders. In nonresponders, there were 50 deaths (75%) in the placebo group and 33 deaths (53%) in the steroid group (hazard ratio 0.57, 95% confidence interval 0.36-0.89, p = .013; relative risk 0.71, 95% confidence interval 0.54-0.94, p = .011). The number of days alive and off the ventilator was 2.6 +/- 6.6 in the placebo group and 5.7 +/- 8.6 in the steroid group (p = .006). There was no significant difference between groups in responders. There was no significant difference between groups in the two subsets of patients without ARDS. Adverse events rates were similar in the two groups. CONCLUSIONS: This post hoc analysis shows that a 7-day treatment with low doses of corticosteroids was associated with better outcomes in septic shock-associated early ARDS nonresponders, but not in responders and not in septic shock patients without ARDS.

Adult↗

PubMed2006

Dopexamine and norepinephrine versus epinephrine on gastric perfusion in patients with septic shock: a randomized study [NCT00134212].

INTRODUCTION: Microcirculatory blood flow, and notably gut perfusion, is important in the development of multiple organ failure in septic shock. We compared the effects of dopexamine and norepinephrine (noradrenaline) with those of epinephrine (adrenaline) on gastric mucosal blood flow (GMBF) in patients with septic shock. The effects of these drugs on oxidative stress were also assessed. METHODS: This was a prospective randomized study performed in a surgical intensive care unit among adults fulfilling usual criteria for septic shock. Systemic and pulmonary hemodynamics, GMBF (laser-Doppler) and malondialdehyde were assessed just before catecholamine infusion (T0), as soon as mean arterial pressure (MAP) reached 70 to 80 mmHg (T1), and 2 hours (T2) and 6 hours (T3) after T1. Drugs were titrated from 0.2 microg kg(-1) min(-1) with 0.2 microg kg(-1) min(-1) increments every 3 minutes for epinephrine and norepinephrine, and from 0.5 microg kg(-1) min(-1) with 0.5 microg kg(-1) min(-1) increments every 3 minutes for dopexamine. RESULTS: Twenty-two patients were included (10 receiving epinephrine, 12 receiving dopexamine-norepinephrine). There was no significant difference between groups on MAP at T0, T1, T2, and T3. Heart rate and cardiac output increased significantly more with epinephrine than with dopexamine-norepinephrine, whereas. GMBF increased significantly more with dopexamine-norepinephrine than with epinephrine between T1 and T3 (median values 106, 137, 133, and 165 versus 76, 91, 90, and 125 units of relative flux at T0, T1, T2 and T3, respectively). Malondialdehyde similarly increased in both groups between T1 and T3. CONCLUSION: In septic shock, at doses that induced the same effect on MAP, dopexamine-norepinephrine enhanced GMBF more than epinephrine did. No difference was observed on oxidative stress.

Aged↗

PubMed2005

Prevention of acquired infections in intubated patients with the combination of two decontamination regimens.

OBJECTIVE: The use of topical polymyxin and tobramycin to prevent intensive care infections is controversial. Moreover, these antibiotics are ineffective against methicillin-resistant Staphylococcus aureus. A decontamination regimen using mupirocin and chlorhexidine could prevent acquired infections, including those involving S. aureus. Because these two regimens could have a complementary role, we evaluated their effects when given both alone and combined. DESIGN: The authors conducted a multiple-center, placebo-controlled, randomized, double-blind study performed according to a 2 x 2 factorial design. SETTING: The study was conducted at three polyvalent medical intensive care units at university-affiliated hospitals in France. PATIENTS: Adult patients (age, > or =18 yrs) intubated for <48 hrs who were likely to be ventilated for >48 hrs. INTERVENTION: Two regimens were used: topical administration of polymyxin/tobramycin (or placebo) and nasal mupirocin with chlorhexidine body washing (or nasal placebo with liquid soap). The patients (n = 515) received polymyxin/tobramycin alone (n = 130), mupirocin/chlorhexidine alone (n = 130), both regimens (n = 129), or all placebos (n = 126) for the period of mechanical ventilation plus 24 hrs. MEASUREMENTS AND MAIN RESULTS: The incidence of total infections acquired from the date of randomization until the termination date of study treatments plus 48 hrs was assessed. There were fewer acquired infections with both regimens than with polymyxin/tobramycin alone (odds ratio, 0.44; 95% confidence interval, 0.26-0.75; p = .003), mupirocin/chlorhexidine alone (0.43; 0.25-0.73; p = .002), or all placebos (0.42; 0.25-0.72; p = .001). There were no differences between polymyxin/tobramycin alone (0.95; 0.59-1.54; p = .84) and mupirocin/chlorhexidine alone (0.98; 0.60-1.58; p = .92) vs. all placebos. The probability of freedom from infection was higher with both regimens than with polymyxin/tobramycin alone (p = .002), mupirocin/chlorhexidine alone (p < .001), or all placebos (p < .001). Infection rates were also significantly lower with both regimens than with polymyxin/tobramycin alone (p = .017), mupirocin/chlorhexidine alone (p < .001), or all placebos (p < .001). CONCLUSION: Acquired infections were substantially reduced by mupirocin/chlorhexidine plus polymyxin/tobramycin, whereas each regimen given alone was ineffective. Whether both regimens could increase Candida infections deserves further investigation.

Administration, Intranasal↗

PubMed2005

Impact of a mis-specification of the response rate under standard treatment in sequential clinical trials.

Phase III trials are aimed at assessing whether new treatments have superior efficacy than standards. Sequential methods, such as the single triangular test (STT) and the double triangular test (DTT), allow for early stopping of such trials. They use stopping boundaries which depend, for a binary endpoint, on pi(0) and pi(1) (response rates under standard and new treatment, respectively) and alpha and beta (type I and II errors, respectively). Thus, a wrong estimation of pi(0) at planning phase might have an influence on their statistical properties. We assessed the extent of this influence by simulations regarding alpha, 1--beta, and average sample number (ASN) and compared the two methods with the one-sided and two-sided single-stage designs (SSD). There was no influence on alpha for any test and the power achieved by the one-sided or two-sided SSD was moderately affected by a wrong estimation of pi(0). However, important drifts (whose magnitude depended on chosen design) were observed for sequential methods concerning power and ASN in case of moderate under- or overestimation of pi(0) (+/-20% compared with its 'true' value). For example, when 'true' values of pi(0) and pi(1) are 0.30 and 0.40, respectively, using design values of 0.10 and 0.20, the power is 0.57 and 0.50 for the STT and DTT, respectively, instead of 0.95. When 'true' values of pi(0) and pi(1) are 0.10 and 0.20, respectively, using design values of 0.30 and 0.40, the ASN under H(0) is 1,309 and 2,019 for the STT and DTT, respectively, instead of 392 and 601, respectively, using the right design. Using sequential methods in comparative clinical trials with binary responses requires a precise knowledge of the response rate under standard treatment to avoid losses in power or inappropriate increases in sample size.

Algorithms↗

PubMed2004

Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis.

OBJECTIVE: To assess the effects of corticosteroids on mortality in patients with severe sepsis and septic shock. DATA SOURCES: Randomised and quasi-randomised trials of corticosteroids versus placebo (or supportive treatment alone) retrieved from the Cochrane infectious diseases group's trials register, the Cochrane central register of controlled trials, Medline, Embase, and LILACS. REVIEW METHOD: Two pairs of reviewers agreed on eligibility of trials. One reviewer entered data on to the computer and four reviewers checked them. We obtained some missing data from authors of trials and assessed methodological quality of trials. RESULTS: 16/23 trials (n = 2063) were selected. Corticosteroids did not change 28 day mortality (15 trials, n = 2022; relative risk 0.92, 95% confidence interval 0.75 to 1.14) or hospital mortality (13 trials, n = 1418; 0.89, 0.71 to 1.11). There was significant heterogeneity. Subgroup analysis on long courses (> or = 5 days) with low dose (< or = 300 mg hydrocortisone or equivalent) corticosteroids showed no more heterogeneity. The relative risk for mortality was 0.80 at 28 days (five trials, n = 465; 0.67 to 0.95) and 0.83 at hospital discharge (five trials, n = 465, 0.71 to 0.97). Use of corticosteroids reduced mortality in intensive care units (four trials, n = 425, 0.83, 0.70 to 0.97), increased shock reversal at 7 days (four trials, n = 425; 1.60, 1.27 to 2.03) and 28 days (four trials, n = 425, 1.26, 1.04 to 1.52) without inducing side effects. CONCLUSIONS: For all trials, regardless of duration of treatment and dose, use of corticosteroids did not significantly affect mortality. With long courses of low doses of corticosteroids, however, mortality at 28 days and hospital morality was reduced.

Adrenal Cortex Hormones↗

PubMed2004

The effect of waiving consent on enrollment in a sepsis trial.

OBJECTIVE: Illustration of the difficulties in approaching critically ill patients for informed consent for inclusion into a randomized controlled trial and the impact of a waiver of consent from the patient's next of kin in the conduction of such studies. DESIGN: Descriptive survey of the inclusion rates into the Ger-Inf-05 study before and after a waiver of consent from the patient's next of kin. SETTING: Nineteen intensive care units in France. PATIENTS: Septic shock patients (n=300) included in a placebo-controlled randomized double-blind study on the efficacy and safety of a 7-day treatment with 50 mg hydrocortisone every 6 h intravenously and 50 microg fludrocortisone every 24 h orally. INTERVENTION: Introduction, 10 months after the beginning of the study, of a waiver of consent from the patient's next of kin if it was not present at the time of the patient's inclusion. MEASUREMENTS AND RESULTS: The mean inclusion rate was four patients per month before the introduction of the waiver of consent and increased to 10 patients per month after the study amendment including the waiver of consent. Informed consent was obtained from the patient himself or herself in 10 patients (3%) and from next of kin in 70 patients (23%). For the 220 other patients (74%), the investigators could not contact the responsible relative within the inclusion period. CONCLUSIONS: Recruitment rate in the Ger-Inf-05 study was clearly improved after the waiver of consent from the patient's next of kin. This probably contributed to the successful completion of the study.

Consent Forms↗

PubMed2004

Effect of preoperative oral sustained-release morphine sulfate on postoperative morphine requirements in elective spine surgery.

Sustained-release morphine sulfate (SRMS) is a painkiller used in oncology. The purpose of our study was to assess its efficacy on postoperative morphine requirements in elective spine surgery. This was a placebo-controlled, randomized, double-blind study. Adults scheduled for spine surgery under general anesthesia were orally administered SRMS (30 mg) or a placebo 2 h before surgery. Primary endpoint was postoperative cumulated morphine consumption through patient-controlled analgesia (PCA) during the 12 h following extubation. Statistical analysis was performed using a sequential method, the triangular test. The study was stopped after the sixth analysis (51 patients had been included; placebo: 26, SRMS: 25). Age, weight, sex ratio, type of surgery, intra-operative sufentanil consumption, anesthesia duration and time to extubation were similar in the two groups. Morphine consumption through PCA during the 12 h following extubation was significantly lower in the SRMS group (mean +/- SD: 10.5 +/- 7.6 mg) compared with placebo group (15.6 +/- 6.0 mg, P = 0.016, sequential analysis). Corresponding unbiased median estimates were 10.6 and 15.8 mg in SRMS and placebo groups, respectively. Morphine consumption through PCA during the 24 h following extubation was also significantly lower in the SRMS group (15.9 +/- 12.7 mg) compared with the placebo group (23.8 +/- 10.9 mg, P = 0.032). Vigilance, nausea and respiratory rate 3 and 6 h after extubation were similar in the two groups. A preoperative oral administration of SRMS (30 mg) induces a 33% reduction of postoperative morphine requirements in patients scheduled for spine surgery without inducing side effects.

Analgesia, Patient-Controlled↗

PubMed2003

Sequential methods and group sequential designs for comparative clinical trials.

Comparative clinical trials are performed to assess whether a new treatment has superior efficacy than a placebo or a standard treatment (one-sided formulation) or whether two active treatments have different efficacies (two-sided formulation) in a given population. The reference approach is the single-stage design and the statistical test is performed after inclusion and evaluation of a predetermined sample size. In practice, the single-stage design is sometimes difficult to implement because of ethical concerns and/or economic reasons. Thus, specific early termination procedures have been developed to allow repeated statistical analyses to be performed on accumulating data and stop the trial as soon as the information is sufficient to conclude. Two main different approaches can be used. The first one is derived from strictly sequential methods and includes the sequential probability ratio test and the triangular test. The second one is derived from group sequential designs and includes Peto, Pocock, and O'Brien and Fleming methods, alpha and beta spending functions, and one-parameter boundaries. We review all these methods and describe the bases on which they rely as well as their statistical properties. We also compare these methods and comment on their advantages and drawbacks. We present software packages which are available for the planning, monitoring and analysis of comparative clinical trials with these methods and discuss the practical problems encountered when using them. The latest versions of all these methods can offer substantial sample size reductions when compared with the single-stage design not only in the case of clear efficacy but also in the case of complete lack of efficacy of the new treatment. The software packages make their use quite simple. However, it has to be stressed that using these methods requires efficient logistics with real-time data monitoring and, apart from survival studies or long-term clinical trials with censored endpoints, is most appropriate when the endpoint is obtained quickly when compared with the recruitment rate.

Animals↗

PubMed2003

Combined effects of enalapril and spironolactone in hamsters with dilated cardiomyopathy.

Chronic angiotensin I-converting enzyme inhibition can be associated with aldosterone escape. We investigated the effects of enalapril, spironolactone, and their combination on hemodynamics and cardiac remodeling in cardiomyopathic hamsters to determine whether these drugs could exert additive effects. Cardiomyopathic hamsters, Bio TO-2 dilated strain, were orally treated with enalapril (20 mg. kg. day ) and/or spironolactone (20 mg. kg. day ) according to a 2 x 2 factorial design from 120 days of age. Animals were investigated at 180 (10 animals per group) and 240 (16 animals per group) days of age. Compared with corresponding untreated groups, enalapril significantly decreased mean blood pressure (-18%); enalapril and spironolactone significantly increased cardiac output (+28%, +11%) and femoral blood flow (+10%, +12%) and significantly decreased systemic (-38%, -17%) and femoral (-26%, -13%) vascular resistances. Enalapril and spironolactone significantly decreased left ventricle cavity area (-21%, -26%) and left (-34%, -47%) and right (-37%, -48%) ventricle collagen density. Spironolactone significantly increased left ventricle wall thickness (+4%). There were significant enalapril x spironolactone interactions for most variables (compared with control group, +52%, +36%, +45% for cardiac output; +26%, +28%, +26% for femoral blood flow; -50%, -30%, -45% for systemic vascular resistance; -33%, -20%, -35% for femoral vascular resistance; -27%, -31%, -40% for left ventricle cavity area; and -46%, -58%, -60% for left and -39%, -50%, -66% for right ventricle collagen density in enalapril, spironolactone, and enalapril + spironolactone groups, respectively). In cardiomyopathic hamsters, enalapril and spironolactone in combination did not improve hemodynamics more than enalapril alone but induced stronger effects than each drug alone on cardiac remodeling.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2002

Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.

CONTEXT: Septic shock may be associated with relative adrenal insufficiency. Thus, a replacement therapy of low doses of corticosteroids has been proposed to treat septic shock. OBJECTIVE: To assess whether low doses of corticosteroids improve 28-day survival in patients with septic shock and relative adrenal insufficiency. DESIGN AND SETTING: Placebo-controlled, randomized, double-blind, parallel-group trial performed in 19 intensive care units in France from October 9, 1995, to February 23, 1999. PATIENTS: Three hundred adult patients who fulfilled usual criteria for septic shock were enrolled after undergoing a short corticotropin test. INTERVENTION: Patients were randomly assigned to receive either hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50- micro g tablet once daily) (n = 151) or matching placebos (n = 149) for 7 days. MAIN OUTCOME MEASURE: Twenty-eight-day survival distribution in patients with relative adrenal insufficiency (nonresponders to the corticotropin test). RESULTS: One patient from the corticosteroid group was excluded from analyses because of consent withdrawal. There were 229 nonresponders to the corticotropin test (placebo, 115; corticosteroids, 114) and 70 responders to the corticotropin test (placebo, 34; corticosteroids, 36). In nonresponders, there were 73 deaths (63%) in the placebo group and 60 deaths (53%) in the corticosteroid group (hazard ratio, 0.67; 95% confidence interval, 0.47-0.95; P =.02). Vasopressor therapy was withdrawn within 28 days in 46 patients (40%) in the placebo group and in 65 patients (57%) in the corticosteroid group (hazard ratio, 1.91; 95% confidence interval, 1.29-2.84; P =.001). There was no significant difference between groups in responders. Adverse events rates were similar in the 2 groups. CONCLUSION: In our trial, a 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events.

Adrenal Insufficiency↗

PubMed2002

Serum ceruloplasmin and ferroxidase activity are decreased in HFE C282Y homozygote male iron-overloaded patients.

BACKGROUND/AIMS: A body of evidence suggests that ceruloplasmin (Cp), the major serum copper-containing protein, acts in iron metabolism due to its ferroxidase activity which appears essential for iron movements and exchanges. METHODS: The present study investigated the serum levels of Cp and its ferroxidase activity in 53 C282Y homozygote genetic hemochromatosis (38 iron overloaded, 15 iron depleted) patients as compared to age and sex-matched healthy volunteers. RESULTS: Serum levels of Cp were significantly decreased in iron-overloaded male hemochromatotic patients vs. the control group (P=0.02). Furthermore, serum ferroxidase activity was strongly and significantly lower in iron-overloaded male hemochromatotic patients (P<0.001). In contrast, in iron-depleted male hemochromatotic patients, who were under maintenance therapy by regular phlebotomies, serum levels of Cp and ferroxidase activity were not statistically different from those observed in controls. CONCLUSIONS: These data: (i) show that serum Cp and ferroxidase activity are decreased when C282Y homozygote men are iron overloaded and normal when iron depleted; (ii) suggest that iron may modulate the Cp gene expression; and (iii) raise the issue of the putative role of decreased serum ferroxidase activity in the phenotypic expression of HFE-1 hereditary hemochromatosis.

Adult↗

PubMed2002

Effects of epinephrine compared with the combination of dobutamine and norepinephrine on gastric perfusion in septic shock.

OBJECTIVE: In septic shock, the alteration of the gut barrier contributes to the development of multiple organ failure. The aim of the study was to compare epinephrine with the combination of dobutamine and norepinephrine on gastric perfusion in patients with septic shock. METHODS: In a prospective randomized study on 2 parallel groups, systemic and pulmonary hemodynamics (arterial and Swan-Ganz catheters), gastric mucosal blood flow (laser Doppler flowmetry technique), hepatic function (indocyanine green clearance), and blood gases were evaluated just before catecholamine infusion and when mean arterial pressure reached 70 to 80 mm Hg. Epinephrine or norepinephrine were titrated (from 0.1 microg/kg per minute, with 0.2 microg/kg per minute increases every 5 minutes). Dobutamine was continuously infused at 5 microg/kg per minute. RESULTS: Twenty-two patients were included (11 in each group). At randomization there was no significant difference between groups. At the time of evaluation, mean arterial pressure was 78 +/- 3 and 77 +/- 5 mm Hg in the epinephrine and dobutamine-norepinephrine groups, respectively. There was no significant difference between groups regardless of the systemic and pulmonary hemodynamic or blood gas variable considered. Nevertheless, compared with dobutamine-norepinephrine, epinephrine tended to induce greater values for cardiac index (5.0 +/- 1.6 versus 4.2 +/- 1.5 L/min per square meter; P =.078) and oxygen transport (617 +/- 166 versus 481 +/- 229 mL/min per square meter; P =.068). Epinephrine also induced significantly greater values of gastric mucosal blood flow (662 +/- 210 versus 546 +/- 200 units; P =.011) but did not modify indocyanine green clearance. CONCLUSIONS: In patients with septic shock, at doses that induced the same mean arterial pressure, epinephrine enhanced more gastric mucosal blood flow than the combination of dobutamine at 5 microg/kg per minute and norepinephrine. This effect was probably a result of higher cardiac index.

Adrenergic alpha-Agonists↗

PubMed2002

Early anti-remodeling effect of labetalol in the congestive heart failure model induced by aortic constriction in the guinea pig.

We investigated the effects of the beta1-beta2-alpha1-blocker, labetalol, in the congestive heart failure (CHF) model induced by aortic constriction in the guinea pig. One hundred days after aortic constriction, 52 animals were given either placebo, labetalol 2 mg/kg/d, or labetalol 20 mg/kg/d for 60 days. Eighteen sham-operated animals were used as controls. Investigations were performed at the end of the treatment period. Compared with sham-operated animals, banded animals receiving placebo showed signs of overt CHF with cardiac, systemic and regional (mesenteric and femoral) hemodynamic dysfunction, and pulmonary and hepatic congestion. An increase in whole heart, atria, and left and right ventricle weights associated with left ventricular cavity enlargement and left and right ventricular wall thickening indicated a remodeling process. Compared with placebo, labetalol did not significantly modify cardiac, systemic, or regional hemodynamic variables but significantly decreased pulmonary and hepatic congestion. Labetalol significantly reduced left ventricular cavity area (-10 and -20% after 2 and 20 mg/kg, respectively) and left ventricular (-4 and -16%) and right ventricular (-4 and -19%) wall thickness. In conclusion, labetalol induced partial regression of cardiac remodeling before hemodynamic improvement. This early anti-remodeling effect could play a role in the favorable effects observed with beta1-beta2-alpha1-blockers in humans.

Adrenergic beta-Antagonists↗

PubMed2002

Systemic and regional hemodynamic and cardiac remodeling effects of candesartan in dilated cardiomyopathic hamsters with advanced congestive heart failure.

The effects of the selective angiotensin II type 1 receptor antagonist candesartan on cardiac, systemic, and regional hemodynamics and on cardiac, pulmonary, and hepatic histomorphometry were investigated in cardiomyopathic hamsters (CMHs), Bio TO-2 dilated strain, with advanced congestive heart failure (CHF). Two groups were treated orally with candesartan cilexetil at 22 or 50 mg/kg/d from 190 days of age and compared with a control group (38 animals/group). Investigations were performed at 225, 255, and 285 days of age. Left ventricle (LV) and systemic blood pressures and cardiac output and mesenteric and femoral blood flows were measured in anesthetized animals. LV cavity area, LV and right ventricle (RV) wall thickness and collagen density, and pulmonary and hepatic congestion were assessed. Compared with the control group, candesartan did not modify cardiac hemodynamics but significantly and dose-dependently decreased systemic vascular resistances (on average: -23 and -32% after 22 and 50 mg/kg, respectively) and increased stroke volume (+32 and +42%) and cardiac output (+27 and +34%). Candesartan did not modify mesenteric vascular resistances and blood flow but significantly and dose-dependently decreased femoral vascular resistances (-19 and -33%) and increased femoral blood flow (+33 and +43%). Candesartan significantly decreased LV cavity area (-14 and -8%) and LV (-15 and -31%) and RV (-16 and -24%) collagen density but did not modify LV and RV wall thickness. Candesartan decreased pulmonary congestion at 255 and 285 days of age but did not modify hepatic congestion. In CMHs with advanced CHF, candesartan cilexetil improves systemic and femoral hemodynamics, partly reverses cardiac remodeling, and decreases pulmonary congestion.

Angiotensin Receptor Antagonists↗

PubMed2002

Combined effects of metoprolol and spironolactone in dilated cardiomyopathic hamsters.

The use of beta-blockers reduces angiotensin II levels, but could not adequately suppress aldosterone production. Thus, the combination of a beta-blocker with an aldosterone receptor antagonist could exert additive effects. The effects of metoprolol and spironolactone and their combination on hemodynamics and cardiac remodeling in cardiomyopathic hamsters (CMH) were investigated. The Bio TO-2 dilated strain of CMH was treated orally with metoprolol (10 mg/kg/day), spironolactone (20 mg/kg/day), or both according to a 2 x 2 factorial design (24 animals per group) from 120 days of age and during 120 days. As compared to corresponding untreated groups, metoprolol significantly decreased mean blood pressure (-7%), and metoprolol and spironolactone significantly increased cardiac output (18% and 19%, respectively), mesenteric blood flow (11% and 14%), and femoral blood flow (13% and 17%), and significantly decreased systemic (-24% and -15%), mesenteric (-14% and -13%) and femoral (-19% and -10%) vascular resistances. Metoprolol significantly increased renal blood flow (22%) and significantly decreased renal vascular resistance (-23%). Metoprolol and spironolactone significantly decreased the cavity area of the left ventricle (-21% and -32%, respectively) and the collagen density of the left (-36% and -39%) and right (-38% and -43%) ventricles. Although the combination did not induce stronger effects than each drug alone on the systemic and most regional hemodynamic variables, it did have a stronger effect on the cardiac remodeling (compared to control group: -24%, -34%, and -46% for the left ventricle cavity area, -33%, -35%, and -62% for collagen density in the left ventricle, and -52%, -57%, and -59% for collagen density in the right ventricle, respectively, in the metoprolol, spironolactone, and metoprolol + spironolactone groups). In CMH, metoprolol and spironolactone combined did not improve hemodynamics more than each drug alone, but did exert additive effects on cardiac remodeling.

Animals↗

PubMedDate not supplied

Septic shock.

Septic shock, the most severe complication of sepsis, is a deadly disease. In recent years, exciting advances have been made in the understanding of its pathophysiology and treatment. Pathogens, via their microbial-associated molecular patterns, trigger sequential intracellular events in immune cells, epithelium, endothelium, and the neuroendocrine system. Proinflammatory mediators that contribute to eradication of invading microorganisms are produced, and anti-inflammatory mediators control this response. The inflammatory response leads to damage to host tissue, and the anti-inflammatory response causes leucocyte reprogramming and changes in immune status. The time-window for interventions is short, and treatment must promptly control the source of infection and restore haemodynamic homoeostasis. Further research is needed to establish which fluids and vasopressors are best. Some patients with septic shock might benefit from drugs such as corticosteroids or activated protein C. Other therapeutic strategies are under investigation, including those that target late proinflammatory mediators, endothelium, or the neuroendocrine system.

Animals↗