Resuscitative Hypothermia Research Articles

Comparison of thermal variations in post-retrieval graft conditioning on rat livers.

Machine perfusion was found an effective tool to recover organ grafts from ischemic insults during preservation. It could be observed that organ integrity is significantly affected by abrupt temperature shifts during hypothermic storage and implantation periods. Studies showed that a gentle and controlled rise of the temperature during oxygenated machine perfusion prior to implantation can protect the tissue from reperfusion injury. Now, the possible role of temperature kinetics upon retrieval of the graft and prior to later cold storage should be investigated. Rat livers were retrieved after cardiac arrest and subjected to a brief ex situ machine perfusion with either hypothermic resuscitation (HR) at 8°C, near-normothermic resuscitation (NR) at 30°C or progressive resuscitation with lowering the temperature in a controlled fashion from 30°C to 8°C (PR). After cold storage (CS), liver functional parameters were evaluated by an established ex vivo reperfusion system. NR and PR resulted in significantly lower release of hepatic enzymes and less production of tumor necrosis factor upon reperfusion compared to CS while HR had a far less protective effect. An increase in bile production was only observed in the PR group, which also significantly increased the recovery of tissue adenosine triphosphate, the amount of which was, however, nearly paralleled by the NR protocol. Within the limitations of this model, it seems that normothermic recirculation appears to be a superior approach for the restitution of warm-ischemically injured liver grafts than immediate hypothermic machine perfusion.

Structure and Function of Porcine Arteries Are Preserved for up to 6 Days Using the HypoRP Cold-storage Solution.

Maintaining functional vessels during preservation of vascularized composite allografts (VCAs) remains a major challenge. The University of Wisconsin (UW) solution has demonstrated significant short-term benefits (4-6 h). Here we determined whether the new hypothermic resuscitation and preservation solution HypoRP improves both structure, survival, and function of pig arteries during storage for up to 6 days. Using porcine swine mesenteric arteries, the effects of up to 6-day incubation in a saline (PBS), UW, or HypoRP solution on the structure, cell viability, metabolism, and function were determined. After incubation at 4°C, for up to 6 days, the structures of the arteries were significantly disrupted, especially the tunica media, following incubation in PBS, in contrast with incubation in the HypoRP solution and to a lesser extent, in UW solution. Those disruptions were associated with increased active caspase 3 indicative of apoptosis. Additionally, while incubation in PBS led to a significant decrease in the metabolic activity, UW and HypoRP solutions allowed a stable to increased metabolic activity following 6 days of cold storage. Functional responsiveness to phenylephrine (PE) and sodium nitroprusside (SNP) decreased over time for artery rings stored in PBS and UW solution but not for those stored in HypoRP solution. Moreover, artery rings cold-stored in HypoRP solution were more sensitive to ATP. The HypoRP solution improved long-term cold storage of porcine arteries by limiting structural alterations, including the collagen matrix, reducing apoptosis, and maintaining artery contraction-relaxation functions for up to 6 days.

Effect of different therapeutic time windows of mild hypothermia on neurological protection from ventricular fibrillation in rabbit models

Objective To investigate the effects of mild hypothermia on post-resuscitation neurological outcome after ventricular fibrillation (VF) in rabbits. Methods Forty-five adult New Zealand rabbits were induced VF by direct current of electricity. The rabbits were randomly(random number) divided into following groups: normothermic resuscitation group (NR), mild hypothermia pre-arrest group (HP), mild hypothermia resuscitation 30 min group (HRe30), mild hypothermia resuscitation 90 min group (HRe90), normothermic sham group (NS), and hypothermia sham group (HS). The rabbits of NR group were observed for 600 min in room temperature after restoration of spontaneous circulation (ROSC). The mild hypothermia was induced by surface cooling, and maintained for 600 min after the aimed low temperature reached. The arterial blood samples were collected for determining neuron-specific enolase (NSE) and thioredoxin (Trx) and the mean arterial pressure (MAP), left ventricular end-diastolic pressure (LVEDP) and left ventricular pressure raise and fall rate (±dp/dtmax) were observed at 15 min before CA, and 30 min, 60 min, 120 min, 360 min and 600 min after ROSC. After the animals were sacrificed at 600 min after ROSC, the whole brain of animals was harvested and observed under light microscope to calculate the apoptotic index of the hippocampal CA1 neurons by using TUNEL method. One-way ANOVA was used to determine the statistical significance between two groups, a two-tailed value of P<0.05 was considered statistically significant. Results (1) Hemodynamically compared with normal temperature groups, HR was lower in hypothermia groups. Compared with NR, HRe30, and HRe90 group, LVEDP was higher in HP group at 30 min after ROSC(3.4±0.8 vs. 4.6±1.0, 4.1±0.5, 4.3±0.2, F=9.85, P=0.019).In HP group, the level of +dp/dtmax was higher than that in NR, HRe30 and HRe90 groups at 30 min and 120 min after ROSC. In HP group, the level of -dp/dtmax was higher than that of NR group at 30 min, 60 min, 120 min, 360 min and 600 min after ROSC. (2) Serologically compared with HP, HRe30 and HRe90 group, NSE levels were higher in NR group at 60 min,120 min and 360 min after ROSC. Compared with NR, HRe30, and HRe90 group, Trx levels in NR group were lower at 60 min,120 min, 360 min and 600 min after ROSC. Compared with HP group, Trx levels in HRe30 and HRe90 groups were higher at 60 min,120 min, 360 min and 600 min after ROSC. (3) Pathologically compared with NR group, histopathological changes in hippocampus CA1 area were milder found in HP, HRe30 and HRe90 groups. AI (%) was lower in HP, HRe30 and HRe90 groups than that in NR group[(62.25±10.43)% vs. (20.61±5.02)%, (25.08±3.92)%, (30.33±7.15)%, P=0.001]. Concusions This study shows that hypothermia should be initiated as soon as possible, and especially early intra-arrest cooling appears to be significantly better than post-ROSC cooling and normothermia. Key words: Post-cardiac arrest syndrome; Mild therapeutic hypothermia; Ventricular fibrillation; Thioredoxin; Neurological protection; Rabbit

Effects of inducible hypothermia on expressions of PGC-1 and SHP in rat model of hemorrhagic shock

Objective To investigate the effects of inducible hypothermia on expressions of peroxisome proliferator activated receptor gamma coactivator-1 (PGC-1) and small heterodimer partner (SHP) in rat model of hemorrhagic shock. Methods SD rats were randomly(random number) divided into three groups: control (C), normothermia (N) and hypothermia (H). Exsanguination was carried out in rats by continuously drawing out venous blood (25 mL/kg) over 15 minutes to establish hemorrhagic shock model. Then, rectal temperatures of rats were maintained by body surface cooling to 32℃ in H group and by body surface warming to 38℃ in N group, respectively. After a shock period of 60 minutes, rats received the infusion of whole blood of their own and lactated Ringer's solution (1∶2) treatment for 60 min. Rats were warmed to 38℃ by body surface warming and monitored for 3 h after resuscitation. Hematocrit(Hct), base excess (BE), lactate (Lac), and glucose (Glu) were recorded before modeling and after different lengths of hemorrhagic shock period (HSP). The expressions of PGC-1 mRNA and SHP mRNA and the levels of their protein in liver were tested by real-time reverse transcription polymerase chain reaction (qRT-PCR) and western blotting, respectively. Results The H group had lower lactate levels and higher BE levels than the N group [(6.3±2.1) vs. (10.4±1.5) and (-4.7±2.5) vs. (-9.0±3.2)] (P< 0.05). At 72 hours after modeling, there were four survivors in the N group and seven survivors in the H group (P< 0.05, Log Rank). The expressions of PGC-1 mRNA and SHP mRNA increased in N group. Hypothermia resuscitation down-regulated PGC-1 mRNA expression, meanwhile, increased expression of SHP mRNA. Both Hypothermia and Normothermia resuscitation increased SHP protein levels, but decreased PGC-1 protein levels. Conclusions Inducible hypothermia ameliorated acidosis and energy metabolism imbalance through adaptive regulation in PGC-1 and SHP. Key words: Hemorrhagic shock; Inducible hypothermia; Peroxisome proliferator activated receptor gamma coactivator-1; Small heterodimer partner; Western blotting; Real-time reverse transcription polymerase chain reaction; Rat; Liver

Effect of hypothermia on the activation of inflammasome in the lung tissue during hemorrhagic shock

Objective To explore the effect of therapeutic hypothermia on the activation of inflammasome in the lung tissue of rats with hemorrhagic shock (HS). Methods Twenty-four male Sprague-Dawley rats were randomly(random number) divided into three groups: sham group, normothermia resuscitation (NR) group and hypothermia resuscitation (HR) group. Rats of each group were subjected to pressure-controlled (MAP 40 mmHg) HS for 1 h, then the NR group and the HR group were resuscitated with lactated Ringer and MAP was maintained at 90 mmHg for 1 h. Four hours later, the rats in each group were sacrificed by exsanguination. Hematoxylin eosin staining was used to observe the injury of lung tissue. The desiccation method was used to detect the edema of lung tissue. RT-PCR and western blot were employed to evaluate the mRNA and protein expression of NLRP-3, IL-1β, caspase-1.Analysis of variance was used for comparison among groups, and SNK-q test was used for comparison between two groups. Results (1) The injury of lung tissue in HR group was significantly milder than that in NR group; (2) Wet/dry (W/D) weight ratio of lung in HR group decrease compared with NR group [HR group 5.85±0.102; NR group 6.471±0.165 8 (t=3.14, P<0.05)]; (3)NLRP-3 and of Caspase-1 protein expression in the HR group were lower than those in NR group. (4) The NLRP-3 mRNA expression in HR group was lower compared with NR group [(HR group 1.027±0.143; NR group 1.3487±0.163 (t=4.36, P<0.05)] and IL-1 mRNA expression in HR group was lower compared with NR group [HR group 162.3±0.125; NR group 2.388±0.229 (t=7.72, P<0.05)]. Conclusions Therapeutic hypothermia attenuated ALI induced by HS in rats by modulation of signal way of inflammasome. Key words: Hypothermia; Hemorrhagic shock; Acute lung injury; Wet/dry weight ratio(W/D) of lung; Inflammasome; Caspase-1; Interleukin-1β

Volume infusion cooling increases end-tidal carbon dioxide and results in faster and deeper cooling during intra-cardiopulmonary resuscitation hypothermia induction.

BackgroundIntra-arrest hypothermia induction may provide more benefit than inducing hypothermia after return of spontaneous circulation. However, little is understood about the interaction between patient physiology and hypothermia induction technology choice during ongoing chest compressions.MethodsAfter 10 min of untreated ventricular fibrillation, mechanical chest compressions were provided for 60 min (100 CPM, 1.25" deep) in 26 domestic swine (30.5 ± 1.7 kg) with concurrent hypothermia induction using one of eight cooling methods. Four cooling methods included volume infusion with cold saline or an ice particulate slurry through the femoral vein or carotid artery (volume infusion cooling group, VC); three included cooling via an intra-vascular heat exchange catheter, nasal cooling, or surface ice bags (no volume cooling group, NVC); and the other was a control group with no cooling (no cooling group, NC). Physiological monitoring included end-tidal carbon dioxide, aortic pressure, right atrial pressure, brain temperature, esophageal temperature, and rectal temperature.ResultsDuring cardiopulmonary resuscitation (CPR), the volume infusion cooling group cooled faster and to lower temperatures than the other groups (VC vs. NVC or NC; ∆T = −5.6 vs. −2.1 °C or −0.6 °C; p < 0.01). The aortic pressure and right atrial pressure were higher in the volume cooling group than the other groups (VC vs. NVC or NC; AOP = 23.6 vs. 16.7 mmHg or 14.7 mmHg; p < 0.02). End-tidal carbon dioxide measurements during CPR were also higher in the volume cooling group (VC vs. NVC; EtCO2 = 23.4 vs. 13.1 mmHg; p < 0.05). Intra-corporeal temperature gradients larger than 3 °C were created by volume cooling during ongoing chest compressions.ConclusionsVolume infusion cooling significantly altered physiology relative to other cooling methods during ongoing chest compressions. Volume cooling led to faster cooling rates, lower temperatures, higher end-tidal carbon dioxide levels, and higher central vascular pressures.IACUC protocol numbers: UPenn (803178), CHOP (997)

Mild Hypothermia Combined with Hydrogen Sulfide Treatment During Resuscitation Reduces Hippocampal Neuron Apoptosis Via NR2A, NR2B, and PI3K-Akt Signaling in a Rat Model of Cerebral Ischemia-Reperfusion Injury.

We investigated whether mild hypothermia combined with sodium hydrosulfide treatment during resuscitation improves neuron survival following cerebral ischemia-reperfusion injury beyond that observed for the individual treatments. Male Sprague-Dawley rats were divided into seven groups (n = 20 for each group). All rats underwent Pulsinelli 4-vessel occlusion. Ischemia was induced for 15min using ligatures around the common carotid arteries, except for the sham group. Immediately after initiating reperfusion, the mild hypothermia (MH), sodium hydrosulfide (NaHS), hydroxylamine (HA), MH + NaHS, MH + HA, and ischemia-reperfusion (I/R) control groups received an intraperitoneal injection of saline, sodium hydrosulfide, hydroxylamine, sodium hydrosulfide, hydroxylamine, and saline, respectively, and mild hypothermia (32 to 33°C) was induced in the MH, MH + NaHS, and MH + HA groups for 6h. The levels of NR2A, NR2B, p-Akt, and p-Gsk-3β in the hippocampus of the MH, NaHS, and MH + NaHS groups were higher than those in the I/R control group, with the highest levels observed in the MH + NaHS group (P < 0.05). Treatment with hydroxylamine reduced the levels of these proteins in the HA and MH + HA groups, compared with the I/R control and MH groups, respectively. The apoptotic index of the CA1 region of the hippocampus was 45.2, 66.5, 63.5, and 84.8% in the MH + NaHS, MH, NaHS, and I/R control groups, respectively (P < 0.05), indicating that the combination treatment shifted the NR2A/NR2B balance in favor of synaptic neuron stimulation and phosphatidylinositol 3'-kinase (PI3K)/Akt signaling. The combination of mild hypothermia and sodium hydrosulfide treatment for resuscitation following ischemia-reperfusion injury was more beneficial for reducing hippocampal apoptosis and pathology than that of mild hypothermia or hydrogen sulfide treatment alone.

Moderate hypothermia ameliorates enterocyte mitochondrial dysfunction in severe shock and reperfusion

BackgroundHypothermia can ameliorate ischemia–reperfusion-induced intestinal injury; however, whether the therapeutic mechanism of hypothermia on hemorrhagic shock, a severe condition of ischemia–reperfusion, is associated with mitochondrial protection in enterocytes is rarely reported. We aimed to evaluate the effects of hypothermia on mitochondria after shock-induced intestinal injury. Materials and methodsA severe hemorrhagic shock model was constructed in Sprague–Dawley rats at induced hypothermic (32°C or 34°C) or normothermic temperatures (37°C), followed by resuscitation with whole shed blood and Ringer lactate (15 mg/kg body weight). After 2 h, 24 rats were killed and their intestinal tissue was collected; the remaining animals were returned to the normothermic environment to observe the survival time. ResultsThere was severe mitochondrial dysfunction in the normothermia group, as well as increased oxidative stress and terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling apoptotic index. As expected, hypothermia treatment decreased mitochondrial permeability transition pore opening and restored the mitochondrial membrane potential and intracellular adenosine triphosphate content. Furthermore, hypothermia elevated mitochondrial-reduced glutathione and decreased mitochondrial malondialdehyde; consistent with the restored mitochondrial function, intestinal cell apoptosis and intestinal histopathologic injury were attenuated, the systemic inflammatory response was mitigated, and survival time was significantly prolonged. Additionally, moderate-induced hypothermia (32°C) had better therapeutic effects than mild hypothermia (34°C). ConclusionsThe results suggest that moderate hypothermia resuscitation is an effective treatment for shock-induced intestinal injury, and its therapeutic mechanism may be related to mitochondrial protection.

Induced hypothermia during resuscitation from hemorrhagic shock attenuates microvascular inflammation in the rat mesenteric microcirculation.

Microvascular inflammation occurs during resuscitation following hemorrhagic shock, causing multiple organ dysfunction and mortality. Preclinical evidence suggests that hypothermia may have some benefit in selected patients by decreasing this inflammation, but this effect has not been extensively studied. Intravital microscopy was used to visualize mesenteric venules of anesthetized rats in real time to evaluate leukocyte adherence and mast cell degranulation. Animals were randomly allocated to normotensive or hypotensive groups and further subdivided into hypothermic and normothermic resuscitation (n = 6 per group). Animals in the shock groups underwent mean arterial blood pressure reduction to 40 to 45 mmHg for 1 h via blood withdrawal. During the first 2 h following resuscitation by infusion of shed blood plus double that volume of normal saline, rectal temperature of the hypothermic groups was maintained at 32°C to 34°C, whereas the normothermic groups were maintained between 36°C to 38°C. The hypothermic group was then rewarmed for the final 2 h of resuscitation. Leukocyte adherence was significantly lower after 2 h of hypothermic resuscitation compared with normothermic resuscitation: (2.8 ± 0.8 vs. 8.3 ± 1.3 adherent leukocytes, P = 0.004). Following rewarming, leukocyte adherence remained significantly different between hypothermic and normothermic shock groups: (4.7 ± 1.2 vs. 9.5 ± 1.6 adherent leukocytes, P = 0.038). Mast cell degranulation index (MDI) was significantly decreased in the hypothermic (1.02 ± 0.04 MDI) versus normothermic (1.22 ± 0.07 MDI) shock groups (P = 0.038) after the experiment. Induced hypothermia during resuscitation following hemorrhagic shock attenuates microvascular inflammation in rat mesentery. Furthermore, this decrease in inflammation is carried over after rewarming takes place.

Abstract 284: Extracorporeal CPR with Therapeutic Hypothermia Plus Percutaneous Coronary Intervention for Patients with Out-of-Hospital Shockable Cardiac Arrest Due to Acute Coronary Syndrome

BACKGROUND: There is insufficient evidence for a treatment bundle including extracorporeal cardiopulmonary resuscitation (ECPR) and therapeutic hypothermia plus percutaneous coronary intervention (PCI) for out-of-hospital cardiac arrest (OHCA) due to acute coronary syndrome (ACS). METHODS: From the SAVE-J, a prospective, multicenter, comparative study of ECPR, ACS patients who arrived at the hospital in cardiac arrest after OHCA due to ventricular fibrillation (VF) were included. We investigated whether ECPR and therapeutic hypothermia plus PCI for ACS had neurological benefit. The primary endpoint was favorable 30-day neurological outcome after OHCA. RESULTS: Of the 454 patients meeting the criteria of the SAVE-J, 280 (61.7%) were ACS, including 165 in the ECPR group and 115 in the non-ECPR group. Based on intention-to-treat analysis, frequency of favorable 30-day neurological outcome was 10.3% (17/165) in the ECPR group and 1.7% (2/115) in the non-ECPR group (p&lt;0.001). By per protocol analysis, frequency of favorable 30-day neurological outcome was 11.3% (17/151) in the ECPR group and 2.2% (2/89) in the non-ECPR group (p&lt;0.001). In the ECPR group (n=165), treatment included therapeutic hypothermia in 91.5% and emergency PCI in 90.3%. After adjustment for confounders, in 131 ACS patients treated with ECPR and therapeutic hypothermia plus PCI, longer collapse-to-hospital-arrival interval (adjusted OR, 0·93, 95% CI, 0.87-0.99) and female (adjusted OR, 0·14, 95% CI, 0.02-0.97) resulted in worse neurological outcome, and lower age and longer duration of cooling showed a tendency toward neurological benefits. CONCLUSION: In ACS patients who arrived at the hospital in cardiac arrest after OHCA due to ventricular fibrillation (VF), a treatment bundle including ECPR, therapeutic hypothermia plus PCI was associated with improved neurological outcome.

Prolonged Induced Hypothermia in Hemorrhagic Shock Is Associated With Decreased Muscle Metabolism

Hemorrhagic shock is a leading cause of trauma-related death in war and is associated with significant alterations in metabolism. Using archived serum samples from a previous study, the purpose of this work was to identify metabolic changes associated with induced hypothermia in a porcine model of hemorrhagic shock. Twelve Yorkshire pigs underwent a standardized hemorrhagic shock and resuscitation protocol to simulate battlefield injury with prolonged evacuation to definitive care in cold environments. Animals were randomized to receive either hypothermic (33°C) or normothermic (39°C) limited resuscitation for 8 h, followed by standard resuscitation. Proton nuclear magnetic resonance spectroscopy was used to evaluate serum metabolites from these animals at intervals throughout the hypothermic resuscitation period. Animals in the hypothermic group had a significantly higher survival rate (P = 0.02) than normothermic animals. Using random forest analysis, a difference in metabolic response between hypothermic and normothermic animals was identified. Hypothermic resuscitation was characterized by decreased concentrations of several muscle-related metabolites including taurine, creatine, creatinine, and amino acids. This study suggests that a decrease in muscle metabolism as a result of induced hypothermia is associated with improved survival.

Skin Necrosis as a Complication of Therapeutic Hypothermia

This case report describes a complication caused by cooling pads used for therapeutic hypothermic resuscitation. The authors hope to highlight and emphasize the importance of a thorough evaluation of all skin surfaces that are in direct contact with such cooling pads. Skin injury from the cooling pads used for therapeutic hypothermia should be recognized as a potential complication of treatment.

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Introduction: Resuscitative therapeutic hypothermia after CPR is recommended for neuroprotection in patients after cardiac arrest. In patients suffering from severe heatstroke rapid cooling and management of ciculatory failure are crucial for prevention of irreversible organ failure, but there are n

Awakening after cardiac arrest and post resuscitation hypothermia: Are we pulling the plug too early?

BackgroundTime to awakening after out-of-hospital cardiac arrest (OHCA) and post-resuscitation therapeutic hypothermia (TH) varies widely. We examined the time interval from when comatose OHCA patients were rewarmed to 37°C to when they showed definitive signs of neurological recovery and tried to identify potential predictors of awakening. MethodsWith IRB approval, a retrospective case study was performed in OHCA patients who were comatose upon presentation to a community hospital during 2006–2010. They were treated with TH (target of 33°C) for 24h, rewarmed, and discharged alive. Comatose patients were generally treated medically after TH for at least 48h before any decision to withdraw supportive care was made. Pre-hospital TH was not used. Data are expressed as medians and interquartile range. ResultsThe 89 patients treated with TH in this analysis were divided into three groups based upon the time between rewarming to 37°C and regaining consciousness. The 69 patients that regained consciousness in ≤48h after rewarming were termed “early-awakeners”. Ten patients regained consciousness 48–72h after rewarming and were termed “intermediate-awakeners”. Ten patients remained comatose and apneic >72h after rewarming but eventually regained consciousness; they were termed “late-awakeners”. The ages for the early, intermediate and late awakeners were 56 [49,65], 62 [48,74], and 58 [55,65] years, respectively. Nearly 67% were male. Following rewarming, the time required to regain consciousness for the early, intermediate and late awakeners was 9 [2,18] (range 0–47), 60.5 [56,64.5] (range 49–71), and 126 [104,151]h (range 73–259), respectively. Within 90 days of hospital admission, favorable neurological function based on a Cerebral Performance Category (CPC) score of 1 or 2 was reported in 67/69 early, 10/10 intermediate, and 8/10 late awakeners. ConclusionFollowing OHCA and TH, arbitrary withdrawal of life support <48h after rewarming may prematurely terminate life in many patients with the potential for full neurological recovery. Additional clinical markers that correlate with late awakening are needed to better determine when withdrawal of support is appropriate in OHCA patients who remain comatose >48h after rewarming.

HEART's Original [症例] 院外心肺停止後脳低体温療法が奏効し社会復帰に成功した肥大型心筋症の1例

HEART's Original [症例] 院外心肺停止後脳低体温療法が奏効し社会復帰に成功した肥大型心筋症の1例

Effect of Induced Hypothermia on Microvascular Inflammation During Hemorrhagic Shock/Resuscitation

IntroductionMicrovascular inflammation caused by hemorrhagic shock is associated with increased morbidity and mortality in trauma patients. Hypothermia has been shown to be a novel approach in preventing morbidity and mortality in several clinical scenarios.ObjectiveOur goal was to determine if induced hypothermia during hemorrhagic shock/resuscitation attenuated leukocyte adherence and mast cell degranulation in the rat mesenteric microcirculation.MethodsIntravital microscopy was used to visualize the mesentery in real time. Ruthenium red was superfused over the mesentery throughout the experiment to assess mast cell degranulation. After a control period, blood pressure was reduced to 40–45 mm Hg for 1 hour by withdrawal of blood. During 2 hours of resuscitation, temperature was reduced to 32–34°C. The animal was then re‐warmed for 2 hours to 37–38°C.ResultsLeukocyte adherence and mast cell degranulation were decreased during hypothermic resuscitation compared to normothermic resuscitation. However, both leukocyte adherence and mast cell degranulation increased during the re‐warming period in comparison to the hypothermic period.ConclusionWe have shown that induced hypothermia during resuscitation attenuates microvascular inflammation, but this response may only be temporary as shown by an increase in leukocyte adherence during the re‐warming period.

Effects of hypothermia resuscitation on expression of peroxisome proliferator activated receptor gamma, inducible nitric oxide synthase and tumor necrosis factor-α genes in lung tissues of rats with hemorrhagic shock

Objective To investigate the effects of different body temperature resuscitation on the expression of peroxisome proliferator activated receptor gamma (PPAR-γ),inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α) genes in the lung tissue of rats with hemorrhagic shock.Methods Thirty-six adult male Wistar rats were randomly assigned to three groups:control group (S),normal thermia group (NR) and hypothermia group (HR).Rats in S control group underwent the surgical procedure but were not bled.Rats in NR group and HR group received normal thermia (37-38 ℃) resuscitation or hypothermia (33-34 ℃) resuscitation respectively during resuscitation and hourly thereafter.Realtime polymerase chain reaction (teal-time PCR) method was used to detect the mRNA expression of PPAR-γ,iNOS and TNF-α in the lung tissutes of rats with hemorrhagic shock after resuscitation for 60 min or 240min.Results (1) As compared with S group,PPAR-γ mRNA expression in NR group and HR group was0.61 ± 0.09 and 1.71 ± 0.16 respectively (P ＜ 0.05) after resuscitation for 60 min following hemorrhagic shock and 0.54 ± 0.08,and 2.82 ± 0.19 (P ＜ 0.05) after resuscitation for 240 min following hemorrhagic shock ; (2) As compared with S group,iNOS mRNA expression in NR group and HR group was 3.43 ±0.27 and 2.21 ±0.28 (P ＜0.05) after resuscitation for 60 min following hemorrhagic shock,and 4.86 ±0.62 and 2.93 ± 0.37 (P ＜ 0.05) after resuscitation for 240 min following hemorrhagic shock; (3) As compared with S group,TNF-α mRNA expression in NR group and HR group was 4.12 ±0.30 and 3.36 ±0.34 (P ＜0.05) after resuscitation for 60 min following hemorrhagic shock,and 5.87 ±0.34 and 4.91 ±0.53 (P ＜ 0.05) after resuscitation for 240 min following hemorrhagic shock.Conclusion Hypothermia resuscitation after hemorrhagic shock can raise the PPAR-γgene expression and inhibit iNOS and TNF-α gene expression in the rat lung tissues.Hypothermia resuscitation can reduce the lung tissue damage. Key words: Hemorrhagic shock; Hypothermia resuscitation; Peroxisome proliferator activated receptor gamma; Inducible nitric oxide synthase; Tumor necrosis factor-α

Short-term, Mild Hypothermia Can Increase the Beneficial Effect of Permissive Hypotension on Uncontrolled Hemorrhagic Shock in Rats

Our previous and other studies have shown that hypotensive or hypothermic resuscitation have beneficial effects on uncontrolled hemorrhagic shock. Whether hypothermia can increase the beneficial effect of hypotensive resuscitation on hemorrhagic shock is not known. Two-hundred and twenty Sprague-Dawley rats were used to make uncontrolled hemorrhagic shock. Before bleeding was controlled, rats received normotensive or hypotensive resuscitation (target mean arterial pressure at 80 or 50 mmHg) in combination with normal (37°C) or mild hypothermia (34°C) (phase II). After bleeding was controlled, rats received whole blood and lactated Ringer's solution resuscitation for 2 h (phase III). The animal survival, blood loss, fluid requirement, cardiac output, and coagulation functions, as well as vital organ function, mitochondrial function, and energy metabolism of liver, kidney and intestines, were noted. Short-term, mild hypothermia before bleeding was controlled increased the beneficial effect of hypotensive resuscitation. Hypothermia further decreased blood loss, oxygen consumption, and functional damage to the liver, kidney, and intestines during hypotensive resuscitation, protected mitochondrial function and energy metabolism (activity of Na(+)-K(+)-ATPase), and further improved survival time and survival rate (hypothermic/hypotensive combined group: survival rate, 9/10; survival time, 616 min; normothermic/normotensive group: 1/10, 256 min; hypothermic/normotensive group: 4/10, 293 min). Hypothermia slightly inhibited coagulation function. Mild hypothermia before bleeding is controlled can increase the beneficial effect of hypotensive resuscitation on uncontrolled hemorrhagic shock. The mechanism underlying the benefits of short-term hypothermia may be related to the decrease in oxygen consumption and metabolism, and protection of mitochondrial and organ functions.

Hypothermia reduces resuscitation fluid volumes required to maintain blood pressure in a rat hemorrhagic shock model

To examine the hypothesis that resuscitative hypothermia would (1) reduce fluid requirements and reactive oxygen species production during a period of resuscitation and (2) improve survival after hemorrhagic shock (HS) in rats. Sixteen rats underwent an HS phase (phase I: 0-75 minutes), with pressure-controlled HS at a mean arterial pressure of 30 mm Hg ± 5 mm Hg; a resuscitation phase (phase II: 75-150 minutes), with fluid resuscitation to maintain mean arterial pressure ≥75 mm Hg; and an observation phase (phase III: from 150 minutes to 72 hours). During phase II, eight rats were randomized into a normothermia group (group 1: 38°C) or a hypothermia group (group 2: 34°C). Fluid requirements during phase II and survival at 72 hours were compared between groups. Plasma levels of Vitamin E and %coenzyme Q9 (%CoQ9) were also assessed. The fluid requirement during resuscitation in phase II was 8.2 ± 1.4 mL/100 g in group 1 versus 2.1 mL/100 g ± 0.7 mL/100 g in group 2 (p < 0.01). Vitamin E level decreased to 10.8 μmol/L ± 1.8 μmol/L during HS in all rats. After resuscitation, it was restored to a baseline level of 15.9 μmol/L ± 3.1 μmol/L in group 2 but remained at 10.2 μmol/L ± 0.8 μmol/L in group 1 (p < 0.05). %CoQ9 did not differ significantly between the groups. At 72 hours, six of eight rats in group 1, and all rats in group 2 survived (NS). In a rat HS model, hypothermia during resuscitation from HS reduces resuscitation fluid volume required to maintain blood pressure and restores Vitamin E to the baseline level, and appears to have no adverse impact on long survival after HS.

Therapeutic hypothermia and neurological outcome after cardiac arrest

The most important clinically relevant cause of global cerebral ischemia is cardiac arrest. Clinical studies showed a marked neuroprotective effect of mild hypothermia in resuscitation. The aim of this study was to evaluate the impact of mild hypothermia on neurological outcome and survival of the patients in coma, after cardiac arrest and return of spontaneous circulation. The prospective study was conducted on consecutive comatose patients admitted to our clinic after cardiac arrest and return of spontaneous circulation, between February 2005 and May 2009. The patients were divided into two groups: the patients treated with mild hypothermia and the patients treated conservatively. The intravascular in combination with external method of cooling or only external cooling was used during the first 24 hours, after which spontaneous rewarming started. The endpoints were survival rate and neurological outcome. The neurological outcome was observed with Cerebral Performance Category Scale (CPC). Follow-up was 30 days. The study was conducted on 82 patients: 45 patients (age 57.93 +/- 14.08 years, 77.8% male) were treated with hypothermia, and 37 patients (age 62.00 +/- 9.60 years, 67.6% male) were treated conservatively. In the group treated with therapeutic hypothermia protocol, 21 (46.7%) patients had full neurological restitution (CPC 1), 3 (6.7%) patients had good neurologic outcome (CPC 2), 1 (2.2%) patient remained in coma and 20 (44.4%) patients finally died (CPC 5). In the normothermic group 7 (18.9%) patients had full neurological restitution (CPC 1), and 30 (81.1%) patients remained in coma and finally died (CPC 5). Between the two therapeutic groups there was statistically significant difference in frequencies of different neurologic outcome (p = 0.006), specially between the patients with CPC 1 and CPC 5 outcome (p = 0.003). In the group treated with mild hypothermia 23 (51.1%) patients survived, and in the normothermic group 30 (81.1%) patients died, while in the group of survived patients 23 (76.7%) were treated with mild hypothermia (p = 0.003). Mild therapeutic hypothermia applied after cardiac arrest improved neurological outcome and reduced mortality in the studied group of comatose survivors.