Search PubMed⌕ Search

Biomedical subjects

P Safar

Publications and source records attributed to P Safar.

At least 19 recordsLinked to original sources
PubMed1998

Glucose plus insulin infusion improves cerebral outcome after asphyxial cardiac arrest.

Hyperglycemia before ischemia worsens cerebral outcome. The aim of this study was to determine the cerebral effects of giving glucose with or without insulin after asphyxial cardiac arrest. Rats underwent 8 min of asphyxial cardiac arrest. After arrest, Group 1 received NaCl; Group 2, insulin; Group 3, glucose; and Group 4, glucose plus insulin, all intravenously. Neurological deficit (ND) scores were 14+/-10%, 22+/-12%, 12+/-10% and 2+/-2% in Groups 1-4, respectively, 72 h after reperfusion. Overall histological damage (HD) scores were 4, 2, 3 and 1, respectively. Group 4 fared significantly better than group 1 on both scores. Glucose after asphyxial cardiac arrest in rats produces no increased brain damage while glucose plus insulin improves cerebral outcome.

Animals↗
PubMed1998

Mapping the active site of factor Xa by selective inhibitors: an NMR and MD study.

The structure of two selective inhibitors, Ac-Tyr-Ile-Arg-Ile-Pro-NH2 and Ac-(4-Amino-Phe)-(Cyclohexyl-Gly)-Arg-NH2, in the active site of the blood clotting enzyme factor Xa was determined by using transferred nuclear Overhauser effect nuclear magnetic resonance (NMR) spectroscopy. They represent a family of peptidic inhibitors obtained by the screening of a vast combinatorial library. Each structure was first calculated by using standard computational procedures (distance geometry, simulated annealing, energy minimization) and then further refined by systematic search of the conformation of the inhibitor docked in the active site and repeating the simulated annealing and energy minimization. The final structure was optimized by molecular dynamics simulations of the inhibitor-complex in water. The NMR restraints were kept throughout the refinement. The inhibitors assume a compact, very well defined conformation, embedded into the substrate binding site not in the same way as a substrate, blocking thus the catalysis. The model allows to explain the mode of action, affinity, and specificity of the peptides and to map the active site.

Amino Acid Sequence↗
PubMed1998

Discovery of a novel, potent, and specific family of factor Xa inhibitors via combinatorial chemistry.

A series of low molecular weight peptide inhibitors of factor Xa, unrelated to any previously described, was identified by screening a combinatorial peptide library composed of L-amino acids. The minimal inhibitory sequence is a tripeptide, L-tyrosinyl-L-isoleucyl-L-arginyl, which competitively inhibits the hydrolysis of small chromogenic substrates by factor Xa but binds in an orientation which prevents a productive nucleophilic attack by serine 195 of the catalytic triad on the carbonyl carbon of the carboxyterminal arginine. The initial leads identified in an octamer combinatorial peptide library ranged in potency from 4 to 15 microM. These peptides were modified into peptide mimetics with a greater than 1000-fold increase in potency while retaining unusual selectivity for factor Xa over the related serine proteases thrombin, factor VIIa/tissue factor, plasmin, activated protein C, kallikrein, and trypsin. One of the most potent analogues, SEL 2711, with a Ki of 0.003 microM for factor Xa and 40 microM for thrombin, is active in in vitro and ex vivo coagulation assays, suggesting the potential application of these inhibitors in anticoagulant therapy.

Anticoagulants↗
PubMed1998

Delayed death after uncomplicated hot tub bathing in dogs and monkeys.

Prolonged heat exposure as in hot tub bathing, although frequently practiced, has occasionally resulted in fatalities that have been explained by an underlying disease. We explored the tolerance of hot water immersion of 60 min in five previously healthy animals (three dogs and two monkeys). With invasive monitoring, experimental body immersion in water at 40-45 degrees C, with core temperature kept at 40-42 degrees C for 60 min, caused no significant cardiovascular, pulmonary or metabolic changes during hyperthermia or for 2 h after return to normothermia. Then secondary deterioration occurred with progressive hypotension, petechial hemorrhages throughout the viscera, gross gastrointestinal hemorrhages and irreversible (hypovolemic) shock. These effects occurred earlier in the monkeys than in the dogs. This shock state did not respond to standard resuscitation attempts. One dog survived the secondary shock state. We conclude that during and after hot tub immersion, good initial tolerance to heat exposure can, several hours after return of normothermia, result in delayed secondary deterioration and death. We recommend that the mechanism of this delayed shock state with apparent capillary leakage be clarified.

Animals↗
PubMed1998

Mild protective and resuscitative hypothermia for asphyxial cardiac arrest in rats.

It has been shown in dogs that mild hypothermia (34 degrees C) during or immediately after ventricular fibrillation cardiac arrest can improve cerebral outcome. The effect of mild hypothermia on outcome after 8 minutes of asphyxiation (5 minutes' cardiac arrest) was studied for the first time in rats. Restoration of spontaneous circulation was with external cardiopulmonary resuscitation and observation to 72 hours. Three groups of 10 rats each were studied. At 72 hours postarrest, compared with the normothermic control group 1, final overall performance categories (OPC) and neurological deficit scores (NDS) were numerically better in the resuscitative (post-arrest) hypothermia group 2 and significantly better in the protective (pre-intra-arrest) hypothermia group 3 (P < .05). Total brain histopathological damage scores (HDS) were 17 +/- 5 in group 1, 14 +/- 6 in group 2 (NS), and 6 +/- 2 in group 3 (P < .001 versus group 1). HDS correlated with OPC (r = .6, P < .05) and NDS (r = .7, P < .05). Mild hypothermia improved cerebral outcome after asphyxial cardiac arrest in rats, more when induced before than after arrest. The model's insult is within the therapeutic window, which makes it also suitable for screening other cerebral resuscitation potentials.

Animals↗
PubMed1998

Moderate hypothermia for 48 hours after temporary epidural brain compression injury in a canine outcome model.

In a previous study with this dog model, post-insult hypothermia of 31 degrees C for 5 h prevented secondary intraventricular pressure (IVP) rise, but during 35 degrees C or 38 degrees C, one-half of the dogs developed delayed IVP rise to brain death. We hypothesized that 31 degrees C extended to 48 h would prevent brain herniation. Using epidural balloon inflation, we increased contralateral IVP to 62 mm Hg for 90 min. Controlled ventilation was to 72 h and intensive care to 96 h. Group 1 dogs (n = 10) were normothermic controls (37.5 degrees C). Group 2 dogs (n = 10) were surface-cooled from 15 to 45 min of balloon inflation and maintained at moderate hypothermia (31 degrees C) to 48 h. Rewarming was from 48 to 72 h. Four additional dogs of hypothermia Group 2 had to be excluded from analysis for pneumonia and/or bleeding diathesis. After balloon deflation, IVP increased to 20 mm Hg or greater at 154 +/- 215 (range 15-720) min following the insult in Group 1 and at 1394 +/- 1191 (range 210-3420) min in Group 2 (p = 0.004), still during 31 degrees C but without further increase during hypothermia. Further IVP rise led to brain death in Group 1 in 6 of 10 dogs at 44 +/- 18 (range 21-72) h (all during controlled ventilation); and in Group 2, in 6 of 10 dogs at 87 +/- 11 (range 72-96) h (p = 0.001), all after rewarming, during spontaneous breathing. Survival to 96 h was achieved by 4 of 10 dogs in Group 1, and by 7 of 10 dogs in Group 2 (NS). Three of the six brain deaths in Group 2 occurred at 96 h. The macroscopically damaged brain volume was only numerically smaller in Group 2. The vermis downward shift was 6.8 +/- 3.5 mm in Group 1, versus 4.7 +/- 2.2 mm in Group 2 (p = 0.05). In an adjunctive study, in 4 additional normothermic dogs, hemispheric cerebral blood flow showed post-insult hypoperfusion bilaterally but no evidence of hyperemia preceding IVP rise to brain death. In conclusion, in this model, moderate hypothermia during and for 48 h after temporary epidural brain compression can maintain a low IVP during hypothermia but cannot prevent lethal brain swelling after rewarming and may cause coagulopathy and pulmonary complications.

Animals↗
PubMed1998

Hypothermia, but not 100% oxygen breathing, prolongs survival time during lethal uncontrolled hemorrhagic shock in rats.

OBJECTIVE: To test the hypothesis that moderate hypothermia (Hth) (30 degrees C) or breathing 100% oxygen (best with both combined) would prolong survival during lethal uncontrolled hemorrhagic shock (UHS) compared with normothermia (38 degrees C) and breathing air. METHODS: Forty Sprague-Dawley rats were anesthetized with halothane during spontaneous breathing of N2O/O2 (50:50). UHS was induced by volume-controlled blood withdrawal of 3 mL/100 g over 15 minutes, followed by 75% tail amputation and randomization to one of four UHS treatment groups (10 rats each): group 1 (control) was maintained on room air and rectal temperature of 38 degrees C; group 2 (Hth) was maintained on air and 30 degrees C; group 3 (O2) was maintained on FiO2 100% (starting immediately after tail cut) and 38 degrees C; and group 4 (O2-Hth) was maintained on FiO2 100% and 30 degrees C. Rats were observed otherwise untreated until death (apnea and pulselessness) or for a maximum of 5 hours. RESULTS: During the initial blood withdrawal, mean arterial pressure (MAP) decreased to an average of 24 mm Hg. Seventeen of 40 rats then showed an increase in MAP (attempted self-resuscitation). Induction of hypothermia increased MAP to around 35 mm Hg at 30 minutes but did not increase bleeding. Additional blood loss from the tail stump averaged 1.0, 2.3, 2.9, and 1.7 mL in groups 1, 2, 3, and 4, respectively (not significant). Breathing 100% oxygen did not affect MAP or blood loss. Survival time was a mean of 47 and 52 minutes in normothermic groups 1 and 3 versus 121 and 135 minutes in hypothermic groups 2 and 4, respectively (p < 0.001, Kaplan-Meier). Breathing FiO2 100% increased PaO2 but did not change MAP, blood loss, or survival time. CONCLUSION: Moderate hypothermia, but not increased FiO2, prolonged survival time during untreated UHS in rats. The effect of hypothermia on survival after resuscitation from UHS needs to be determined.

Animals↗
PubMed1998

Prolonged severe hemorrhagic shock and resuscitation in rats does not cause subtle brain damage.

OBJECTIVE: Some patients who survived severe hemorrhagic shock (HS) seem to exhibit persistent subtle neurobehavioral deficits. This finding is of concern if limited hypotensive fluid resuscitation is applied in hypotensive victims with penetrating trauma. This study was designed to determine whether subtle brain damage would occur in rats after severe prolonged HS. We hypothesized that rats surviving HS with mean arterial pressure (MAP) controlled at 40 mm Hg for 60 minutes would recover with slight permanent brain damage in terms of cognitive function without morphologic loss of neurons and that rats surviving HS with MAP at 30 mm Hg for 45 minutes (60 minutes were not tolerated) would have grossly abnormal brain function and loss of neurons. METHODS: Under light nitrous oxide-halothane anesthesia, spontaneously breathing rats underwent MAP-controlled HS (HS phase I), volume resuscitation to normotension and invasive monitoring to 60 minutes (resuscitation phase II), and observation to 10 days with detailed assessment of cognitive function (observation phase III). Five conscious rats served as normal controls. Three treatment groups were compared: group 1, shams (11 of 12 rats survived to 10 days); group 2, HS at MAP 40 mm Hg for 60 minutes (10 of 17 rats survived); group 3, HS at 30 mm Hg for 45 minutes (10 of 14 rats survived). RESULTS: On post-HS day 10, all normal controls and all survivors of all three groups were functionally normal with overall performance category = 1 (normal) (overall performance category 1 = normal, 5 = death) and neurologic deficit scores < or = 7% (neurologic deficit scores 0-10% = normal, 100% = brain death). Post-HS beam balance, beam walking, and Morris water maze test results in HS groups 2 and 3 showed latencies not significantly different from those in shams and normal controls. Light microscopic scoring of five selectively vulnerable brain regions and other regions in five coronal sections revealed no ischemic (pyknotic, shrunken, eosinophilic) neurons in any of the survivors to 10 days. There was no statistical difference between normal controls, sham animals, and both HS groups in the number of normal neurons counted in the hippocampal CA-1 region in the 10-day survivors. All nonsurvivors died with intestinal necrosis. CONCLUSION: HS at MAP 40 mm Hg for 60 minutes or MAP 30 mm Hg for 45 minutes does not cause subtle functional or histologic brain damage in surviving rats. Controlling MAP at 30 mm Hg carries a risk of sudden cardiac arrest. These data suggest that limited fluid resuscitation, to maintain MAP at about 40 mm Hg, as recommended for victims of penetrating trauma with uncontrolled HS, is safe for the brain.

Animals↗
PubMed1997

Future directions for resuscitation research. V. Ultra-advanced life support.

Standard external cardiopulmonary resuscitation (SECPR) frequently produces very low perfusion pressures, which are inadequate to achieve restoration of spontaneous circulation (ROSC) and intact survival, particularly when the heart is diseased. Ultra-advanced life support (UALS) techniques may allow support of vital organ systems until either the heart recovers or cardiac repair or replacement is performed. Closed-chest emergency cardiopulmonary bypass (CPB) provides control of blood flow, pressure, composition and temperature, but has so far been applied relatively late. This additional low-flow time may preclude conscious survival. An easy, quick method for vessel access and a small preprimed system that could be taken into the field are needed. Open-chest CPR (OCCPR) is physiologically superior to SECPR, but has also been initiated too late in prior studies. Its application in the field has recently proven feasible. Variations of OCCPR, which deserve clinical trials inside and outside hospitals, include 'minimally invasive direct cardiac massage' (MIDCM), using a pocket-size plunger-like device inserted via a small incision and 'direct mechanical ventricular actuation' (DMVA), using a machine that pneumatically drives a cup placed around the heart. Other novel UALS approaches for further research include the use of an aortic balloon catheter to improve coronary and cerebral blood flow during SECPR, aortic flush techniques and a double-balloon aortic catheter that could allow separate perfusion (and cooling) of the heart, brain and viscera for optimal resuscitation of each. Decision-making, initiation of UALS methods and diagnostic evaluations must be rapid to maximize the potential for ROSC and facilitate decision-making regarding long-term circulatory support versus withdrawal of life support for hopeless cases. Research and development of UALS techniques needs to be coordinated with cerebral resuscitation research.

Cardiopulmonary Resuscitation↗
PubMed1997

Asphyxiation versus ventricular fibrillation cardiac arrest in dogs. Differences in cerebral resuscitation effects--a preliminary study.

UNLABELLED: We explored the hypothesis that brain damage after cardiac arrest caused by ventricular fibrillation (VF) needs different therapies than that after asphyxiation, which has been studied less thoroughly. In 67 healthy mongrel dogs of both sexes cardiac arrest (at normothermia) by ventricular fibrillation (no blood flow lasting 10 min) or asphyxiation (no blood flow lasting 7 min) was reversed by normothermic external cardiopulmonary resuscitation, followed by intermittent positive-pressure ventilation for 20 h, and intensive care to 96 h. To ameliorate ischemic brain damage, the calcium entry blocker lidoflazine or a solution of free radical scavengers (mannitol and L-methionine in dextran 40) plus magnesium sulphate, was given intravenously immediately upon restoration of spontaneous circulation. Outcome was evaluated as functional deficit, brain creatine kinase (CK) leakage into the cerebrospinal fluid (CSF) and brain morphologic changes. Lidoflazine seemed to improve cerebral outcome after VF but not after asphyxiation. Free radical scavengers plus magnesium sulphate seemed to improve cerebral outcome after asphyxiation, but not after VF. After VF, scattered ischemic neuronal changes in multiple brain regions dominated, and total brain histopathologic damage scores correlated with final neurologic deficit scores at 96 h (r = 0.66) and with peak CK levels in CSF (r = 0.81). After asphyxiation, in addition to the same ischemic neuronal changes, microinfarcts occurred, and there was no correlation between total brain histopathologic damage scores and neurologic deficit scores or CK levels in CSF. CONCLUSIONS: Different mechanisms of cardiac arrest, which cause different morphologic patterns of brain damage, may need different cerebral resuscitation treatments.

Animals↗
PubMed1997

Hypothermia and minimal fluid resuscitation increase survival after uncontrolled hemorrhagic shock in rats.

OBJECTIVE: To test the hypothesis that protective-preservative moderate hypothermia during uncontrolled hemorrhagic shock (UHS) in rats increases survival. DESIGN: Randomized outcome study in rats. MATERIALS AND METHODS: UHS phase I of 90 minutes, with initial withdrawal of 3 mL/100 g of blood plus tail amputation, was followed by hemostasis and all-out resuscitation phase II from 90 to 150 minutes, and observation phase III to 72 hours. Forty male rats under light anesthesia and spontaneous breathing were randomized into four groups: Group 1 received no fluid resuscitation during UHS and normothermia (37.5 degrees C) throughout. Group 2 received no fluid resuscitation and hypothermia (30 degrees C) from 15 to 120 minutes. Group 3 received lactated Ringer's solution to maintain mean arterial pressure at 40 mm Hg during UHS and normothermia. Group 4 received lactated Ringer's solution to a mean arterial pressure of 40 mm Hg during UHS and hypothermia from 15 to 120 minutes. RESULTS: UHS phase I was survived by 0 of 10 rats in group 1, 7 of 10 in group 2, 5 of 10 in group 3, and 10 of 10 in group 4 (p < 0.01 for group 1 vs. 2, 3, or 4; p < 0.05 for group 4 vs. 3). Survival to 72 hours was achieved by 0 of 10 rats in group 1, 3 of 10 in group 2 (p < 0.001 vs. group 1), 1 of 10 in group 3, and 7 of 10 in group 4 (p < 0.001 vs. group 1, and p < 0.01 vs. group 3). All 72-hour survivors were neurologically normal. Necropsies in rats that died early during phase III showed edema and gastrointestinal hemorrhages. CONCLUSIONS: Moderate hypothermia or limited (hypotensive) fluid resuscitation --best both combined--increases survival during and after UHS in rats.

Animals↗
PubMed1997

Hyperthermia-induced cardiac arrest in monkeys: limited efficacy of standard CPR.

BACKGROUND: Successful resuscitation from heatstroke cardiopulmonary arrest has been only partially explored and the data covering the post resuscitation pathophysiology leading to secondary arrest is, in most cases, insufficient. HYPOTHESIS: Following heatstroke-cardiopulmonary arrest, successful resuscitation may be achieved by standard CPR with surface cooling and administration of glucose. We ponder the sequence of early circulatory responses and the pathophysiological changes following successful resuscitation. METHODS: We exposed 12 pigtail monkeys to total-body hyperthermia (cerebral T 42 degrees C) until cardiac arrest ensued. Standard external CPR with surface cooling and glucose 5% IV were administered for up to 30 min. Control group A (n = 6) was compared with experimental group B (n = 6), which received additional steroid, glucagon and hypertonic glucose during CPR attempts. RESULTS: No significant differences were found between the outcome of the two groups. The 30-min CPR attempt succeeded in restoration of spontaneous circulation (ROSC) in 8/12 monkeys-5 animals from group A and 3 in group B. The animals in whom resuscitation was unsuccessful had significantly prolonged periods of rectal temperature exceeding 42.5 degrees C (p < 0.05), and significantly higher rectal temperatures at the end of 30 min of CPR and cooling (p < 0.05). All the resuscitated animals later rearrested at 158 +/- 68 (95-228) min after ROSC; pulmonary edema occurred in 6/8 animals. CONCLUSIONS: We conclude that experimentally-induced heatstroke can be transiently reversed by standard resuscitative procedures, but is followed by a delayed, irreversible, secondary shock state, which could not be prevented by the treatment we employed. We were, however, able to document in detail the pathophysiologic processes involved in the resuscitation, and the irreversible shock one sees after "successful" CPR.

Animals↗
PubMed1997

Introduction to Wolf Creek IV Conference.

Early milestones of resuscitation research culminated in the 1950s in the documentation of modern external cardiovascular resuscitation (CPR) steps "ABC," followed by advanced and prolonged life support. Implementation of guidelines has been suboptimal. Self-training of the public in life-supporting first aid, including CPR-ABC-available since the 1970s-is only now being re-evaluated and hopefully implemented. Standard external CPR potency is inadequate for reliably restoring spontaneous circulation and saving the brain after prolonged arrests or in patients with sick hearts. Ultra-advanced life-support methods such as open-chest CPR and emergency cardiopulmonary bypass should be tried for bridging standard external CPR-resistant hearts to recovery or repair. Outcome studies in large animals can be fully controlled, in contrast to randomized clinical outcome trials, which have limitations. The HIV paranoia must not lead to abandoning the teaching of steps A and B, which are essential for any kind of coma, asphyxial arrest, and prolonged ventricular fibrillation arrest. Sternal compressions alone can produce some ventilation in animals, but not reliably in comatose humans. For cerebral resuscitation after cardiac arrest, the outcome benefit of the hypertensive bout, other cerebral blood flow-promoting measures, and mild resuscitative hypothermia have been documented in outcome models of large animals and are ready for clinical feasibility trials. The Wolf Creek CPR researchers' conferences I, II, and III were meant to advise the guidelines-setting committees of the American Heart Association and other agencies. The ten topics of Wolf Creek IV, published in this issue of New Horizons, were different in design and objective. There was an appropriate emphasis on fully automatic external defibrillation by lay rescuers, which has the potential for a breakthrough effect. Wolf Creek V, which we recommend to be conducted around the turn of the millennium, should focus on the pathophysiology and therapeutics of respiratory, cardiac, and cerebral resuscitation in general, and on organ, cellular, and molecular level research into how cells, organs, and organisms die, and how acute dying processes might be reversed. What to teach whom and how should be left to guideline conferences of agencies.

Animals↗
PubMed1996

Utstein-style guidelines for uniform reporting of laboratory CPR research. A statement for healthcare professionals from a task force of the American Heart Association, the American College of Emergency Physicians, the American College of Cardiology, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, the Institute of Critical Care Medicine, the Safar Center for Resuscitation Research, and the Society for Academic Emergency Medicine. Writing Group.

Explore the source record for details and available documents.

Animals↗