No long-term benefit from hypothermia after severe traumatic brain injury with secondary hypoxemia in rats

Courtney Robertson, Robert Clark, C. Edward Dixon, Steven Graham, Henry Alexander, Stephen Wisniewski, Donald Marion, Peter Safar, Patrick Kochanek

Research output: Contribution to journalArticle

Abstract

Introduction: Many reports have shown benefit from hypothermia in traumatic brain injury (TBI); but its effect in the setting of TBI with secondary insult remains undefined. Clinical studies show an increase in morbidity and mortality after severe TBI with secondary brain insult. 1 In experimental rat models, outcomes were worse in brain injury with secondary hypoxia. 2 Recently, we characterized a model of TBI with secondary hypoxemia and reported prominent neuronal apoptosis after injury. 3,4 We hypothesized that hypothermia would improve outcome after controlled-cortical impact (CCI) with secondary hypoxemic insult in rats. Methods: Rats were subjected to severe CCI injury followed by 30 min of hypoxemia (PaO 2=35-45 mm Hg). 3 Rats were then randomized to normothermia (NT=37°C, n=19), immediate hypothermia (IHT=32°C, after CCI, n=10), or delayed hypothermia (DHT=32°C, after hypoxemia, n=14) for 4 h. Motor (beam balance/ beam walking, d 1-5), cognitive (Morris Water Maze [MWM], d 14-21) and histologic outcome (lesion volume, hippocampal neuron counts, d21) were evaluated. Results: Motor and MWM performance were impaired, but did not differ between groups. Lesion volumes did not differ significantly between groups (NT=65.3 mm 3 ±6.9, IHT=50.2±8.2, DHT=53.7±7.9). Hippocampal neuron counts (CA1,CA3) were decreased on the injured side, but did not differ between groups (NT-CAI = 19.8±4.2 cells/hpf, NT-CA3=19.8±4.6, IHT-CA1 = 13.2±8.7, IHT-CA3= 15.6±7.3, DHT-CA1 = 13.7±5.8, DHT-CA3=18.5±7.3). Mortality rate did not differ significantly between groups. Conclusions: Immediate or delayed hypothermia did not improve long-term outcome after severe CCl with secondary hypoxemia in rats. The severity of the combined insult may be outside of the therapeutic window of opportunity. Clinical studies 5 have excluded patients with secondary insult, and have indicated that hypothermia is of limited efficacy in the subset of severely injured (GCS 3-4) patients. Novel therapeutic approaches or combination therapies may by necessary in this setting.

Original languageEnglish (US)
JournalCritical Care Medicine
Volume27
Issue number1 SUPPL.
StatePublished - 1999
Externally publishedYes

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Hypothermia
Neurons
Mortality
Water
Wounds and Injuries
Brain Injuries
Walking
Hypoxia
Traumatic Brain Injury
Theoretical Models
Therapeutics
Apoptosis
Morbidity
Brain

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Robertson, C., Clark, R., Dixon, C. E., Graham, S., Alexander, H., Wisniewski, S., ... Kochanek, P. (1999). No long-term benefit from hypothermia after severe traumatic brain injury with secondary hypoxemia in rats. Critical Care Medicine, 27(1 SUPPL.).

No long-term benefit from hypothermia after severe traumatic brain injury with secondary hypoxemia in rats. / Robertson, Courtney; Clark, Robert; Dixon, C. Edward; Graham, Steven; Alexander, Henry; Wisniewski, Stephen; Marion, Donald; Safar, Peter; Kochanek, Patrick.

In: Critical Care Medicine, Vol. 27, No. 1 SUPPL., 1999.

Research output: Contribution to journalArticle

Robertson, C, Clark, R, Dixon, CE, Graham, S, Alexander, H, Wisniewski, S, Marion, D, Safar, P & Kochanek, P 1999, 'No long-term benefit from hypothermia after severe traumatic brain injury with secondary hypoxemia in rats', Critical Care Medicine, vol. 27, no. 1 SUPPL..
Robertson, Courtney ; Clark, Robert ; Dixon, C. Edward ; Graham, Steven ; Alexander, Henry ; Wisniewski, Stephen ; Marion, Donald ; Safar, Peter ; Kochanek, Patrick. / No long-term benefit from hypothermia after severe traumatic brain injury with secondary hypoxemia in rats. In: Critical Care Medicine. 1999 ; Vol. 27, No. 1 SUPPL.
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abstract = "Introduction: Many reports have shown benefit from hypothermia in traumatic brain injury (TBI); but its effect in the setting of TBI with secondary insult remains undefined. Clinical studies show an increase in morbidity and mortality after severe TBI with secondary brain insult. 1 In experimental rat models, outcomes were worse in brain injury with secondary hypoxia. 2 Recently, we characterized a model of TBI with secondary hypoxemia and reported prominent neuronal apoptosis after injury. 3,4 We hypothesized that hypothermia would improve outcome after controlled-cortical impact (CCI) with secondary hypoxemic insult in rats. Methods: Rats were subjected to severe CCI injury followed by 30 min of hypoxemia (PaO 2=35-45 mm Hg). 3 Rats were then randomized to normothermia (NT=37°C, n=19), immediate hypothermia (IHT=32°C, after CCI, n=10), or delayed hypothermia (DHT=32°C, after hypoxemia, n=14) for 4 h. Motor (beam balance/ beam walking, d 1-5), cognitive (Morris Water Maze [MWM], d 14-21) and histologic outcome (lesion volume, hippocampal neuron counts, d21) were evaluated. Results: Motor and MWM performance were impaired, but did not differ between groups. Lesion volumes did not differ significantly between groups (NT=65.3 mm 3 ±6.9, IHT=50.2±8.2, DHT=53.7±7.9). Hippocampal neuron counts (CA1,CA3) were decreased on the injured side, but did not differ between groups (NT-CAI = 19.8±4.2 cells/hpf, NT-CA3=19.8±4.6, IHT-CA1 = 13.2±8.7, IHT-CA3= 15.6±7.3, DHT-CA1 = 13.7±5.8, DHT-CA3=18.5±7.3). Mortality rate did not differ significantly between groups. Conclusions: Immediate or delayed hypothermia did not improve long-term outcome after severe CCl with secondary hypoxemia in rats. The severity of the combined insult may be outside of the therapeutic window of opportunity. Clinical studies 5 have excluded patients with secondary insult, and have indicated that hypothermia is of limited efficacy in the subset of severely injured (GCS 3-4) patients. Novel therapeutic approaches or combination therapies may by necessary in this setting.",
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AU - Robertson, Courtney

AU - Clark, Robert

AU - Dixon, C. Edward

AU - Graham, Steven

AU - Alexander, Henry

AU - Wisniewski, Stephen

AU - Marion, Donald

AU - Safar, Peter

AU - Kochanek, Patrick

PY - 1999

Y1 - 1999

N2 - Introduction: Many reports have shown benefit from hypothermia in traumatic brain injury (TBI); but its effect in the setting of TBI with secondary insult remains undefined. Clinical studies show an increase in morbidity and mortality after severe TBI with secondary brain insult. 1 In experimental rat models, outcomes were worse in brain injury with secondary hypoxia. 2 Recently, we characterized a model of TBI with secondary hypoxemia and reported prominent neuronal apoptosis after injury. 3,4 We hypothesized that hypothermia would improve outcome after controlled-cortical impact (CCI) with secondary hypoxemic insult in rats. Methods: Rats were subjected to severe CCI injury followed by 30 min of hypoxemia (PaO 2=35-45 mm Hg). 3 Rats were then randomized to normothermia (NT=37°C, n=19), immediate hypothermia (IHT=32°C, after CCI, n=10), or delayed hypothermia (DHT=32°C, after hypoxemia, n=14) for 4 h. Motor (beam balance/ beam walking, d 1-5), cognitive (Morris Water Maze [MWM], d 14-21) and histologic outcome (lesion volume, hippocampal neuron counts, d21) were evaluated. Results: Motor and MWM performance were impaired, but did not differ between groups. Lesion volumes did not differ significantly between groups (NT=65.3 mm 3 ±6.9, IHT=50.2±8.2, DHT=53.7±7.9). Hippocampal neuron counts (CA1,CA3) were decreased on the injured side, but did not differ between groups (NT-CAI = 19.8±4.2 cells/hpf, NT-CA3=19.8±4.6, IHT-CA1 = 13.2±8.7, IHT-CA3= 15.6±7.3, DHT-CA1 = 13.7±5.8, DHT-CA3=18.5±7.3). Mortality rate did not differ significantly between groups. Conclusions: Immediate or delayed hypothermia did not improve long-term outcome after severe CCl with secondary hypoxemia in rats. The severity of the combined insult may be outside of the therapeutic window of opportunity. Clinical studies 5 have excluded patients with secondary insult, and have indicated that hypothermia is of limited efficacy in the subset of severely injured (GCS 3-4) patients. Novel therapeutic approaches or combination therapies may by necessary in this setting.

AB - Introduction: Many reports have shown benefit from hypothermia in traumatic brain injury (TBI); but its effect in the setting of TBI with secondary insult remains undefined. Clinical studies show an increase in morbidity and mortality after severe TBI with secondary brain insult. 1 In experimental rat models, outcomes were worse in brain injury with secondary hypoxia. 2 Recently, we characterized a model of TBI with secondary hypoxemia and reported prominent neuronal apoptosis after injury. 3,4 We hypothesized that hypothermia would improve outcome after controlled-cortical impact (CCI) with secondary hypoxemic insult in rats. Methods: Rats were subjected to severe CCI injury followed by 30 min of hypoxemia (PaO 2=35-45 mm Hg). 3 Rats were then randomized to normothermia (NT=37°C, n=19), immediate hypothermia (IHT=32°C, after CCI, n=10), or delayed hypothermia (DHT=32°C, after hypoxemia, n=14) for 4 h. Motor (beam balance/ beam walking, d 1-5), cognitive (Morris Water Maze [MWM], d 14-21) and histologic outcome (lesion volume, hippocampal neuron counts, d21) were evaluated. Results: Motor and MWM performance were impaired, but did not differ between groups. Lesion volumes did not differ significantly between groups (NT=65.3 mm 3 ±6.9, IHT=50.2±8.2, DHT=53.7±7.9). Hippocampal neuron counts (CA1,CA3) were decreased on the injured side, but did not differ between groups (NT-CAI = 19.8±4.2 cells/hpf, NT-CA3=19.8±4.6, IHT-CA1 = 13.2±8.7, IHT-CA3= 15.6±7.3, DHT-CA1 = 13.7±5.8, DHT-CA3=18.5±7.3). Mortality rate did not differ significantly between groups. Conclusions: Immediate or delayed hypothermia did not improve long-term outcome after severe CCl with secondary hypoxemia in rats. The severity of the combined insult may be outside of the therapeutic window of opportunity. Clinical studies 5 have excluded patients with secondary insult, and have indicated that hypothermia is of limited efficacy in the subset of severely injured (GCS 3-4) patients. Novel therapeutic approaches or combination therapies may by necessary in this setting.

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