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Peter Safar

Publications and source records attributed to Peter Safar.

24 records · Page 2Linked to original sources
PubMed2002

Antioxidant Tempol enhances hypothermic cerebral preservation during prolonged cardiac arrest in dogs.

The authors are systematically exploring pharmacologic preservation for temporarily unresuscitable exsanguination cardiac arrest in dogs. They hypothesized that the antioxidant Tempol improves cerebral outcome when added to aortic saline flush at the start of cardiac arrest. In study A, no drug (n = 8), Tempol 150 mg/kg (n = 4), or Tempol 300 mg/kg (n = 4) was added to 25 mL/kg saline flush at 24 degrees C (achieving mild cerebral hypothermia) at the start of 20-minute cardiac arrest. In study B, no drug (n = 8) or Tempol 300 mg/kg (n = 7) was added to 50 mL/kg saline flush at 2 degrees C (achieving moderate cerebral hypothermia) at the start of 40-minute cardiac arrest. Cardiac arrest was reversed with cardiopulmonary bypass. Mild hypothermia lasted for 12 hours, controlled ventilation was sustained to 24 hours, and intensive care was provided for up to 72 hours. In study A, overall performance category 1 or 2 (good outcome) was achieved in all eight dogs treated with Tempol compared with three of eight dogs in the control group ( P = 0.03). In study B, good outcome was achieved in all seven dogs treated with Tempol versus only two of 8 dogs in the control group ( P = 0.007). In both studies, neurologic deficit scores were significantly better in the Tempol group, but not total histologic damage scores. At 72 hours, electron paramagnetic resonance spectroscopy of Tempol revealed direct evidence for its presence in the brain. Single- and double-strand DNA damage, nitrotyrosine immunostaining, total antioxidant reserve, and ascorbate acid levels were similar between groups, and thiol levels were decreased after Tempol in study B. The authors conclude that when added to aortic saline flush at the start of prolonged cardiac arrest, the antioxidant Tempol can enhance mild or moderate hypothermic cerebral preservation in terms of improved functional outcome. The mechanisms involved in this beneficial effect need further clarification.

Animals↗
PubMed2002

Systemic hypothermia, but not regional gut hypothermia, improves survival from prolonged hemorrhagic shock in rats.

BACKGROUND: Extracorporeal blood perfusion of the gut or enterectomy can improve survival during hemorrhagic shock (HS), suggesting that the gut may be of primary importance in resuscitation. We hypothesized that cooling the gut alone could improve survival in a rat HS model and avoid potential deleterious effects of systemic hypothermia. METHODS: Thirty-two Sprague-Dawley rats were anesthetized with halothane. The gut (small intestine, cecum, and colon) was exteriorized. The right atrial (T ), rectal, and gut (T ) intraluminal temperatures were monitored. HS was induced by withdrawal of 2 mL of blood per 100 g body weight over 10 minutes. Mean arterial pressure was then maintained at 35 to 40 mm Hg to HS 90 min. From HS 20 min to resuscitation time 1 h, rats were randomized into four groups (n = 8 each): normothermia (T and T approximately 38.0 degrees C), gut-25 degrees C (T approximately 38 degrees C, T approximately 25 degrees C, induced by rinsing the gut with cooled saline), gut-33 degrees C (T approximately 38 degrees C, T approximately 33 degrees C), and systemic hypothermia (T approximately 33 degrees C, T approximately 25 degrees C). At HS 90 min, shed blood and Ringer's solution were infused to restore normotension. Survival, metabolism, and tissue damage were observed to 72 hours. RESULTS: Blood pressure was not different between groups. Compared with the normothermia group, the systemic hypothermia group had lower base deficit and lactate, and needed less fluid during resuscitation for normotension (p < 0.05), but these values were not different in the gut hypothermia groups. In addition, there were no significant improvements in tissue protection induced by regional gut hypothermia, whereas the systemic hypothermia group had lower plasma potassium, lower ornithine carbamoyltransferase (marker of liver injury), and higher glucose levels after HS (all p < 0.05). All rats in the systemic hypothermia group survived to 72 hours, whereas there was only one survivor in the normothermia group, two in the gut-33 degrees C group, and none in the gut-25 degrees C group (all p < 0.05 vs. systemic hypothermia). CONCLUSION: Cooling the gut alone does not improve acute survival from HS, suggesting that early deaths are not secondary to gut ischemia. Mild systemic hypothermia allowed 100% survival from prolonged HS.

Animals↗
PubMed2002

Early antioxidant therapy with Tempol during hemorrhagic shock increases survival in rats.

BACKGROUND: Hemorrhagic shock (HS) is associated with the generation of reactive oxygen species, which may contribute to delayed multiple organ system failure and death. Previous studies have shown that the antioxidant Tempol improved physiologic variables, although not necessarily outcome, in septic shock and HS. We hypothesized that the combination of free Tempol with polynitroxylated albumin (PNA)-bound Tempol (which prolongs half-life and decreases toxicity) improves outcome after HS in rats. METHODS: In study 1, HS was induced by blood withdrawal of 3 mL/100 g over 15 minutes. Mean arterial pressure was maintained at 40 mm Hg with either infusion of normal saline or withdrawal of blood from 20 to 90 minutes. Resuscitation (90-270 minutes) was with infusion of shed blood. Observation was to 72 hours. At HS 45 min, albumin (ALB) (n = 10) or PNA + Tempol (n = 10) was infused slowly (1 mL/100 g/h) until 120 minutes. Study 2 was the same as study 1 (n = 6 per group), but terminated at 150 minutes. Study 3 was the same as study 1, but started with ALB or PNA + Tempol (n = 7 per group) at 20 minutes. The primary outcome variable in studies 1 and 3 was survival, whereas the primary outcome variables in study 2 were antioxidant reserve (ability of the serum or tissue homogenate to scavenge peroxyl radicals produced by 2,2'-azobis [2-aminodipropane]-dihydrochloride) in serum and small intestine, and low-molecular-weight thiols in tissues (liver, small intestine, and kidney). RESULTS: In study 1, 72-hour survival was 1 of 10 (ALB group) versus 2 of 10 (PNA + Tempol group). At 90 minutes, pH was lower in the ALB group versus the PNA + Tempol group (p = 0.02) and remained low. Arterial lactate increased to 8.9 +/- 3.2 (mean +/- SD) versus 6.5 +/- 1.8 mmol/L (p = 0.04) and base excess was -9.6 +/- 4.3 versus -5.2 +/- 3.2 mmol/L (p = 0.01) (ALB vs. PNA + Tempol groups, respectively). In study 2, antioxidant reserve in serum was lower in the ALB group versus the PNA + Tempol group (p = 0.002). There were no differences between groups in antioxidant reserve in the small intestine or low-molecular-weight thiols in liver, kidney, and small intestine. In study 3, 72-hour survival was zero of seven (ALB group) versus five of seven (PNA + Tempol group) (p = 0.02). Heart rate and systolic blood pressure during late HS were higher in the ALB group in studies 1 and 3 (p < 0.05). CONCLUSION: When infused early in HS, PNA + Tempol can increase survival. When given late, it significantly improves acid-base and serum antioxidant status, without an effect on survival. Additional studies will be required to determine whether early resuscitation with PNA + Tempol attenuates reactive oxygen species-mediated injury as the mechanism for preventing the progression toward multiple organ failure and death after HS. The results suggest that antioxidant therapy with Tempol deserves further study as a potential adjunct in the initial resuscitation from HS.

Acid-Base Equilibrium↗
PubMed2002

Effects of mild hypothermia on survival and serum cytokines in uncontrolled hemorrhagic shock in rats.

Previous studies have suggested benefit of mild hypothermia during hemorrhagic shock (HS). This finding needs additional confirmation and investigation into possible mechanisms. Proinflammatory cytokines are mediators of multiple organ failure following traumatic hemorrhagic shock and resuscitation. We hypothesized that mild hypothermia would improve survival from HS and may affect the pro- and anti-inflammatory cytokine response in a rat model of uncontrolled HS. Under light halothane anesthesia, uncontrolled HS was induced by blood withdrawal of 3 mL/100 g over 15 min followed by tail amputation. Hypotensive (limited) fluid resuscitation (to prevent mean arterial pressure [MAP] from decreasing below 40 mmHg) with blood was started at 30 min and continued to 90 min. After hemostasis and resuscitation with initially shed blood and Ringer's solution, the rats were observed for 72 h. The animals were randomized into two HS groups (n = 10 each): normothermia (38 degrees C +/- 0.5 degrees C) and mild hypothermia (34 degrees C +/- 0.5 degrees C) from HS 30 min until resuscitation time (RT) 60 min; and a sham group (n = 3). Venous blood samples were taken at baseline, RT 60 min, and days 1, 2, and 3. Serum interleukin (IL)-1beta, IL-6, IL-10, and tumor necrosis factor (TNF)-alpha concentrations were quantified by ELISA. Values are expressed as median and interquartile range. Survival time by life table analysis was greater in the hypothermia group (P = 0.04). Survival rates to 72 h were 1 of 10 vs. 6 of 10 in the normothermia vs. hypothermia groups, respectively (P = 0.057). All cytokine concentrations were significantly increased from baseline at RT 60 min in both HS groups, but not in the shams. At RT 60 min, in the normothermia vs. hypothermia groups, respectively, IL-1beta levels were 185 (119-252) vs. 96 (57-135) pg/mL (P = 0.15); IL-6 levels were 2242 (1903-3777) vs. 1746 (585-2480) pg/mL (P = 0.20); TNF-alpha levels were 97 (81-156) vs. 394 (280-406) pg/mL (P= 0.02); and IL-10 levels were 1.7 (0-13.3) vs. 15.8 (1.9-23.0) pg/mL (P = 0.09). IL-10 remained increased until day 3 in the hypothermia group. High IL-1beta levels (>100 pg/mL) at RT 60 min were associated with death before 72 h (odds ratio 66, C.I. 3.5-1255). We conclude that mild hypothermia improves survival time after uncontrolled HS. Uncontrolled HS induces a robust proinflammatory cytokine response. The unexpected increase in TNF-alpha with hypothermia deserves further investigation.

Animals↗
PubMed2002

The role of the central nervous system in heatstroke: reversible profound depression of cerebral activity in a primate model.

BACKGROUND: The neurological manifestations of heatstroke victims vary. The exact sequence of the central nervous system (CNS) changes during lethal hyperthermia has only been partially explored, and the data covering the post-resuscitation CNS changes, which in most cases lead to secondary cardiac arrest, are insufficient. HYPOTHESIS: Following heating of the organism to cardiopulmonary arrest, successful resuscitation may be achieved by standard cardiopulmonary resuscitation (CPR), plus glucose and surface cooling. There is a characteristic sequence of neurological responses to hyperthermia preceding cardiopulmonary arrest, and questionable reversibility following successful resuscitation. METHODS: We exposed 12 pigtail monkeys under light anesthesia to total body hyperthermia (cerebral T = 42 degrees C) until cardiac arrest. We monitored EEG, mean arterial pressure (MAP), intracranial pressure (ICP), epidural temperatures, PaO2, PaCO2, serum sodium, osmolality, blood glucose, pupillary diameter, light response, corneal reflex, extremity movement, and seizures. RESULTS: During hyperthermia EEG frequency decreased and amplitude increased, followed by burst suppression pattern of the EEG. Then during severe hypoglycemia, EEG seizure activity and isoelectric EEG occurred when MAP and cerebral perfusion pressure (CPP) decreased while ICP was almost unchanged. Pupils were first responsive to light and became gradually unresponsive with maximal dilation, correlating with low CPP. After temporarily successful cardiopulmonary resuscitation (restoration of spontaneous circulation), normal EEG tracing and reversibility of the unresponsive pupils were observed. As shock led to secondary rearrest, deterioration with depression of all cerebral functions was documented. Some 147 min after restoration of spontaneous circulation, brains were macroscopically (and microscopically) normal in six of the eight monkeys. CONCLUSIONS: The acute cerebral derangements during and after lethal hyperthermia are reversible. The cause of death is probably not CNS damage, but systemic hemodynamic deterioration.

Animals↗