flunarizine and Heart-Arrest

To investigate the cerebro-protective effect of flunarizine i.v. in patients successfully resuscitated from ventricular fibrillation outside hospital, a double-blind, placebo-controlled randomized study was started in February 1988 in West-Berlin with all eight Mobile Intensive Care Units and ten major hospitals participating. Start of treatment was in the patient's home immediately after restoration of stable circulatory conditions. Primary endpoints reduction of mortality due to hypoxic brain damage and more rapid improvement after cardiac arrest and resuscitation. Inclusion criteria men and women without age limit, ventricular fibrillation prior to or upon arrival of a MICU, primarily successful cardiac resuscitation with continuing unconsciousness. Recruitment of patients will end January 31st, 1990. An inclusion of about 500 patients is expected.

Topics: Clinical Trials as Topic; Double-Blind Method; Flunarizine; Heart Arrest; Humans; Injections, Intravenous; Medical Records; Research Design

In order to determine whether the calcium blockers verapamil and/or magnesium sulfate decrease neurological morbidity after cardiac arrest, all out-of-hospital cardiac arrests (290) occurring during a nine-month period in five participating hospitals were retrospectively studied. Twenty-nine patients met the criteria for inclusion in this study. Each had an unwitnessed, out-of-hospital cardiac arrest and was comatose (no purposeful response to pain) 20 minutes after the restoration of spontaneous circulation (ROSC). Eighteen patients (calcium blocker group) received verapamil and/or magnesium sulfate at some point after ROSC, while eleven patients received standard ACLS therapy (control group). Age, arrest time, cardiopulmonary resuscitation (CPR) time, and cerebral ischemic time were comparable in the two groups. In the calcium blocker group, seven of 18 patients regained consciousness, and six of these seven survived. All six survivors appeared neurologically normal upon discharge and at three and six months of follow-up. While no demonstrably adverse effects were seen after the administration of magnesium sulfate, 56% of the patients who received verapamil had a significant drop in blood pressure. In the control group, three of 11 patients regained consciousness and two of the three left the hospital alive. Both survivors were disabled--one severely and one moderately. Follow-up after three and six months revealed no significant improvement in their disability. Overall, six of 18 patients experienced clinically complete neurological recovery in the calcium blocker group, while none of the 11 patients in the control group made a complete neurological recovery (P = 0.06).

Topics: Aged; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Circulation; Cinnarizine; Clinical Trials as Topic; Flunarizine; Heart Arrest; Humans; Middle Aged; Neurologic Manifestations; Neuropsychological Tests; Piperazines

Anoxic depolarization (AD) and failure of ion homeostasis play an important role in ischemia-induced neuronal injury. In the present study, different drugs with known ion-channel-modulating properties were examined for their ability to interfere with cardiac-arrest-elicited AD and with the changes in the extracellular ion activity in rat brain. Our results indicate that only drugs primarily blocking membrane Na+ permeability (NBQX, R56865, and flunarizine) delayed the occurrence of AD, while compounds affecting cellular Ca2+ load (MK-801 and nimodipine) did not influence the latency time. The ischemia-induced [Na+]e reduction was attenuated by R56865. Blockade of the ATP-sensitive K+ channels with glibenclamide reduced the [K+]e increase upon ischemia, indicating an involvement of the KATP channels in ischemia-induced K+ efflux. The KATP channel opener cromakalim did not affect the AD or the [K+]e concentration. The ischemia-induced rapid decline of extracellular calcium was attenuated by receptor-operated Ca2+ channel blockers MK-801 and NBQX, but not by the voltage-operated Ca2+ channel blocker nimodipine, R56865, and flunarizine.

Topics: Adenosine Triphosphate; Animals; Benzothiazoles; Calcium; Dizocilpine Maleate; Flunarizine; Glyburide; Heart Arrest; Hypoxia; Ion Channels; Male; Nimodipine; Piperidines; Potassium; Potassium Channels; Quinoxalines; Rats; Rats, Wistar; Sodium; Thiazoles

A rat cardiopulmonary arrest model was used to study the effects of flunarizine on survival and on the development of postischemic brain damage. Ischemia was induced by a combination of hypovolemia and intracardiac injection of a cold potassiumchloride solution. To validate the model; survival rate and histological damage were assessed after ischemic periods ranging from 5 to 20 minutes. A 6-minute cardiac arrest period was withheld for further therapeutic investigations. In one group (n = 12), flunarizine was administered successively in doses of 0.5 mg/kg intravenous at 5 minutes, 10 mg/kg intraperitoneal at 1 hour, and 20 mg/kg orally at 16 and 24 hours after recirculation. The second group (n = 13) received only the vehicle. Flunarizine, although not affecting mortality; significantly reduced the mean number of ischemic neurons in CA1 hippocampus from 83% in the control to 44% in the drug-treated series (P = 0.014). The results are indicative of the usefulness of this cardiac arrest model to study morphologic aspects of cerebral injury. The results obtained with flunarizine show the effectiveness of this drug even when it is administered after a severe ischemic insult such as global complete ischemia.

Topics: Animals; Cell Survival; Cerebral Infarction; Disease Models, Animal; Flunarizine; Heart Arrest; Hippocampus; Male; Neurons; Rats; Rats, Inbred Strains; Resuscitation; Shock; Time Factors

Neuronal calcium overloading after complete ischemia-anoxia of the brain might be the primary process initiating chemical cascades which lead to cell death. According to this hypothesis calcium-entry blocking agents act on the final common pathway of brain damage. Flunarizine, a selective calcium-entry blocker (without influence on heart rate and on cardiac contractile force), was administered to 12 unconscious patients, recovering from cardiac arrest (CA) of cardiac origin, according to a strict dose-range infusion protocol. Blood-pressure and heart rate (HR) were recorded before, during (t = 10 min, 20 min) and after (t = 30 min, 2 h, 4 h, 6 h, 8 h) each flunarizine infusion (maximum 4 infusions). A significant, although not clinically relevant, decrease in heart rate was noted during the first infusion. Systolic (SBP) and diastolic blood pressure (DBP) also decreased during the infusion without reaching statistical significance. Plasma levels of flunarizine were determined before and after each infusion (t = 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h). Flunarizine plasma concentrations declined very rapidly after cessation of each infusion. Sequential half-lives were in the order of 11-19 min and 5-7 h, and primarily reflect rates of distribution between the systemic circulation and the rapidly equilibrating tissues such as the brain. No substantial accumulation of flunarizine was described and plasma levels were proportional to the give dose. Therefore, flunarizine pharmacokinetics can be considered as linear for doses up to 50 mg.

Topics: Cardiovascular System; Flunarizine; Heart Arrest; Humans; Osmolar Concentration

Topics: Animals; Brain; Cerebrovascular Circulation; Cinnarizine; Disease Models, Animal; Dogs; Flunarizine; Heart Arrest; Humans; Oxygen Consumption; Time Factors

A 10-minute cardiac arrest was produced in dogs by electrical fibrillation of the heart. Recovery of cerebral function was monitored by estimating the cerebral metabolic rate of oxygen consumption (CMRO2), cerebral blood flow (CBF), electroencephalograph (EEG) and extent of neurological deficit. The study group received flunarizine (0.1 mg/kg intravenously) at the beginning of resuscitation, while control animals were given the drug vehicle. By four hours after resuscitation, CMRO2 in flunarizine-treated dogs was 121 +/- 43% of pre-arrest baseline, as compared with 37 +/- 9% in control animals (P less than 0.02). In the flunarizine group, CBF was 83 +/- 21% of baseline, while it was only 31 +/- 8% in controls (P less than 0.01). As compared with the control group, no other significant changes were detected in electrocardiographic, hemodynamic, or biochemical parameters in the flunarizine-treated dogs. A significant improvement in the visual EEG score (P less than 0.001) and neurological deficit (P less than 0.05) was seen in flunarizine-treated dogs six hours after ischemic insult.

Topics: Animals; Brain; Brain Diseases; Cerebrovascular Circulation; Cinnarizine; Dogs; Electrocardiography; Electroencephalography; Flunarizine; Heart Arrest; Oxygen Consumption; Piperazines; Resuscitation

A 10-min cardiac arrest was produced in alfentanil-anesthetised dogs by electrical fibrillation of the heart. Recovery of cerebral function was monitored by 3 separate EEG techniques and visual assessment of neurologic deficit. The EEG techniques were visual scoring, broad-band power spectral analysis and period-amplitude analysis. The treatment group (n = 8) received flunarizine (0.1 mg/kg i.v.) at the beginning of resuscitation, while control animals (n = 8) were given the drug vehicle. A significant improvement in the visual EEG score and neurologic deficit 6 h after insult was noted in flunarizine-treated dogs. The extent of neurologic recovery was significantly correlated with the visual EEG score, with the relative power in the alpha frequency band (7.5-13.5 c/s) and with the percentage of zero-cross frequency.

Topics: Animals; Brain; Cinnarizine; Dogs; Electroencephalography; Flunarizine; Heart Arrest; Resuscitation; Time Factors

Perfusion of the cerebral cortex during closed chest CPR in dogs, generating systolic pressures of 60 to 70 mmHg, is only 10% of pre-arrest blood flow. In contrast, internal cardiac massage produces normal cortical perfusion rates. Following a 20-min perfusion arrest, during pressure controlled reperfusion, cortical flow rates decay to less than 20% normal after 90 min of reperfusion. This appears to be due to increasing cerebral vascular resistance, and is not due to rising intracranial pressure. The post-arrest cortical hypoperfusion syndrome is prolonged with cortical flow remaining below 20% normal up to 18 hr post arrest. The use of a variety of calcium antagonists, including flunarizine, lidoflazine, verapamil, and Mg2+, immediately post-resuscitation maintains cerebral vascular resistance and cortical perfusion at normal levels. A prospective blind trial of the calcium antagonist lidoflazine following a 15-min cardiac arrest in dogs and resuscitation by internal massage, demonstrates amelioration of neurologic deficit in the early postresuscitation period.

Topics: Adenosine Triphosphate; Animals; Brain; Calcium; Cell Membrane; Cerebral Cortex; Cerebrovascular Circulation; Cinnarizine; Dogs; Fatty Acids, Nonesterified; Flunarizine; Heart Arrest; Heart Massage; Hypoxia, Brain; Ischemia; Lidoflazine; Nervous System Diseases; Resuscitation

Twelve dogs were anesthetized and instrumental for determination of CVP, arterial pressure, intracranial pressure, left atrial pressure, and frontal cerebral cortical blood flow (CCBF) by the thermal method. A catheter was introduced into the venous return of the cerebral confluence to allow determination of cerebral A-V oxygen saturation differences. The animals were placed on cardiac bypass using a circuit from the right atrium to the pulmonary artery and a second circuit from the left ventricular apex to the left femoral artery. A heat exchanger was used to maintain a constant blood temperature of 37 C in the output of the left side bypass circuit. All animals were heparinized during bypass. Ventricular fibrillation was induced after completion of the bypass surgery. Two dogs served as controls. Pre-arrest determinations of hemoglobin, glucose, CCBF, and cerebral A-V oxygen differences were taken. Full circulatory arrest was carried out for 20 minutes by shutting off the cardiac bypass. Resuscitation was achieved by resumption of bypass perfusion. Acid-base balance was corrected quickly, and pre-arrest perfusion pressure was achieved and maintained for 90 minutes. All pressure parameters were monitored continuously. All pre-arrest determinations were repeated at 20, 40, 60, and 90 minutes post resuscitation. Five dogs were treated with 6 microgram/kg flunarizine administered IV drip over 10 minutes immediately post reperfusion. Five dogs were not treated post arrest. Treated animals had a prompt return of CCBF rates equal to or greater than pre-arrest flow, which persisted throughout the period of post-arrest observation. Untreated animals had markedly reduced CCBF and increased resistance. CCBF uniformly proceeded to near zero flow by 90 minutes. The ICP was not significantly altered by treatment.

Topics: Animals; Blood Pressure; Calcium; Cerebrovascular Circulation; Cinnarizine; Dogs; Flunarizine; Heart Arrest; Intracranial Pressure; Models, Biological; Piperazines; Resuscitation; Vascular Resistance

Topics: Animals; Cinnarizine; Disease Models, Animal; Flunarizine; Heart Arrest; Hypoxia; Male; Piperazines; Rats; Rats, Inbred Strains; Vasodilator Agents