Bleeding and hemostasis during normo- and hypothermia : studies on porcine and rat models
Author: Heinius, Göran
Date: 2010-02-19
Location: Aulan, Södersjukhuset
Time: 09.00
Department: Institutionen för klinisk forskning och utbildning, Södersjukhuset / Department of Clinical Science and Education, Södersjukhuset
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Thesis (1.577Mb)
Abstract
Background: Numerous animal studies have shown protective effects of
hypothermia (HT) on hemorrhagic shock. These findings do not correlate
with clinical findings, were studies on trauma registers have shown that
HT is an independent factor of death when associated with trauma. HT
affects hemostasis, but is just one of many factors that cause the
coagulopathy often seen in trauma patients with uncontrolled bleedings.
To what extent HT per se contributes to the hemorrhage and hence, the
deterioration of shock is virtually unknown. In this thesis we
investigate HTs impact on uncontrolled hemorrhage, but also if rebleeding
volumes could be affected by hemostatic drugs or different resuscitation
regimes.
Methods: I: 18 pigs were randomized to HT (n = 10) or normothermia (NT) (n = 8). A volume controlled hemorrhagic shock was induced by a 40 % exsanguination of estimated blood volume (EBV). HT animals were cooled to 32.5 degrees C and rewarmed again after 2 hours. The observation time (OT) was 420 minutes. II: 23 pigs were randomized to receive tranexamic acid (n = 11) or placebo (n = 12). Uncontrolled hemorrhage was induced by lacerating the aorta, producing an exsanguination estimated to 35 40 % of EBV. These animals were not actively cooled. Rebleeding events were monitored by ultrasonic probes. OT was 130 minutes. Thrombelastography (TEG) was used to evaluate coagulation changes in study I and II. III: 40 rats were randomized to HT (n = 20) or NT (n = 20). Uncontrolled hemorrhage was induced by puncturing the femoral artery, producing an exsanguination estimated to 24 % of EBV. HT animals were cooled to 30 degrees C and rewarmed again at 90 minutes. The incidence, on-set time, duration and volume of rebleedings were followed. OT was 180 minutes. IV: 60 rats, all cooled and processed according to the protocol of study III, were randomized to 3 different resuscitation groups; Low (LRe), Medium (MRe) or High (HRe) or Medium resuscitation +Desmopressin (MRe + D) (n = 4 x 15).
Results: I: HT induced a coagulopathy apparent at temperatures < 35degrees C, and reversible upon rewarming. There were no differences in hemodynamics, blood chemistry and mortality between groups at the end of the study period. II: There were no differences in rebleeding or mortality between the tranexamic acid and placebo groups. Non- survivors had significantly higher rebleeding volumes compared to survivors. At the end of observation, there was a strong correlation between an aggravated coagulopathy, as measured by TEG, and total bleeding volumes. III: HT animals had significantly higher rebleeding volumes (HT = 43 % vs. NT = 3 % of EBV). Rebleeding volumes were larger in the HT group even at temperatures > 35 degrees C. Much higher blood pressure, induced by cooling, was seen in the HT group. IV: There were significantly higher rebleeding volumes in the HRe group and a trend towards higher mortality in the LRe group. No significant differences in the number or volume of rebleeding and no difference in mortality between the MRe + D and MRe groups was seen.
Conclusions: HT induces a coagulopathy that is reversible upon rewarming. During trauma and uncontrolled hemorrhage, other factors than HT contribute to this coagulopathy. Hemodynamic changes provoked by cooling and HT, i.e. a rise in blood pressure, contribute to repeated rebleeding and hence, continuous hemorrhage. An MRe resuscitation regime seems most beneficial for outcome during HT and uncontrolled hemorrhage. Tranexamic acid at NT and desmopressin at HT conditions does not reduce rebleeding in penetrating trauma with uncontrolled hemorrhage.
Methods: I: 18 pigs were randomized to HT (n = 10) or normothermia (NT) (n = 8). A volume controlled hemorrhagic shock was induced by a 40 % exsanguination of estimated blood volume (EBV). HT animals were cooled to 32.5 degrees C and rewarmed again after 2 hours. The observation time (OT) was 420 minutes. II: 23 pigs were randomized to receive tranexamic acid (n = 11) or placebo (n = 12). Uncontrolled hemorrhage was induced by lacerating the aorta, producing an exsanguination estimated to 35 40 % of EBV. These animals were not actively cooled. Rebleeding events were monitored by ultrasonic probes. OT was 130 minutes. Thrombelastography (TEG) was used to evaluate coagulation changes in study I and II. III: 40 rats were randomized to HT (n = 20) or NT (n = 20). Uncontrolled hemorrhage was induced by puncturing the femoral artery, producing an exsanguination estimated to 24 % of EBV. HT animals were cooled to 30 degrees C and rewarmed again at 90 minutes. The incidence, on-set time, duration and volume of rebleedings were followed. OT was 180 minutes. IV: 60 rats, all cooled and processed according to the protocol of study III, were randomized to 3 different resuscitation groups; Low (LRe), Medium (MRe) or High (HRe) or Medium resuscitation +Desmopressin (MRe + D) (n = 4 x 15).
Results: I: HT induced a coagulopathy apparent at temperatures < 35degrees C, and reversible upon rewarming. There were no differences in hemodynamics, blood chemistry and mortality between groups at the end of the study period. II: There were no differences in rebleeding or mortality between the tranexamic acid and placebo groups. Non- survivors had significantly higher rebleeding volumes compared to survivors. At the end of observation, there was a strong correlation between an aggravated coagulopathy, as measured by TEG, and total bleeding volumes. III: HT animals had significantly higher rebleeding volumes (HT = 43 % vs. NT = 3 % of EBV). Rebleeding volumes were larger in the HT group even at temperatures > 35 degrees C. Much higher blood pressure, induced by cooling, was seen in the HT group. IV: There were significantly higher rebleeding volumes in the HRe group and a trend towards higher mortality in the LRe group. No significant differences in the number or volume of rebleeding and no difference in mortality between the MRe + D and MRe groups was seen.
Conclusions: HT induces a coagulopathy that is reversible upon rewarming. During trauma and uncontrolled hemorrhage, other factors than HT contribute to this coagulopathy. Hemodynamic changes provoked by cooling and HT, i.e. a rise in blood pressure, contribute to repeated rebleeding and hence, continuous hemorrhage. An MRe resuscitation regime seems most beneficial for outcome during HT and uncontrolled hemorrhage. Tranexamic acid at NT and desmopressin at HT conditions does not reduce rebleeding in penetrating trauma with uncontrolled hemorrhage.
List of papers:
I. Heinius G, Wladis A, Hahn RG, Kjellström BT (2002). "Induced hypothermia and rewarming after hemorrhagic shock." J Surg Res 108(1): 7-13
Pubmed
II. Drobin D, Sjostrand F, Piros D, Hedin A, Heinius G, Hahn RG (2005). "Tranexamic acid does not prevent rebleeding in an uncontrolled hemorrhage porcine model." J Trauma 59(4): 976-83
Pubmed
III. Heinius G, Hahn R, Sonden A (2010). "Hypothermia increases rebleeding in a novel uncontrolled hemorrhage rat model." (Submitted)
IV. Heinius G, Hahn R, Sonden A (2010). "Effects of desmopressin and different intravenous fluid regimes on uncontrolled bleeding during hypothermia." (Manuscript)
I. Heinius G, Wladis A, Hahn RG, Kjellström BT (2002). "Induced hypothermia and rewarming after hemorrhagic shock." J Surg Res 108(1): 7-13
Pubmed
II. Drobin D, Sjostrand F, Piros D, Hedin A, Heinius G, Hahn RG (2005). "Tranexamic acid does not prevent rebleeding in an uncontrolled hemorrhage porcine model." J Trauma 59(4): 976-83
Pubmed
III. Heinius G, Hahn R, Sonden A (2010). "Hypothermia increases rebleeding in a novel uncontrolled hemorrhage rat model." (Submitted)
IV. Heinius G, Hahn R, Sonden A (2010). "Effects of desmopressin and different intravenous fluid regimes on uncontrolled bleeding during hypothermia." (Manuscript)
Issue date: 2010-01-29
Rights:
Publication year: 2010
ISBN: 978-91-7409-796-2
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