Sub-hypothermia therapy is one of the treatments for patients with severe head injury. The objective of the therapy is to treat traumatic brain injury (TBI) by alleviating brain edema, protecting blood brain barrier (BBB), and preventing subsequent damage to neurons. It can protect brain function by depressing metabolism, reducing the release of excitatory amino acids and free radicals, reducing the level of lactic acid, and lowering the damage of cytoskeletal structure.1 However, sub-hypothemia may affect patients’ coagulatory function including amendment to hypercoagulation state or hyperfibrinolysis and platelet (PLT) functional disturbance. 2,3 This study aimed to observe how sub-hypothermia therapy exerts effects on coagulopathy of patients after head injury.
Auto hemagglutination analysator (SysmexCA-1500, Japan), sub-hypothermia therapy equipment (HGT-200, Zhuhai, China), breathing machine (Drager Evita 2, Germany), ultra cold freezer (TY1379, Japan), super-speed refrigerated centrifuge (KUBOTA6900, Japan), enzyme analysis equipment (Benchmark, USA), and enzyme-linked immuno-assay (ELISA) emboitement kit (provided by Haikou Kehua Biotechnology Company, China, made by DADE Company, USA) were used to detect fibrinogen (Fbg), tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), antithrombin-III (AT-III), and D-dimer.
Forty-three patients (30 males and 13 females) with isolated severe head injury who had been treated from October 2006 to September 2007 were enrolled in this study. Causes of injury included traffic accident injury (19 patients), wound in a fall (15) and blunt injury (9). All of the patients were unconscious when admitted (Glasgow coma scale (GCS) ≤5 in 15 patients and GCS 6-8 in 28 patients). The first CT scanning after head injury showed contusion and laceration of the brain in the frontal and temporal lobes, but no patients underwent craniotomy. On admission, 7 patients had lateral corodiastasis, 4 had bilateral corodiastasis (excluding cerebral hernia), 10 had irregular pupils, and 22 had no change of pupils. Twenty-two patients presented with hemiparalysis and 35 with Babinski’s sign.
Inclusion criteria were isolated severe head injury; admission within 4 hours after head injury; GCS ≤8; unequivocal contusion and laceration of the brain shown by CT scanning; age ranging from 16 to 70 years; informed consent signed if enrolled in this study, and those who could accept hypothermia therapy immediately after admission.
Exclusion criteria were combined injury; open cranio-cerebral injury; traumatic shock; pregnant women or menstrual women; patients with hepatic diseases, blood diseases, or diseases affecting blood clotting; anticoagulation therapy; those transferred to other hospitals or withdrawn from this study; surgical operations; patients with severe complication receiving hypothermia therapy; patients who died within 72 hours or accepted component blood transfusion and drug treatment promoting coagulation or fibrinolysis, etc.
The 43 patients were randomly divided into two groups according to gender on admission. Twenty patients (13 males and 7 females) were in group A (sub-hypothermia group) with age ranging from 16 to 66 years, averaging (37.05±15.67) years. The remaining 23 patients were in group B (control group) with age ranging from 18 to 61 years, averaging (38.96±14.18) years. All patients were taken into neurosurgery intensive care unit immediately after incision of the trachea or tracheal intubation on admission. Assisted respiration or controlled respiration was given by a breathing machine and the body temperature was reduced by ice blanket, ice cap and ice cubes. Hibernation and muscle relaxant (aminazine 100 mg + promethazine 100 mg + tracium 200-400 mg+ normal sodium 500 ml) were given simultaneously to reduce shaking. The body temperature of the patients in group A was kept to 32.0-35.0°C. Patients of group B accepted the same treatment to keep the body temperature about 37.0-38.0°C. Apart from the body temperature, patients of both groups were subjected to the same conventional therapy. The patients in the two groups were not significantly different in gender and age (P=0.381, P=0.632). GCS scores showed no significant difference between group A (GCS 3-5 in 7 patients and GCS 6-8 in 13) and group B (GCS 3-5 in 8 patients and GCS 6-8 in 15) (P=0.619).
Collection and detection of samples
Blood samples (1.8 ml) were taken from the ulnar vein of each patient at 12, 24, 48 and 72 hours after head trauma and mixed with 0.13 mmol/L natrium citricum (1:9) as anticoagulant. Plasma was separated to detect the levels of Fbg, t-PA, PAI-1 and D-dimer at normal temperature.
SPSS 11.5 software package was used for statistical analysis. The numerical value was expressed as mean ± standard deviation (SD). The statistical methods included one-way analysis of variance (ANOVA), general linear models and the chi-square test. P <0.05 was considered statistically significant.
Coagulation test (Table)
General linear models test showed that Fbg level was higher in the sub-hypothermia group than that in the control group. There was a significant difference between the two groups at 12, 24 and 48 hours respectively (P=0.000, 0.000, 0.024).
D-dimer level was lower in the sub-hypothermia group than that in the control group. Analysis of solo effects showed that D-dimer level was significantly different between the two groups at 12 and 24 hours respectively (P=0.026, 0.020). But there was no significant difference between the two groups at 48 and 72 hours respectively (P=0.378, 0.247).
t-PA level was lower in group A than that in group B, and the difference was significant at 72 hours (P=0.006), but not significant at the other time points (P=0.140, 0.125, 0.112, respectively).
PAI-1 level was lower in group A than that in group B at the same time point, and the difference was significant at 24 hours (P=0.015), but not significant at 12, 48 and 72 hours (P=0.246, 0.095, 0.414, respectively).
The clinical outcomes of patients were evaluated by the Glasgow outcome score (GOS) at 6 months after head injury. In 20 patients of group A, 7 showed GOS 1-3, and 13 GOS 4-5. In the other 23 patients of group B, 15 showed GOS 1-3 and 8 GOS 4-5. The difference between groups A and B was significant (P=0.047).
Sub-hypothermia therapy at 30-35°C can reduce significantly the mortality and disability of patients with severe head injury.4 This therapy has the following mechanisms underlying brain protection:5-7 (1) reducing oxygen capacity of brain tissue and lactic acid accumulation; (2) protecting BBB and alleviating brain edema; (3) inhibiting endogenous toxicity damage to brain tissue; (4) reducing calcium influx in neurocytes and blocking up the cell damage of calcium overload; (5) preventing damage to constitutive protein in brain cells and promoting repair of structure and function of brain cells.
How does sub-hypothermia exert effects on coagulation disorder after head injury? In the existing literature, the influence of sub-hypothermia on the blood clotting function of such patients has been ignored. Sub-hypothermia has such complications as platelet-reduction and hemorrhage.8 Hypothermia can result in coagulation disorder but this effect can not be identified by conventional methods such as prothrombin time (PT) and activated partial thromboplastin time (APTT), which are always used below 37°C. In addition, both in vivo and in vitro experiments have indicated that hypothermia can destroy platelet function and platelet formation but activate fibrinolysis. Watts and colleagues9 discovered the lower body temperature the more likely bleeding.
On the other hand, sub-hypothermia can improve the post-trauma hyper-coagulation state.10 One mechanism of sub-hypothermia is to reduce oxygen consumption of brain tissue, decrease lactic acid accumulation, reduce brain edema, inhibit endogenous product generation and release, reduce Ca2+ inflow, inhibit neurotoxicity of thrombins, thus inhibit the release of thromplastin from brain tissue and alleviate the hyper-coagulation state. Another mechanism is to inhibit blood coagulation factor and enzymes. So hypothermia can prevent not only hyper-coagulation state but also hyperfibrinolysis after head injury and it may be an energetic and useful treatment for preventing subsequent cerebral hemorrhage following trauma. Can hypothermia improve the post-trauma hyper-coagulation state or aggravate subsequent hyperfibrinolysis? There are few reports about it.
Since all patients in this study had severe head injury, we observed coagulation and fibrinolysis in order to judge the relationship between coagulation and prognosis after hypothermia therapy.
We found that the Fbg level of the patients decreased more obviously in the control group than in the sub-hypothermia group. This result indicated that sub-hypothermia can lower the consumption of Fbg, reduce the post-TBI hyper-coagulation state, and decrease hyperfibrinolysis. The levels of D-dimer increased obviously at all time points after TBI, but they were lower in patients of the sub-hypothermia group than in the control group. The rising of D-dimer level indicates that the patients with severe TBI had coagulation disorder after trauma. The fact that the change in the sub-hypothermia group was smaller than that in the control group indicates that the hyper-coagulation state of the sub-hypothermia group was mild. We observed that t-PA level was higher in the control group than that in the sub-hypothermia group. This indicates that hyperfibrinolysis was slight in the sub-hypothermia group. PAI can inhibit t-PA quickly and efficiently and increase in the hyper-coagulation state. In our study, PAI in the sub-hypothermia group was lower than that in the control group; but the difference was not significant. This indicates that post-head injury hyper-coagulation state exists for a short time only.
The results of this study indicate that sub-hypothermia is able to ameliorate the coagulation disorder of patients with severe head injury. Instead of worsening hyperfibrinolysis, sub-hypothermia can improve the post-TBI hyper-coagulation state and subsequent hyperfibrinolysis. This finding was different from that reported elsewhere9 becasue sub-hypothermia given to patients within 4 hours post TBI improved effectively the hyper-coagulation state.
One more reason is that sub-hypothermia with body temperature ranging from 32°C to 35°C had little effect on hyperfibrinolysis. In contrast, the consumption of blood coagulation factors decreases and subsequent hyperfibrinolysis is improved because the hyper-coagulation state has been controlled in the early period.
In a word, sub-hypothermia therapy can regulate coagulation disorder following severe traumatic head injury. In the first 72 hours in our study, the patients displayed heperfibrinolysis. However, if sub-hypothermia was given to them, the fibrinolysis system could be inhibited and the complications caused by subsequent hyperfibrinolysis could be reduced. The patients in the sub-hypothermia group had better outcome than those in the control group. Thus sub-hypothermia is useful to improve the outcome of the patients with head injury, and improvement of coagulation disorder is one of the underlying mechanisms for sub-hypothermia therapy.
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