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Protective effects of OP-2507 [15-cis-(4-propylcyclohexyl)-16,17,18,19,20-pentanor-9-deoxy -9 alpha, 6-nitrilo-PGF1 methyl ester] against cerebral anoxia and edema were investigated in a variety of experimental models in mice and rats. OP-2507 given s.c. or p.o. led to a consistent and dose-dependent prolongation of survival time against cerebral anoxia in hypobaric and normobaric hypoxia, KCN-induced anoxia and decapitation-induced gasping. Furthermore, treatment with 0.03-0.1 mg/kg s.c. or 0.3 mg/kg p.o. of OP-2507 was found to be effective against the changes of cerebral energy metabolites and cyclic nucleotides in hypoxic brain. In brain ischemia induced by bilateral ligation of common carotid arteries of rats, a reduction in specific gravity of cortex and an increase in water content of brain were observed, in accordance with changes of cerebral energy metabolites. These edematous and biochemical changes were prevented by the treatment with 0.01-0.03 mg/kg s.c. of OP-2507. These results indicate a potential usefulness of OP-2507 in protecting the brain from oxygen insufficiency resulting from cerebral ischemia.

The pathogenesis and management of hypoxic-ischemic encephalopathy in the term infant is reviewed. Specifically, the potential significance of a variety of factors on the pathogenesis of brain injury is discussed including changes in cerebral blood flow, brain swelling, carbohydrate status, alterations in ion homeostasis, and synaptic activity. Management is reviewed in terms of prevention, supportive care, corrections of metabolic derangements, control of seizures, and prevention of fluid overload.

The protective effect of flunarizine against cerebral hypoxia-anoxia was investigated with various experimental models in mice and rats. The effect of flunarizine was compared with those of cinnarizine, verapamil and pentobarbital. The oral treatment of animals with flunarizine resulted in a consistent and long-lasting-protection against cerebral hypoxia-anoxia in all the models examined: Cytotoxic anoxia by KCN injection, hypercapnic anoxia induced by stopping artificial respiration, hypobaric hypoxia and normobaric hypoxia. The minimal effective dose of flunarizine was 1 to 20 mg/kg. The activity of flunarizine was 4 to 30 times as potent as that of cinnarizine and pentobarbital. Verapamil showed little or no protective effect. The mode of action of flunarizine was different from that of pentobarbital, which showed protection at anaesthetizing doses. These results indicate that flunarizine possesses a universal protective effect against cerebral hypoxia-anoxia, through the mechanism involved remains to be clarified. Hence, it is suggested that flunarizine might exert a beneficial effect on oxygen insufficiency of the brain resulting from cerebral ischemia.

The protective effects of nicergoline (NCG) against anoxic brain damages in animals were compared with those of dihydroergotoxine (DHE) and phentolamine (PTA). NCG (16 mg/kg, i.p.) prolonged the survival time of mice under hypobaric hypoxia, but DHE and PTA shortened the time. NCG (1-16 mg/kg, i.p. and 16-64 mg/kg, p.o.), like DHE, dose-dependently prolonged the survival time of mice after a lethal dose of KCN (3 mg/kg, i.v.), but PTA did not. NCG (8-128 micrograms/kg, i.v.), like DHE, dose-dependently protected against disappearance of EEG of rats in histotoxic anoxia induced by a sublethal dose of KCN (1.5 mg/kg, i.v.), but PTA did not. Its protective effect was 10 times or more stronger than that of DHE. NCG (1-16 mg/kg, i.p.) dose-dependently promoted recovery from behavioral disorders and disturbance of cerebral energy metabolism of mice in histotoxic anoxia induced by a sublethal dose of KCN (1.8 mg/kg, i.v.). NCG (100 microM), like DHE, showed antagonistic action against inhibition of cerebral cytochrome oxidase activity by KCN, but PTA did not. The ED50 values of NCG, DHE and PTA for the protective effect against adrenaline-induced death in mice were 1.18, 0.27 and 0.35 mg/kg (i.p.), respectively. 7) These results suggest that NCG may show protective effects against the anoxic brain damages due to its ameliorating action on cerebral energy metabolism, mainly contributed by an activation of cerebral cytochrome oxidase, without relation to its alpha-blocking action.

Management of cardiac arrest depends on a four-minute period of potential reversibility. Success depends on immediate diagnosis, documentation of the onset of cardiac arrest, and establishment of treatment priorities. Pupillary dilation, complete in two minutes, serves to verify the onset and duration of cardiac arrest. Treatment involves two phases--the emergency phase of oxygenation and perfusion and the definitive phase of restoring the spontaneous effective heartbeat. The two mechanisms of cardiac arrest, ventricular fibrillation and asystole, are characterized, and the conditions necessary for each to occur are listed. The treatment of ventricular fibrillation is defibrillation, whereas ventricular asystole responds to cardiac stimuli--a precordial blow, epinephrine, or calcium. The mnemonic "SALT CAN ADD GOOD TIME" is suggested as a guide for drug dosage, and a treatment flowchart is outlined.

Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.

Thirty-six rabbits were subjected to 15-minute periods of stagnant cerebral hypoxia while blood flow to the rest of the body was preserved. After this ischemic interval the animals, divided into three groups, received either saline, phenytoin, 15 mg/kg IV, or thiopental 10 mg/kg IV and 10 mg/kg IM. Histologic examination of tissue sections of the brains, 72 hours after ischemia, indicated that phenytoin afforded significant protection (p less than 0.001) of neurons in the hippocampus and in the dentate nucleus when compared to saline, while the findings noted after thiopental were not statistically significant when compared to placebo. No statistically significant difference was noted between the two drugs. Neuron destruction was seen only in rabbits receiving either saline (92%) or thiopental (50%).

The protective effect of 1-[2-(2-chlorobenzoyl)-4-nitrophenyl]-2-(diethylaminomethyl) imidazole fumarate (Y-9179) against cerebral anoxia was investigated with a variety of experimental models in mice and rats. Y-9179, at doses lower than 1 mg/kg, showed a consistent protective action against the cerebral anoxia in all of the models studied: hypoxia, ischemia, histotoxic and asphyxic anoxia. The antianoxic activity of Y-9179 was found to be about 100 times greater than that of pentobarbital. This anti-anoxic effect was observed at very small doses at which neither sedation nor motor depression was induced. There was no decrease in the protective effect or no adverse effect even at as high a dose as 30 mg/kg, which corresponded to about 150 times the effective dose. The universal anti-anoxic properties of Y-9179 may be useful both clinically and as a pharmacological tool to elucidate the physiological significance of cerebral anoxia.

Midazolam is an imidazobenzodiazepine with unique properties when compared with other benzodiazepines. It is water soluble in its acid formulation but is highly lipid soluble in vivo. Midazolam also has a relatively rapid onset of action and high metabolic clearance when compared with other benzodiazepines. The drug produces reliable hypnosis, amnesia, and antianxiety effects when administered orally, intramuscularly, or intravenously. There are many uses for midazolam in the perioperative period including premedication, anesthesia induction and maintenance, and sedation for diagnostic and therapeutic procedures. Midazolam is preferable to diazepam in many clinical situations because of its rapid, nonpainful induction and lack of venous irritation. Compared with thiopental, midazolam is not as rapid acting nor predictable in hypnotic effect. It will not replace thiopental as an induction agent. Advantages of midazolam over thiopental are those of the more versatile pharmacologic properties of a benzodiazepine compared with a barbiturate such as amnestic and anxiolytic properties. Midazolam should be a useful addition to the formulary.

An attempt was made to establish hypoxic cultured neurons from chick embryo hemispheres as an in vitro model for testing cerebroprotective drug effects. Hypoxia was induced by adding 1 mmol/l KCN to the incubation medium of the cells. After various time periods (15-120 min), the cyanide-containing medium was replaced by fresh medium so that the cells could recover from hypoxia. High-energy phosphate levels of the cells and the protein content of the cultures were determined as indicators of the cell viability and response. The cells showed a rapid and pronounced decrease in the levels of high-energy phosphates during cytotoxic hypoxia, and after removal of cyanide the energy state was restored again within few minutes. The protein content of the cultures remained unchanged. Pentobarbital inhibited the breakdown of the high-energy phosphates during hypoxia and accelerated their restitution during the recovery period. The results suggest that hypoxic cultured neurons could be a useful model for testing cerebroprotective drug effects.

Hippocampal tissue slices in vitro were exposed to periods of hypoxia of different durations. Addition of pentobarbital to the perfusion medium significantly increased the duration of hypoxia that was survived by CA1 pyramidal cells.

Compensatory-adaptive reaction of the brain to hypoxia depends on destructive and reparative processes developing in neuronal and glial elements. A drastic tension and reconstruction of the energy apparatus--mitochondria occurs, as well as reversible disturbances in informative connections between the nucleus and cytoplasm and between nerve fibers and synapses. As a result, structural-functional activity of organells decreases along with changes in metabolic processes. Destructive processes in oligodendroglia, at all stages of the experiment, are more pronounced than in neurons. Preliminary injection of hydroxybutyric acid to the animals preserves the cellular energy potential under hypoxia, that is evident from the lack of severe alterations in mitochondria and other organells. Mechanisms of the adaptive-compensatory reaction in cortical neurons under hypoxia are connected with tension and reconstruction of all organells of the brain cellular elements and with biochemical shifts of lactate dehydrogenase enzymes.

2-oxopyrollidine acetamide (piracetam) is said to protect the cerebral cortex against hypoxia. Since surgery is believed to aggravate cerebral hypoxia and the consequent neurological dysfunction, patients undergoing surgery for brain tumours or ruptured cerebral aneurysms were studied. A random, non-stratified study of 100 patients showed that a significantly higher percentage of patients receiving piracetam attain or maintain a normal or near-normal level of consciousness postoperatively than those receiving a placebo. No side-effects or interaction of piracetam with other medications were noted.

To study the cerebral protective effects of hypothermia in arterial hypoxia, anesthetized (70% N2O), mechanically ventilated rats were cooled to a body temperature of 27 C. Hypoxia was induced by decreasing the oxygen content in the inspired gas mixture either to 6-7 per cent or to 2.5-3 per cent. This reduced mean PaO2 to about 25 and 11-12 torr, respectively. At PaO2 torr, there was no change in cerebral blood flow (CBF), cerebrla oxygen consumption (CMRO2), or labile tissue metabolites. The absence of signs of cerebral hypoxia could be attributed to an effect of temperature and pH on the hemoglobin-oxygen dissociation curve. Thus, at 27 C with a PaO2 of 25 torr the total oxygen content (TO2) of arterial blood remained greater than 15 ml (100 ml)-1, about three times the value obtained at this PO2 in normothermic rats. At PaO2 11-12 torr, arterial TO2 was reduced to about 5 ml (100 ml) (-1). The hypoxia induced no change in CMRO2, a threefold increase in CBF, a moderate lactacidosis in the tissue, and a small decrease in phosphocreatine content, but no change in ATP, ADP, or AMP. These changes are less marked than those occurring at the same arterial TO2 in normothermic rats. It is concluded that hypothermia exerts a pronounced protective effect on the brain in hypoxic hypoxia, and that two mechanisms are involved. First, since hypothermia shifts the oxyhemoglobin-dissociation curve towards the left, and prevents or minimizes a rightward shift due to acidosis, it maintains a high TO2 in arterial blood at a given PaO2. Second, by reducing CMRO2, and thereby presumably also cellular energy requirements, hypothermia exerts a protective effect at the cellular level.

The prehospital emergency treatment of craniocerebral trauma tries to avoid secondary cerebral lesions by controlling respiration and circulation. The therapy consists of heavy sedation with Midazolam, analgesia with morphine, artificial hyperventilation, PaO2 over 12 kPa and average arterial pressure above 80 mmHg. Our series of 46 patients recovered between 1982-1988 had a hospital mortality of 23%. 46% of the patients were polytraumatized. A normal neurologic state 6 months from the accident was registered in 86.4%. For 13.6% it was slightly pathological and no vigilant coma state was reported. The most effective rehabilitation method at the site of the accident has to secure the cerebral oxygen supply and reduce potential increase in intracranial pressure for avoid secondary cerebral lesions.

A case is presented of an infant who may have been immersed in water for 15 minutes, presenting apparently dead by instant assessment criteria, who was resuscitated and rehabilitated to make an excellent recovery.

Physostigmine, at 0.1, 0.2 and 0.3 mg/kg, was tested for effect on the survival of mice exposed to 5% O2-95% N2. Some treated animals survived for one hour under the hypoxic atmosphere (2 out of 14 at 0.1 mg/kg and 8 out of 28 at 0.2 and 0.3 mg/kg), an event never observed in untreated controls. The physostigmine-treated animals that died before the hour showed a dose-related increase in survival time from 4.3 min (untreated controls) to 27.6 min (0.3 mg/kg physostigmine). The effect of physostigmine may be related to its reported ability to increase cerebral blood flow and decrease cerebral oxygen consumption

The purpose of the present study was to approach the compound(s) responsible for the beneficial effects of an extract of Ginkgo biloba leaves (EGB) on animals subjected to hypoxia. In this first approach we compared the effects of the flavone and the non-flavone fraction of EGB with those of the whole extract on mice in lethal hypoxia (3.5% O2), on brain energy metabolism of artificially ventilated rats inspiring 7% O2, and on local cerebral blood flow (LCBF) of normoxic rats. The latter two experimental settings should also extend the knowledge about the underlying mechanisms of the antihypoxidotic actions. EGB as well as its non-flavone fraction considerably prolonged the survival time of mice under lethal hypoxia. EGB retarded the breakdown of brain energy metabolism in the hypoxic artificially ventilated rat. A corresponding effect was exerted by the non-flavone fraction while the flavone fraction even worsened the metabolic state. The non-flavone fraction increased LCBF in the majority of 35 examined brain regions; a similar effect could be seen after EGB-treatment, while the flavone fraction caused only minor alterations of LCBF. We conclude that the non-flavone fraction of EGB carries the antihypoxidotic activity. Metabolic effects are suggested to cause this activity. Further studies are necessary to elucidate the effective compound within this fraction.

Three groups of adult mongrel dogs were subjected to 15 minutes of toal circulatory arrest. One group was infused with one liter of Krebs-Hensleit solution and kept normothermic, one group was infused similarly and their body temperature was lowered to 10 to 15 degrees C., and the third group was kept normothermic and infused with hyperkalemic solution. Adenosine triphosphate (ATP) and creatine phosphate levels in the brain during and after the ischemic period were not significantly different in the three groups and glycogen levels tended to remain higher in the hypothermic group. None of the normothermic dogs survived, but all of the hypothermic and hyperkalemic animals survived and were grossly normal. These data indicate that hyperkalemai does offer some protection to the brain during periods of circulatory arrest. It also appears that survival and persistence of brain function do not correlate necessarily with levels of high energy compounds in the brain.

Arnfred's mouse model was used to test the effect of thiopental during hypoxia (5% O2) and anoxia, with and without simultaneous administration of nitrous oxide. As found by Arnfred and others, thiopental without N2O more than doubled survival time during hypoxia (from 5.2 +/- 0.6 to 13.9 +/- 2.6 min). This effect was completely offset by simultaneous use of N2O (from 13.9 +/- 2.6 to 4.8 +/- 0.7 min). Thiopental without N2O also increased survival time during complete anoxia (from 26 +/- 1 to 59 +/- 1 sec). This effect was diminished by 58% when N2O was added (from 59 +/- 1 to 40 +/- 1 sec). We conclude that nitrous oxide diminishes the effect of barbiturates upon survival time in hypoxic and anoxic mice.

Anesthetized and nonanesthetized animals (white rats and cats) were used to study the effect of dibasol and its new imidazo analogs (designated AKS-67 and AKS-87) on animal tolerance to gravitational effects and cerebral ischemia (ligation of both carotid arteries) as well as on systemic arterial pressure and tone of cerebral and peripheral vessels (resistographically) in the postischemic period. The drugs were administered 30-90 min before exposure. It was found that in nonanesthetized rats dibasol and AKS-87 increased tolerance to cranio-caudal acceleration and decreased it to caudo-cranial acceleration, whereas AKS-67 produced a distinct protective effect regardless of the vector. In anesthetized rats (bilateral carotid ligation) AKS-67 and AKS-87 increased acceleration tolerance and dibasol produced no protective effect. Dibasol enhanced postischemic hypotension while AKS-67 and AKS-87 delayed or completely arrested it. For aerospace medicine the drug AKS-67 is of particular importance because it increases significantly animal tolerance to acceleration and stabilizes arterial pressure in the postischemic period.