ABSTRACT
Background
We aimed to assess the effects of pre-hospital mild therapeutic hypothermia (MTH) on patients with severe traumatic brain injury (sTBI).
Methods
Eighty-six patients with sTBI were prospectively enrolled into the pre-hospital MTH group and the late MTH group (initiated in hospital). Patients in the pre-hospital MTH group were maintained at a tympanic temperature of 33°C–35°C before admission and continued to be treated with a therapeutic hypothermia device for 4 days. Patients in the late MTH group were treated with the same MTH parameters. Intracranial pressure (ICP), complications and Glasgow Outcome Scale (GOS) scores were monitored.
Results
ICP was significantly lower for patients in the pre-hospital MTH group 24, 48, and 72 h after treatment (17.38 ± 4.88 mmHg, 18.40 ± 4.50 mmHg, and 16.40 ± 4.13 mmHg, respectively) than that in the late MTH group (20.63 ± 3.00 mmHg, 21.80 ± 6.00 mmHg, and 18.81 ± 4.50 mmHg) (P < .05). The favorable prognosis (GOS scores 4–5) rate in the pre-hospital MTH group was higher tha n the late MTH group (65.1% vs. 37.2%, respectively; P < .05) without complications .
Conclusion
Pre-hospital MTH for patients with STBI can reduce ICP and improve neurological outcomes.
Introduction
Severe traumatic brain injury (sTBI) is a major cause of mortality and morbidity after trauma despite advances in treatment (Citation1). After the traumatic primary injury, some patients suffer secondary brain injuries because of hypoxia, hypercapnia and hypotension (Citation1,Citation2). The management of sTBI mainly focuses on such prevention of secondary ischemic brain injury by optimizing the balance between cerebral oxygen delivery and utilization, and the pre-hospital management is important for better outcome (Citation3–6). Mild therapeutic hypothermia (MTH) is a potent neuroprotectant against acute sTBI (Citation1,Citation2,Citation7–11), which can reduce primary injury and apoptosis as well as inhibit the formation and release of harmful endogenous factors after injury (Citation9,Citation11–14). Our previous studies have shown that selective head cooling with MTH can achieve “brain hypothermia” quickly and reduce the complications of systemic mild hypothermia for patients with sTBI (Citation13,Citation15,Citation16). The meta-analysis demonstrated that therapeutic hypothermia might increase the mortality rate of patients with sTBI, with the significant increase in the risk of pneumonia. Patients with sTBI with elevated intracranial hypertension could benefit from hypothermia in therapeutic management when initiated within 24 hours (Citation2,Citation17–19).It is suggested that initiating MTH sooner rather than later is ideal (Citation2,Citation17–19). Despite the promise the technique holds, the effects of the pre-hospital MTH for patients with TBI are not so good for patients with hypoxic-ischemic injury.
In order to evaluate the effects of pre-hospital MTH in patients with sTBI, we conducted a clinical trial and evaluated its neuroprotective effects for patients with sTBI.
Materials and methods
Clinical data and methods
General information
This prospective study presents the data between 2011 and 2017 from the three-levels of first-class comprehensive hospital at Affiliated Hospital of Hangzhou Normal University, China. The clinical trial is with the Trial registration number ISRCTN14110527. According to Good Clinical Practice standards, the research protocol was approved by the institutional review board and by the ethical committees of the Affiliated Hospital of Hangzhou Normal University and Declaration of Helsinki principles were strictly adhered to. Since the patients in this study were incapable of granting informed consent, the investigators obtained this from the patient’s legal guardians or by health proxy, before proceeding with the advised treatment.
All the patients met the following criteria (Citation1): a history of TBI (Citation2); Glasgow Coma Scale (GCS) of 8 to 4 at enrollment (Citation7); the brain injury with swollen hemisphere apparent on subsequent sequential computed tomography (CT) scans. We excluded patients such as patients with shock after trauma, patients with polytrauma, with GCS 3 and those with any previous disabling neurological disease.
Randomization and masking
Allocation was concealed by an online password protected randomization algorithm (Medidata Balance; Medidata Solutions, New York City, NY). The patient was assigned to one of the following two groups (pre-hospital and late MTH groups) using a randomization table. Randomization 1:1 was performed by paramedics using sequentially numbered, opaque, sealed envelopes. Since it was difficult for investigators to be unblinded to pre-hospital application of external cooling techniques as they would see the cooling blankets and ice packs for the patient (Citation13,Citation15,Citation16), bias will be minimized by concealed treatment allocation before randomization, and allocation sequence was protected until assignment. The medical staff in charge of the patient were not involved in data collection. A single trained assessor and the data analyzer were blind to the treatment group. Therefore, biased grouping was avoided, and adherence to the principles of random and equilibrium is ensured.
Clinical data collection
Of 5284 adult patients with TBI, 86 patients were enrolled in our clinical trial. There were 44 male and 42 female patients with sTBI, with age ranging from 18 to 65 (41.8 ± 10.9) years. Patients were 1:1 randomly assigned into pre-hospital and late MTH groups (n = 43 each). Both groups complied with inclusion/exclusion criteria. The pre-hospital time intervals of the patients in both groups are 47.1 ± 11.7 (minutes) versus 43.9 ± 14.6 (minutes), respectively, P > .05. The analysis was by the original assigned groups. The majority of clinical data between groups were comparable and not significantly different (P > .05, ).
Table 1. Main clinical and demographic characteristics between the two groups
Application of therapeutic hypothermia
Over the period of data collection, though minor changes in process in the pre-hospital or in-hospital care occurred, the application of therapeutic hypothermia did not change. In the early MTH group, a therapeutic hypothermia device was used to treat patients with sTBI mainly by cooling the head and neck (with ice packs as adjuvants) as previously described (Citation13,Citation15,Citation16,Citation20). After the ambulance attendant physician administered necessary first aid on-site, MTH was initiated by the emergency medical services paramedics and doctors (one of whom was our qualified staff for therapeutic hypothermia). Patients were maintained at a tympanic temperature of 33–35°C with ear thermometers till hospital admission. For those requiring emergency surgery, surgical treatment was performed after emergency preoperative preparation, and the state of MTH was maintained during surgery. For the late MTH group, MTH was started after patients were admitted into the ICU (Citation13). MTH in the ICU was achieved with a therapeutic hypothermia device and cooling blankets after being admitted into the ICU. For both pre-hospital and late MTH groups, the MTH procedure was as follows (Citation13,Citation15,Citation16,Citation20). Cold water (4°C) was injected into the cooling blanket with sustained circulation. The target temperature in the brain tissue or deep nasopharyngeal space (with nasopharyngeal temperature probe) was set at 33–35°C. For those who failed to effectively reach the target temperature within 1 h, machine-bagged ice packs were placed on the neck or near the inguinal artery for adjuvant systemic cooling. The presence and number of ice packs were adjusted according to the monitored temperature. Brain temperature was generally lowered to the target temperature level within 1–2 h of treatment in order to achieve cooling. Meanwhile, patients received a sedation mixture via intravenous infusion for 24 h. The cooling materials were removed after 4 d of effective cooling, and natural rewarming was used to terminate hypothermia.
Monitoring parameters
The following parameters of patients in both groups were monitored at admission or after operation (Citation1): Brain and rectal temperature: brain temperature was monitored using a semiconductor temperature probe aseptically inserted 10 mm into the brain parenchyma or residual cavity where intracranial hematoma were evacuated, and rectal temperature was measured using another monitor (Citation15,Citation16,Citation20) (Citation2); Intracranial pressure (ICP): Continuous recording of ICP was applied in all patients for 96 hours with the ICP monitor system (Camino-MPM1, Integra LifeSciences CO, Plainsboro, New Jersey, USA.). A drainage catheter was introduced about 5 cm or so into the right lateral ventricles via the anterior horn, with the intraventricular pressure probe at the level of interventricular foramen (Citation15,Citation16);To avoid the possible intracraninal infection, we always removed such intracranial devices as ICP probe 3 days after surgery (Citation7). Heart rate, respiratory rate, blood pressure, and arterial oxygen saturation, using an multiparameter monitor(Model NO: 90309, Space Lab, Medical. Inc., Issaquah, Washington, USA) (Citation21). Complications such as pneumonia, gastrointestinal bleeding, thrombocytopenia, and electrolyte disturbances; and (Citation17) Glasgow Outcome Scale (GOS) score (1 = death, 2 = vegetative state, 3 = severe disability, 4 = moderate disability, 5 = mild or no disability), evaluated at 6 months of follow-up after TBI.
Statistical analysis
Continuous data were expressed as mean ± SD, and intergroup comparison of the means was performed using the t-test. The mortality and good recovery rate were compared between groups using the chi-squared test. The significance level was set as α = 0.05, and P-value < 0.05 was considered to be statistically significant. All statistical analyses were carried out using SPSS statistical software (SPSS for Windows version 10.0; SPSS, Chicago, IL, USA).
Results
Intracranial pressure
The ICP was significantly reduced in the pre-hospital MTH group 24, 48, and 72 h after treatment compared with that in the late MTH group (P < .01, ). The ICP peak occurred in both groups at 48 h after injury.
Table 2. Comparison of intracranial pressure dynamics between the two groups (mean ± SD)
Prognosis comparison
The pre-hospital MTH group had significantly different good recovery and low mortality rates compared with that of the late MTH group (P < .05) (). The favorable prognosis rate (GOS scores 4–5) was significantly higher in the pre-hospital MTH group than that in the late MTH group (65.1% vs. 37.2%, respectively; P < .05).
Table 3. Comparison of prognosis between the two groups (number of cases)
Comparison of the incidence of complications
No serious complications associated with MTH occurred. Pulmonary infection occurred in 15 patients (34.9%) in the pre-hospital MTH group and in 14 patients (32.6%) in the late MTH group (P < .05). The incidences of gastrointestinal bleeding, electrolyte disturbances, and renal dysfunction were comparable between groups, and no serious consequences were observed after appropriate treatment.
Discussion
To mitigate the secondary and primary brain injury in patients with TBI, many basic research and clinical trials have been performed for the innovation of pharmacological treatments and temperature managements (Citation8,Citation22–24). With the results of many results, targeted temperature management (TTM) including therapeutic hypothermia has been recognized as one promising candidate of neuroprotective treatment for some subgroup patients with TBI (Citation15,Citation16,Citation25–28).
Although there is insufficient evidence to support the routine use of prophylactic hypothermia for neuroprotection after TBI (Citation29), the MTH is effective at reduction of increased ICP with systemic management inclusive of the Physician-Staffed Emergency Medical Services (P-EMS) (Citation1–4,Citation6,Citation16,Citation29). Our present study showed that ICP was significantly lower for patients in the pre-hospital MTH group than that in the late MTH group 24, 48, and 72 h after treatment. No serious complications associated with MTH therapy were observed. The incidence of pulmonary infection was higher in the pre-hospital MTH group than that in the late MTH group. This is similar to the previous study (Citation11,Citation15–17,Citation26–30). While MTH may have played a dual protection/exacerbation role by reducing inflammation on the one hand and aggravating posttraumatic immune suppression on the other, the complication ultimately caused no serious consequences with appropriate treatment.
In sTBI, MTH mainly protects brain tissue through a multitude of different pathways by decreasing the abnormal production of free radicals and the inflammatory cascade as well as cell death pathways of apoptosis and necrosis, thus improving cerebral perfusion pressure and controlling intracranial hypertension (Citation9,Citation11,Citation17,Citation31–33). Unlike several RCT studies (Citation2,Citation12,Citation17–19), our present study consists of some hypothermia studies (Citation15–17,Citation25,Citation34). There is some evidence to suggest that MTH may be of benefit for some subgroups of patients with sTBI (Citation35).
The best effects of therapeutic hypothermia in our present study might lie in the following factors. We excluded the patients with GCS 3, and all patients in our study reached their target temperature. While in POLAR-RCT (The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury-Randomized Clinical Trial) study (Citation18), a significant number of patients in the hypothermia group never reached the target temperature of 33°C (19% had hypothermia withdrawn early and a further 13% did not reach 33°C), and enrollment of patients without sTBI in the out-of-hospital setting before full evaluation might be another factor for the incorrect application of prophylactic hypothermia rather than therapeutic hypothermia. Furthermore, the clinicians and patients’ families were not blinded to the intervention in the POLAR-RCT study.
In our opinion, to ensure a protective effect of pre-hospital MTH for sTBI, the following aspects must be taken into account: 1) appropriate selection of therapeutic indication, such as sTBI with GCS 8–4, increased ICP or fever, 2) MTH safety factors such as the extent of hypothermia, the starting time, and the duration of hypothermia. The longer durations of hypothermia such as 5 days or more might be more effective for a subgroup of patients with sTBI (Citation13,Citation15,Citation16); 3) The focused treatment is based on the type of cranial injury; and 4) other concurrent treatments (Citation13,Citation24).
This study did have some limitations. The numbers of patients recruited seems small enough to show a treatment effect. The ICP data on day 4 after treatment were not available. We failed to control intracranial pressure within the desired range for patients in both groups, possibly related to the patient etiology with brain swelling after sTBI (Citation29). Our results, combined with current knowledge, indicate that more studies should be conducted to determine the mechanism, the threshold of initiation of MTH, and adverse effects of MTH (Citation2,Citation17,Citation18,Citation21,Citation27,Citation28,Citation31,Citation36,Citation37). Appropriate unified physiological and biological indicators can be selected for effective monitoring. Moreover, multicenter clinical trials of TTM will help determine the exact protective mechanism of MTH on brain tissue and prevent possible side effects of MTH when treating sTBI.
Conclusion
In conclusion, this study demonstrated that pre-hospital MTH can reduce intracranial hypertension and improve clinical outcomes for patients with sTBI. The therapy is a simple, practical, and effective measure applicable for the treatment of patients with sTBI.
Acknowledgments
The present study was supported by the Scientific Research Fund of Affiliated Hospital Hangzhou Normal University, the Science and Technology Department of Hangzhou, China (No.20120533Q22, 20150733Q18,20191203B103). The authors gratefully acknowledge the Second Affiliated Hospital of Zhejiang University.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
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