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31. |
Endothelin receptor antagonist bosentan improves microcirculatory blood flow in splanchnic organs in septic shock |
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Critical Care Medicine,
Volume 31,
Issue 1,
2003,
Page 203-210
Vladimir Krejci,
Luzius Hiltebrand,
Dominique Erni,
Gisli Sigurdsson,
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摘要:
ObjectiveSplanchnic ischemia is believed to play an important role in the development of multiple organ dysfunction in septic shock. The vasoconstrictor peptide endothelin can produce an intense and sustained splanchnic vasoconstriction and is increased in sepsis. The aim of this investigation was to study the effects of an endothelin antagonist on microcirculatory blood flow in multiple abdominal organs during septic shock.DesignProspective, controlled animal study.SettingUniversity-affiliated research laboratory.SubjectsFifteen anesthetized and mechanically ventilated pigs.InterventionsSeptic shock was induced by fecal peritonitis. After 120 mins of sepsis, eight animals received 10 mg/kg bosentan intravenously followed by an intravenous infusion at 5 mg·kg−1·hr−1whereas seven (controls) received isotonic saline. At 240 mins after induction of sepsis both groups received hydroxyethyl starch, 20 mL/kg intravenously, to convert hypodynamic septic shock to hyperdynamic sepsis.Measurements and Main ResultsMicrocirculatory blood flow was measured simultaneously and continuously in the jejunal muscularis, pancreas, liver, kidney, skeletal muscle, and gastric, jejunal, and colon mucosa by using a multiple-channel laser Doppler flow meter. After 120 mins, all animals had developed signs of hypodynamic sepsis with decreased cardiac index, mean arterial blood pressure, and gastric mucosal pH. Microcirculatory blood flow in the pancreas and liver had decreased by 20% and in the jejunal muscularis by >40% (p< .01) whereas it remained virtually unchanged in the gastric, jejunal, and colonic mucosa. After 240 mins, cardiac index, mean arterial blood pressure, gastric mucosal pH, and microcirculatory blood flow in the gastric mucosa, colon mucosa, jejunal muscularis, and pancreas had all deteriorated in the controls, whereas in the bosentan-treated group, cardiac index and microcirculatory blood flow in the pancreas, gastric, and colon mucosa improved. During hyperdynamic sepsis, cardiac index increased above baseline in both groups but significantly more in the bosentan group. In the control group, microcirculatory flow returned to baseline in most tissues except in skeletal muscle and jejunal muscularis. In the bosentan group, microcirculatory flow returned to or increased above baseline in all tissues except in the muscularis of the jejunum.ConclusionsThe endothelin receptor antagonist bosentan significantly improved microcirculatory blood flow in many splanchnic organs and in peripheral tissues during septic shock. The results of this study are consistent with the hypothesis that endothelin plays an important role in the regulation of microcirculatory blood flow in splanchnic as well as in peripheral tissues during septic shock.
ISSN:0090-3493
出版商:OVID
年代:2003
数据来源: OVID
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32. |
Linkage disequilibrium between tumor necrosis factor (TNF)-&agr;–308 G/A promoter and TNF-&bgr;NcoI polymorphisms: Association with TNF-&agr; response of granulocytes to endotoxin stimulation |
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Critical Care Medicine,
Volume 31,
Issue 1,
2003,
Page 211-214
Michael Heesen,
Dagmar Kunz,
Bernd Bachmann-Mennenga,
Hans Merk,
Brunhilde Bloemeke,
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摘要:
ObjectiveControversial data have been reported on the association between the tumor necrosis factor (TNF)-&agr;–308 G&U279C;A promoter polymorphism or the TNF-&agr;NcoI polymorphism with TNF-&agr; plasma concentrations. The purpose of this study was to evaluate whether there is a linkage disequilibrium between the two polymorphisms. Moreover, the influence of these polymorphisms on the TNF-&agr; synthesis of activated granulocytes was studied.DesignAnalysis of TNF-&agr; concentrations of human whole blood after endotoxin stimulation.SettingMedical research laboratory.PatientsHealthy human volunteers.InterventionsNone.Measurements and Main ResultsHealthy human volunteers were genotyped for both TNF polymorphisms by means of polymerase chain reaction. TNF-&agr; plasma concentrations were determined with chemiluminescence after incubation of whole blood with endotoxin. A strong (p< .0001) linkage disequilibrium was found for the TNF-&bgr;NcoI and the TNF-&agr;–308 genetic polymorphisms. Almost all individuals homozygous for the TNF-B2 allele of the TNF-&bgr;NcoI polymorphism were also TNF-&agr;–308 G homozygotes. Carriers of the TNF-&agr;–308 genotype AG had a significantly higher TNF-&agr; production capacity than G homozygotes. The TNF-&bgr;NcoI genotype TNF-B1/TNF-B2 was associated with significantly higher TNF-&agr; concentrations than the genotype TNF-B2/TNF-B2. Individuals homozygous for the TNF-B2 and the TNF-&agr;–308 G alleles had a significantly reduced TNF-&agr; response compared with individuals heterozygous for both TNF polymorphisms.ConclusionsA linkage disequilibrium between the two TNF polymorphisms was found. This study revealed a significant association between genotype and phenotype for both TNF polymorphisms. Heterozygosity for both TNF polymorphisms is associated with an increased TNF-&agr; response.
ISSN:0090-3493
出版商:OVID
年代:2003
数据来源: OVID
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33. |
Low-dose terlipressin improves systemic and splanchnic hemodynamics in fluid-challenged endotoxic rats* |
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Critical Care Medicine,
Volume 31,
Issue 1,
2003,
Page 215-220
Pierre Asfar,
Marc Pierrot,
Nary Veal,
Frédéric Moal,
Frédéric Oberti,
Vincent Croquet,
Olivier Douay,
Yves Gallois,
Jean-Louis Saumet,
Philippe Alquier,
Paul Calès,
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摘要:
ObjectiveVasopressin has been used to treat arterial hypotension associated with hyperdynamic vasoplegic states, but detrimental effects on splanchnic circulation have been reported. We tested the effects of a low-dose vasopressin analogue, terlipressin (6 &mgr;g/kg), on systemic and splanchnic hemodynamics in fluid-challenged endotoxic rats (lipopolysaccharide, 30 mg/kg in 1 hr).DesignProspective, randomized, controlled experimental study with repeated measures.SettingInvestigational animal laboratory.SubjectsA total of 77 rats were divided into five groups: group C, control (17 rats); group E, LPS (18 rats); group EF, LPS plus fluid challenge (18 rats); group EFT, LPS plus fluid challenge plus terlipressin (18 rats); and group ET, LPS plus terlipressin (seven rats).InterventionsRats were anesthetized, mechanically ventilated, and instrumented to measure heart rate, mean arterial pressure, and abdominal aortic and mesenteric vein indexed blood flows; ileal microcirculation was assessed by laser Doppler. After LPS infusion, rats experienced an endotoxic shock and were resuscitated after the allocation group. The fluid challenge was targeted to maintain mean arterial pressure of >90 mm Hg and aortic blood flow at baseline values.Measurements and Main ResultsTerlipressin significantly (p< .05) increased mean arterial pressure without decreasing indexed aortic blood flow and heart rate in the fluid-challenged endotoxic rats (EFT) compared with EF rats and had detrimental effects in hypodynamic endotoxic rats (ET). Fluid challenge significantly (p< .05) increased mesenteric vein blood flow in both the EF and EFT groups, and terlipressin had no detrimental effect on mesenteric blood flow. Terlipressin significantly (p< .05) increased ileal microcirculation in fluid-challenged endotoxic rats (EF and EFT) but not in hypodynamic endotoxic rats (E and ET).ConclusionLow-dose terlipressin in fluid-challenged endotoxic rats improved systemic and splanchnic hemodynamics and improved the ileal microcirculation.
ISSN:0090-3493
出版商:OVID
年代:2003
数据来源: OVID
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34. |
Protegrin-1 increases bacterial clearance in sepsis but decreases survival |
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Critical Care Medicine,
Volume 31,
Issue 1,
2003,
Page 221-226
Lars Steinstraesser,
Olaf Burghard,
Jean Nemzek,
Ming-Hui Fan,
Andrew Merry,
Daniel Remick,
Grace Su,
Hans-Ulrich Steinau,
Stewart Wang,
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ISSN:0090-3493
出版商:OVID
年代:2003
数据来源: OVID
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35. |
Determinants of tidal volume during high-frequency oscillation* |
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Critical Care Medicine,
Volume 31,
Issue 1,
2003,
Page 227-231
Khaled Sedeek,
Muneyuki Takeuchi,
Klaudiusz Suchodolski,
Robert Kacmarek,
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摘要:
ObjectiveHigh-frequency oscillation has been proposed for use in adult acute respiratory distress syndrome. However, limited data are available on the effect of pressure amplitude and rate (Hz) on tidal volumes delivered during high-frequency oscillation in adults.DesignProspective, animal model, lung injury study.SettingLarge-animal laboratory of a university-affiliated medical center.SubjectsNine sheep (29.2 ± 2.4 kg).InterventionsSevere lung injury was induced by repeated saline lung lavage. After stabilization, high-frequency oscillation was initiated at a mean airway pressure equal to the point of maximum curvature on the deflation limb of the pressure-volume curve (26 ± 1.9 cm H2O). Tidal volume at all combinations of rates of 4, 6, 8, and 10 Hz, pressure amplitudes of 30, 40, 50, and 60 cm H2O, and inspiratory/expiratory ratios of 1:1 and 1:2 (using the Sensormedics 3100B oscillator) were measured. Flow was measured by a pneumotachometer, amplified and digitized at 1000 Hz. Three breaths were analyzed at each setting.Measurements and Main ResultsAt both inspiratory/expiratory ratios, tidal volume was directly proportional to pressure amplitude and inversely proportional to frequency. During an inspiratory/expiratory ratio of 1:1, at 60 cm H2O pressure amplitude and 4 Hz, a tidal volume of 129.1 ± 34.8 mL (4.4 ± 1.2 mL/kg) was delivered.ConclusionsAt low rates and high-pressure amplitudes in this model, tidal volumes approaching conventional mechanical ventilation can be delivered during high-frequency oscillation.
ISSN:0090-3493
出版商:OVID
年代:2003
数据来源: OVID
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36. |
Genetic background conditions the effect of sex steroids on the inflammatory response during endotoxic shock |
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Critical Care Medicine,
Volume 31,
Issue 1,
2003,
Page 232-236
Heiko Trentzsch,
Dylan Stewart,
Antonio De Maio,
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摘要:
ObjectiveThe contribution of gender to the mortality and morbidity of trauma patients is controversial. In addition, a genetic contribution has been recently indicated. The influence of these two variables was studied in a murine model of endotoxemia.DesignProspective, controlled, and randomized animal study.SettingA university research laboratory.SubjectsFemale and male mice (6–8 wks old) were injected withEscherichia colilipopolysaccharide (15 mg/kg). Additionally, mice were gonadectomized and supplemented with 5-&agr;-dihydrotestosterone (357 mg/day), 17-&bgr;-estradiol (23.8 &mgr;g/day), or placebo for 21 days and injected with lipopolysaccharide. Tumor necrosis factor-&agr; was measured in plasma samples obtained after 1.5 hrs of lipopolysaccharide injection.Measurements and Main ResultsHigher tumor necrosis factor-&agr; plasma levels were observed in C57BL/6J (B6) female mice as compared with males. Because this phenotype is not sex linked, we evaluated the role of sex steroids. Castrated male B6 mice showed higher lipopolysaccharide-induced tumor necrosis factor-&agr; plasma levels than nonoperated controls. These lipopolysaccharide-induced tumor necrosis factor-&agr; levels were further increased after the administration of 17-&bgr;-estradiol to castrated B6 male mice as compared with nonoperated male or female mice. In addition, 17-&bgr;-estradiol-supplemented castrated mice showed a higher frequency of mortality than castrated males without hormone replacement or nonoperated mice. Analysis of castrated male mice from other strains (A/J, DBA/2J, AKR/J, BALB/cJ) supplemented with 17-&bgr;-estradiol presented the opposite effect, a reduction in lipopolysaccharide-induced tumor necrosis factor-&agr; plasma levels.ConclusionsThese results suggest that sex steroids can modulate the inflammatory response and the outcome after injury in mice. The effect of sex steroids depends on the genetic background.
ISSN:0090-3493
出版商:OVID
年代:2003
数据来源: OVID
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37. |
Modulation of serum cytokine levels by a novel superoxide dismutase mimetic, M40401, in anEscherichia colimodel of septic shock: Correlation with preserved circulating catecholamines* |
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Critical Care Medicine,
Volume 31,
Issue 1,
2003,
Page 237-245
Heather Macarthur,
Daniel Couri,
Gerald Wilken,
Thomas Westfall,
Andrew Lechner,
George Matuschak,
Zhoumou Chen,
Daniela Salvemini,
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摘要:
ObjectivesWe have shown previously that inactivation of catecholamines by superoxide anions contributes to the loss of vascular reactivity to norepinephrine and the subsequent hypotension that develops in Gram-negative endotoxic shock. In addition to their vasopressor actions, catecholamines, via &bgr;-adrenoceptor activation, are important regulators of cytokine production. Here we examined if maintenance of serum catecholamine levels by the superoxide dismutase mimetic, M40401, modulates serum cytokine levels and arterial hypotension in anEscherichia coli–infected conscious rat model of septic shock.DesignControlled laboratory animal study.SettingUniversity animal research laboratory.SubjectsPathogen-free male Sprague-Dawley rats (n = 51).InterventionsConscious, antibiotic-treated animals with chronic in-dwelling carotid arterial and jugular venous catheters were intravenously infected with 1010liveE. colibacteria (O55:B5, n = 51) over 30 mins, ending at time = 0 hrs. At 0.5 or 3 hrs, infected rats were administered an intravenous infusion of either M40401 (n = 33) or 0.9% saline (n = 18) for 6 hrs at a rate of 1 mL/h. In additional experiments, anesthetized animals with catheterized left femoral arteries and veins were administered a dose-range of norepinephrine (0.1–1 &mgr;g/kg) as bolus intravenous injections. Thereafter,E. colilipopolysaccharide (4 mg/kg, n = 6) was administered as a 0.3-mL slow bolus intravenous injection. One hour later, the norepinephrine protocol was repeated, after which the rats were administered an intravenous infusion of either M40401 or 0.9% saline for 15 mins. At 2 hrs, the dose response to norepinephrine was repeated.Measurements and Main ResultsRats infected with liveE. coliexhibited a biphasic fall in mean arterial pressure, with mortality reaching 83% by 24 hrs. Rats treated with M40401 (0.25, 2.5, or 25 &mgr;g·kg−1·hr−1) 3 hrs after bacteremic sepsis maintained a normal mean arterial pressure, and mortality was dose-dependently reduced to 44, 33, and 22%, respectively, at 24 hrs. Furthermore, serum catecholamine levels were diminished inE. coli–infected rats treated with saline compared with rats treated with M40401. In separate experiments,E. coli–infected rats were administered M40401 (25 &mgr;g·kg−1·hr−1) 0.5 hr after bacterial challenge. Blood samples taken at 0, 1.5, 3.5, and 6 hrs were analyzed for tumor necrosis factor-&agr;, interleukin (IL)-1&bgr;, IL-6, and IL-10 and for norepinephrine and epinephrine. Serum levels of tumor necrosis factor-&agr; and IL-1&bgr; were significantly depressed in M40401-treated septic rats, whereas IL-10 was elevated. Moreover, serum catecholamine levels were greater in M40401-treated septic rats at the same time points. IL-6 levels were unaffected by M40401 treatment. Finally we examined whether treatment with M40401 could reverse the hyporeactivity to norepinephrine typifying early septic shock. Using theE. colilipopolysaccharide (4 mg/kg) challenged anesthetized rat model of shock, we demonstrated that the vasoconstrictor ability of norepinephrine was indeed restored after M40401 treatment (25 &mgr;g/kg).ConclusionPostinfection treatment with the superoxide dismutase mimetic M40401 protects against hypotension, vascular hyporeactivity to catecholamines, and mortality associated with septic shock. Such beneficial effects correlate with both reduced oxidative inactivation of serum catecholamines and a reduction in canonical cytokine mediators of inflammation.
ISSN:0090-3493
出版商:OVID
年代:2003
数据来源: OVID
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38. |
Temperature sensitivity of glycolysis during sepsis |
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Critical Care Medicine,
Volume 31,
Issue 1,
2003,
Page 246-249
Philippe Sébert,
Christophe Kervran,
Erwan L’Her,
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摘要:
ObjectiveTo investigate the temperature sensitivity of glycolysis during sepsis.DesignA prospective, randomized, controlled animal study.SettingThe Physiological Department of a University Hospital.SubjectsTen male Sprague-Dawley rats, weighing 400–500 g.InterventionsThe rats were assigned to either a septic (n = 5) or a sham-control group (n = 5). After anesthesia (H0), experimental sepsis was induced by a cecal ligation and perforation, and the left lateral gastrocnemius was sampled. Four hours later (H4), a second anesthesia was performed to sample the contralateral muscle. The sham-control group underwent the same procedures, but the cecum was neither ligated nor incised.Measurements and Main ResultsGlycolytic flux (JB, the rate at which glycogen can be used in muscle) and the transition time (t99: the time required for the transition from aerobic to anaerobic metabolism) were measured by using spectrophotometry. The measurements were performed at seven different temperature levels, ranging from 32 to 42°C. For each measured variable, the temperature sensitivity of glycolysis was assessed by computing the Q10values, which is the variation ratio of the measured variable, attributed to a 10°C temperature increase. In control rats, anesthesia and surgical procedures induced a JBincrease (7.9 ± 1.6 at H0vs. 11.9 ± 2.1 &mgr;mol·min−1·gtissue−1at H4,p< .05) without any t99variation. Whatever the group (control or septic), the same temperature variation induced an effect that was approximately three times higher in the hypothermia (<37°C) than in the hyperthermia range (>37°C;p< .05). However, a loss in thermal sensitivity was observed in septic rats in the hyperthermia range (Q10= 1.2 ± 0.1 for septic animals vs. 2.3 ± 0.4 for control animals;p< .05).ConclusionsThis study demonstrates that glycolysis is more sensitive to temperature in the hypothermia range than in the hyperthermia range. The loss in thermal sensitivity at >37°C in septic rats suggests that sepsis may induce a dysregulation of glycolysis. From an energetic point of view, this signifies that hyperthermia may by itself impair energy metabolism without improving energy production and thus must be treated during sepsis.
ISSN:0090-3493
出版商:OVID
年代:2003
数据来源: OVID
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39. |
Effect ofin vitrohemodilution with hydroxyethyl starch and dextran on the activity of plasma clotting factors |
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Critical Care Medicine,
Volume 31,
Issue 1,
2003,
Page 250-254
Georg Petroianu,
Wolfgang Maleck,
Katharina Koetter,
Jie Liu,
Andrea Schmitt,
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摘要:
ObjectiveA recent thrombelastography study indicated a compromisedin vitroblood coagulation after 10:10 (equal parts of blood and infusion) and 10:4 (10 parts blood to four parts infusion) hemodilution with several plasma substitutes. Oncovertin N (Oncovertin) (a 10% dextran 40 solution) had the strongest anticoagulant effect of all solutions tested, and HAES-sterile 10% (HAES) (a 10% hydroxyethyl starch 200/0.5 solution) showed the strongest effect of five different hydroxyethyl starch preparations. The aim of this study was to determine howin vitrohemodilution with HAES and Oncovertin affects the activity of coagulation factors.DesignHAES and Oncovertin were tested to determine the intrinsic effect of colloid molecules, as opposed to hemodilutionper se. Normal saline (NaCl) and nonlactated Ringer solution were used as noncolloidal controls.SettingUniversity research institute.PatientsSix healthy volunteers.InterventionsTwenty milliliters of blood was obtained from each subject.Measurements and Main ResultsProthrombin index, activated partial prothrombin time, soluble fibrin monomers, and the activity of coagulation factors I, II, V, VII, VIII, IX, X, XI, and XII were measured with the Behring Chromotimer according to the manufacturer’s instructions. Two dilution ratios of citrated blood to infusion were used: 10:10 (equal parts of blood and infusion) and 10:4 (10 parts blood to four parts infusion). Baseline was undiluted. Hemodilution with NaCl at both 10:4 and 10:10 influenced the coagulation variables measured. The activities of factors I, VII, and soluble fibrin monomers were less influenced than expected by hemodilution alone. The activities of factors II, V, IX, and XI were significantly (p< .04) lower with both 10:4 and 10:10 dilution with NaCl. In the assays for factors IX, XI, and XII, clots formed immediately after adding the appropriate reagents in the presence of Ringer solution at 10:10 hemodilution, so that the activities of those factors could not be measured. For the other factors and for 10:4 dilution, the outcome after Ringer solution was similar to that of NaCl. The activities were less influenced after 10:4 hemodilution with both HAES and Oncovertin than after dilution with NaCl and Ringer solution, with no significant differences from baseline. At 10:10 hemodilution with both HAES and Oncovertin, several factor activities were significantly (p< .04) lower than baseline.ConclusionsBoth NaCl and Ringer solution cause measurable effects on coagulation factors at 10:4 hemodilution that can be explained by hemodilution alone. The effects on clotting factors of 10:4 hemodilution with HAES and Oncovertin were not significant. Even at 10:10 hemodilution with HAES or Oncovertin, the reduction in factor activities, although significantly (p< .04) different from baseline, was less than what was expected by dilution alone.
ISSN:0090-3493
出版商:OVID
年代:2003
数据来源: OVID
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40. |
Quantitative evaluation of the neuroprotective effects of hypothermia ranging from 34°C to 31°C on brain ischemia in gerbils and determination of the mechanism of neuroprotection |
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Critical Care Medicine,
Volume 31,
Issue 1,
2003,
Page 255-260
Yoshimasa Takeda,
Kenji Namba,
Tomoyasu Higuchi,
Shingo Hagioka,
Ken Takata,
Masahisa Hirakawa,
Kiyoshi Morita,
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摘要:
ObjectiveThe present study was designed to determine whether the predominant factor responsible for neuroprotection of hypothermia ranging from 31 to 34°C is prolongation of onset of ischemic depolarization or suppression of neuronal injury during ischemic depolarization and to quantitatively determine the neuroprotective effects of hypothermia of 34°C and 31°C.DesignProspective animal study.SettingA university research laboratory.SubjectsEighty-nine gerbils.InterventionsBilateral common carotid arteries were occluded for 3–20 mins. The brain temperature was set at 37°C, 34°C, or 31°C before and during ischemic depolarization.Measurements and Main ResultsDC potentials were measured in the CA1 region, where histologic evaluation was performed 7 days later. Onset times of ischemic depolarization were 1.3 ± 0.2, 1.6 ± 0.4, and 2.4 ± 0.7 mins at 37°C, 34°C, and 31°C, respectively. The logistic regression curve demonstrated a close relationship between duration of ischemic depolarization and neuronal damage and showed a rightward shift by lowering the brain temperature. In the 37°C, 34°C, and 31°C groups, the durations of ischemic depolarization causing 50% neuronal damage were estimated to be 8.0, 14.2, and 26.0 mins, respectively, and the ischemia times causing 50% neuronal damage were estimated to be 4.9, 8.1, and 14.2 mins, respectively.ConclusionsThe onset of ischemic depolarization was prolonged in the 34°C and 31°C groups by only 0.3 and 1.1 mins, respectively, compared with that in the 37°C group. Most of the neuroprotection by hypothermia was attributed to the suppression of neuronal injury during ischemic depolarization, suggesting that hypothermia has neuroprotective effects if it is initiated during the ischemic depolarization period. The results also indicate that the neuroprotective effect at 31°C is about three times greater than that at 34°C and that neuronal cells can withstand 2.9 times longer duration of ischemia at 31°C than at 37°C.
ISSN:0090-3493
出版商:OVID
年代:2003
数据来源: OVID
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