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Mild induced hypothermia for patients with severe traumatic brain injury after decompressive craniectomy
Journal of Critical Care 39 (2017) 267–270
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Journal of Critical Care journal homepage: www.jccjournal.org
Mild induced hypothermia for patients with severe traumatic brain injury after decompressive craniectomy Chunhai Tang, MD, PhD a,b, Yun Bao, MD, PhD a,1, Min Qi, MD, PhD a,c, Lizhi Zhou, MD, PhD a,d, Fan Liu, MD, PhD a, Jian Mao, MD, PhD a, Qingmei Lei, MD, PhD a,e, Songtao Qi, MD, PhD a,⁎, Binghui Qiu, MD, PhD a,⁎ a
Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China Department of Neurosurgery, Tenth Affiliated Hospital, Guangxi Medical University, Guangdong Province, China First College of Clinical Medicine, Southern Medical University, Guangzhou City, Guangdong Province, China d Department of Biostatistics, school of biostatistics, Southern Medical University, Guangzhou City, Guangdong Province, China e Department of Nursing, Nanfang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China b c
a r t i c l e
i n f o
Keywords: Traumatic brain injury Hypothermia Craniectomy Intracranial pressure Outcome
a b s t r a c t Purpose: To evaluate the efficacy and safety of mild induced hypothermia for intracranial hypertension in patients with traumatic brain injury after decompressive craniectomy. Methods: A total of 60 adults with intracranial pressure (ICP) of more than 20 mm Hg after decompressive craniectomy were randomly assigned to standard care (control group) or hypothermia (32°C-35°C) plus standard care. Then, ICP, cerebral perfusion pressure, Glasgow Outcome Scale score, and complications were assessed. Results: There was a significant difference in ICP and cerebral perfusion pressure between the 2 groups. Favorable outcomes occurred in 12 (40.0%) and 7 (36.5%) patients in the hypothermia and control groups, respectively (P = .267). Kaplan-Meier curves revealed a marked difference in survival between the hypothermia and control groups (P = .032). There were significant differences in pulmonary infection and electrolyte disorders between the hypothermia and control groups (P = .038 and .033, respectively). Conclusion: Mild induced hypothermia can reduce intracranial hypertension after decompressive craniectomy, decreasing patient mortality. Hypothermia should be considered one of the main treatments for intracranial hypertension after decompressive craniectomy in patients with traumatic brain injury. © 2016 Elsevier Inc. All rights reserved.
1. Introduction About 1 million people die annually, whereas 10 million are seriously injured in accidents, which constitute the primary cause of traumatic brain injury (TBI). Low-income and industrial countries have the highest mortality and disability rates, respectively, in patients with severe closed TBIs [1-3]. To improve patient outcomes, several options are available, including decompressive craniectomy, hyperosmolar therapy, prophylactic hypothermia, cerebrospinal fluid drainage, sedation and analgesia, muscle relaxants, pentobarbital treatment, and hyperventilation [4]. Decompressive craniectomy provides satisfactory intracranial pressure (ICP) control and a favorable outcome in neurocritical care patients with refractory intracranial hypertension, and has been used for the treatment of intracranial hypertension associated with TBI [5,6]. However, with secondary causes of injury, a subset of patients still have intracranial hypertension after decompressive craniectomy, ⁎ Corresponding authors at: Guangzhou Dadao Bei Street 1838#, Guangzhou, PR China. Tel.: +86 20 61641801; fax: +86 20 61641806. E-mail address: [email protected] (S. Qi). 1 Yun Bao is a co-first author of this article.
http://dx.doi.org/10.1016/j.jcrc.2016.12.012 0883-9441/© 2016 Elsevier Inc. All rights reserved.
which is more difficult to treat. Whether hypothermia can also be used to reduce intracranial hypertension in such patients remains unknown. The aim of this study was to evaluate the efficacy and safety of mild induced hypothermia for intracranial hypertension in patients with severe TBI after decompressive craniectomy.
2. Methods 2.1. Study design This was a randomized, controlled, double blind trial; informed consent was obtained from patients' families. Each subject was assigned to 1 of 2 treatment groups in the neurologic intensive care unit of our brain center, using a randomization table. Allocation and randomization were concealed to blind study investigators for patient grouping, and the allocation sequence was protected until assignment. The attending physicians were not involved in data collection, and the nursing staff and surgical team were not aware of the patient grouping. Therefore, biased grouping was avoided. This study was approved by the medical ethics committee of Nanfang Hospital, Southern Medical University.
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2.2. Patients From January 2012 to January 2016, 60 patients admitted to the intensive care unit in our department after TBI showed elevated ICP (N20 mm Hg) after decompressive craniectomy within 24 hours. All patients met the following criteria: (1) primary, closed TBI; (2) ICP N20 mm Hg after decompressive craniectomy, with no overt reversible cause; (3) N16 years of age; (4) men or nonpregnant women; (5) clear history of head injury; (6) GCS 3-8 on admission or after resuscitation; (7) availability of a cooling device or technique for more than 72 hours; and (8) brain injury confirmed by sequential computed tomography scanning within 6 hours of trauma. Patients were excluded with one or more of the following criteria: (1) pregnancy; (2) younger than 16 years or older than 70 years; (3) multiple injuries, hemorrhagic shock, or no bilateral pupil fixed on initial examination; (4) no spontaneous breathing; (5) bilateral hemi-craniectomy or bifrontal craniectomy selection; (6) external ventricular drainage for ICP control or monitoring; and (7) history of serious heart, lung, brain and other diseases. The participants were randomly assigned to standard (control group, ≥36°C) and hypothermia plus standard (hypothermia group, 32°C-35°C) treatment groups. Randomization was performed by the method of minimization for allocation to balance assignments according to gender, age, Glasgow Coma Scale (GCS) motor score, causes of injury, and pupillary response. The control group comprised 30 patients with 28 men and 2 women; meanwhile, the hypothermia group was composed of 30 patients, including 23 men and 7 women. General patient characteristics were similar between the 2 groups. All patients were administered routine treatments in the intensive care unit of the neurosurgery department according to “Guidelines for the management of severe traumatic brain injury,” published by the American Brain Injury Association in 2007. Unilateral hemi-craniectomy was performed within 6 hours of injury. For ICP monitoring, Codman Micro Sensor (Codman & Shurtleff Inc, Raynham, Mass) was used. Postoperative ICP was recorded every hour, with intracranial hypertension managed according to the Brain Trauma Foundation guidelines. Hypothermia was induced with a water-circulating cooling blanket (Blanketro II 222R, Cincinnati, USA). Rewarming was considered after 48 hours at a rate of 0.25°C per hour, provided that ICP was 20 mm Hg or less for more than 24 hours. In the control group, patient body temperature was maintained in the normal range, between 36°C and 37°C. Cooling in patients with body temperature lower than 38.5°C was carried out with an ice bag; antipyretic analgesics were used with body temperature higher than 38.5°C. Active anti-infective treatment was administered when infection was suspected. 2.3. Data collection The following data were recorded: baseline demographic characteristics; Glasgow Outcome Scale (GOS) score at 6 months after injury; ICP at randomization; temperature at randomization; mean arterial pressure, cerebral perfusion pressure (CPP), and temperature measured hourly on days 1 through 5; and complications such as intracranial infection, pulmonary infection, electrolyte imbalance, hyperglycemia, stress ulcer, and renal malfunction. Electrolyte disorders are defined as follows: hypernatremia (serum sodium N145 mmol/L), hyperkalemia (serum potassium N5 mmol/L), hyponatremia (serum sodium b135 mmol/L), and hypokalemia (serum potassium b3. 5 mmol/L). Unfavorable and favorable outcomes were defined at 6 months after injury by GOS scores of 1-3 and 4-5, respectively. 2.4. Statistical analysis Data were analyzed with SPSS version 20.0. (IBM Corp, Armonk, NY). Descriptive statistics were presented as frequency (percentage) or
mean ± SD. Categorical variables were compared by the χ2 test or Fisher exact test. Kaplan-Meier survival curves were generated and compared by the log-rank test. P b .05 was considered statistically significant. 3. Results The 60 patients who underwent primary decompressive craniectomy for TBI included 51 men and 9 women. Mean age was 41.07 ± 14.56 years (range, 18-63 years). Head injuries resulted from traffic accidents (n = 47), falls (n = 10), and other causes (n = 3). Neurologic assessment before decompressive craniectomy showed a mean GCS of 4.98 ± 1.57. Pupillary examination identified 31 patients with one or no nonreacting pupil, and 29 with both nonreacting pupils. Computed tomographic scan revealed 39 cases of intracranial hemorrhage, 16 of diffuse brain injury, and 5 of contusion/other anomalies. The main patient characteristics are shown in Table 1. 3.1. ICP and CPP A repeated-measures analysis was performed to compare the 2 groups from days 1 to 7 after randomization in ICP and CPP (Fig. 1). There were significant differences in ICP and CPP between the 2 groups (hypothermia vs control; P b .001). 3.2. Outcome The surviving patients were followed up at the outpatient department for a period ranging from 6 to 48 months. Six months after brain injury, no significant difference in overall neurologic outcome (GOS score) between the 2 groups was found (Table 2). Favorable outcomes occurred in 12 (40.0%) and 7 (36.5%) patients of the hypothermia and control groups, respectively (P = .267). Mortality rates were 10.0% in the hypothermia group and 33.3% in control patients (P = .057). Fig. 2 depicts Kaplan-Meier survival curves for both patient groups with or without hypothermia, revealing a marked difference (P = .032). 3.3. Complications The main complications observed in patients with TBI are summarized in Table 3. There were significant differences in pulmonary infection and electrolyte disorders between the hypothermia and control groups (P = .038 and .033, respectively). Among the 30 patients treated with hypothermia, hypernatremia occurred in 11 and hyperkalemia in 3 patients. In the control group, hypernatremia occurred in 4 and hyperkalemia in 1 patients. Hypernatremia was Table 1 Clinical characteristics of study patients with severe TBI Variable
Hypothermia (n = 30)
Control (n = 30)
P
Age (y) GCS score GCS of 5-8, no. (%) GCS of 3-4, no. (%) Pupillary response Both reacting, no. (%) Bilaterally fixed/dilated, no. (%) Unilaterally fixed/dilated, no. (%) Mechanism of injury Traffic accident, no. (%) Fall accident, no. (%) Others, no. (%) Major findings on computed tomographic scans Intracranial hematoma, no. (%) Diffuse brain injury, no. (%) Contusions and others, no. (%)
42.47 ± 13.93
39.67 ± 15.26
13 (43.4) 17 (56.7)
12 (40.0) 18 (60.0)
1.000
13 (43.3) 1 (3.3) 16 (53.3)
16 (53.3) 3 (10.0) 11 (36.7)
.327
24 (80.0) 4 (13.3) 2 (6.7)
23 (76.7) 6 (20.0) 1 (3.3)
.794
18 (60.0) 9 (30.0) 3 (10.0)
21 (70.0) 7 (23.3) 2 (6.7)
.711
.461
C. Tang et al. / Journal of Critical Care 39 (2017) 267–270
269
Fig. 2. Kaplan-Meier survival curves for TBI patients after primary decompressive craniectomy with or without hypothermia.
Fig. 1. Changes of ICP and CPP over time in the 2 groups.
more frequent in the hypothermia group than in the control group (P b .05). Meanwhile, no significant differences in the remaining complications were observed between the hypothermia and control groups (P N .05).
4. Discussion Traumatic brain injury, as a common neurocritical disease in neurosurgery, remains the leading cause of death and disability among trauma patients [7]. A severe complication of moderate or severe TBI is acute increase of ICP [8]. Elevated ICP can cause reduced perfusion pressure, brain damage, and cerebral hernia [9]. Decompressive craniectomy, a second-tier therapeutic measure for increased ICP, can effectively control ICP elevation [10]. However, some patients develop increased ICP after decompressive craniectomy. Treatment of intracranial hypertension after decompressive craniectomy counts among the most challenging neurosurgical procedures. The protective effects of profound hypothermia on the brain have been largely reported. Moderate hypothermia reduces secondary brain injury and improves behavioral outcome in animals after TBI [11]. Numerous studies have established that neuroprotective effects conferred by moderate hypothermia are multifunctional and attributed to decreased ICP, decreased overall cerebral metabolic rate, reduced cerebral blood flow, decreased cerebral metabolic requirement for oxygen, altered neurotransmitter release, and maintenance of the blood-brain barrier [12-14]. Mild induced hypothermia is effective in some patients with craniocerebral injury [7]. Can hypothermia become a treatment of choice for increased ICP after decompressive craniectomy?
Table 2 Clinical outcomes at 6 months after TBI GOS score
Hypothermia group (n = 30)
Control group (n = 30)
1 2 3 4 5
3 (10. 0) 9 (30.0) 4 (23.3) 6 (20.0) 5 (16.7)
10 (33.3) 8 (26.7) 4 (20.0) 2 (6.7) 4 (13.3)
The objective of this study was to evaluate the efficacy and safety of mild induced hypothermia for intracranial hypertension in patients with severe TBI after decompressive craniectomy. As shown above, hypothermia further lowered ICP values even after decompressive craniotomy. Furthermore, CPP in the hypothermia group was significantly higher than control values. These findings suggested that hypothermia could constitute a good option when decompressive craniectomy is unable to reduce ICP to an optimal level. It was suggested that hypothermia can be used to reduce ICP effectively and improve treatment effectiveness in TBI patients [15,16]. Meanwhile, Andrews et al [17] proposed that in patients with ICP N 20 mm Hg after TBI, therapeutic hypothermia plus standard care to reduce ICP results in improved outcomes compared with standard care alone. So far, it remains unclear which patients benefit from hypothermia. In this study, patients with intracranial hypertension and TBI after decompressive craniectomy benefited from hypothermia. These findings are different from those reported by other hypothermia trials in TBI. The discrepancy might result from a prolonged use of hypothermia (≥3 days). Furthermore, this specific TBI subgroup (patients with increased ICP after decompressive craniectomy) may benefit from hypothermia. Despite a wide scientific consensus that hypothermia can reduce ICP effectively, many controversies still exist regarding its application in TBI patients. Meanwhile, others believe that hypothermia would cause a variety of complications, such as sinus tachycardia, low blood capacity, coagulation disorders, infection, shivering, hyperglycemia, electrolyte disorders, and gastrointestinal dysfunction [18]. Indeed, the potential complications and high risk of low temperature cannot be overlooked, and hypothermia cannot be used as a routine treatment in patients with severe TBI [19]. In this research, the incidence rates of electrolyte disorders and pulmonary infection in the hypothermia group was higher than control values. Infection is considered one of the major complications associated with hypothermia, likely because hypothermia deteriorates the immune function [20]. The above complications were managed without severe sequela. However, strict monitoring of patients is important. To avoid other complications, the following
Table 3 Main complications of 2 groups of patients with severe TBI Complications
Hypothermia group (n = 30)
Control group (n = 30)
P
Intracranial infection Hyperglycemia Electrolyte disorders Hypernatremia Hyponatremia Hyperkalemia Hypokalemia Pulmonary infection Renal malfunction Stress ulcer
4 (13.3) 7 (23.3) 16 (53.3) 11 (36.7) 4 (13.3) 3 (10.0) 2 (6.7) 20 (66.7) 4 (13.3) 3 (10.0)
4 (13.3) 5 (16.7) 7 (23.3) 4 (13.3) 1 (3.3) 1 (3.3) 1 (3.3) 11 (36.7) 3 (10.0) 4 (13.3)
1.000 .748 .033 .037 .353 .612 1.000 .038 1.000 1.000
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strategies can be used: rapidly achieving the target temperature, avoiding temperature fluctuations during the maintenance phrase, starting rewarming until ICP falls below 20 mm Hg at least 24 hours, and rewarming slowly. 5. Conclusion Although hypothermia effects remain controversial, the current study demonstrated that hypothermia could not only reduce ICP but also decrease mortality in patients with severe TBI after craniectomy. In TBI patients with intracranial hypertension after decompressive craniectomy, hypothermia can be considered the primary treatment option. Disclosures Nothing to disclose. Acknowledgments This study was supported by key Clinical Specialty Discipline Construction Program, President Foundation of Nanfang Hospital, Southern Medical University (2015C028). Science and Technology Planning Project of Guangdong Province, China (2012B091100463, 2013B021800304). References [1] Sandestig A, Romner B, Grande PO. Therapeutic hypothermia in children and adults with severe traumatic brain injury. Ther Hypothermia Temp Manag 2014;4:10–20. [2] Georgoff P, Meghan S, Mirza K, Stein SC. Geographic variation in outcomes from severe traumatic brain injury. World Neurosurg 2010;74:331–45. [3] Hofman K, Primack A, Keusch G, Hrynkow S. Addressing the growing burden of trauma and injury in low- and middle-income countries. Am J Public Health 2005;95:13–7. [4] Carney NA. Guidelines for the management of severe traumatic brain injury. Methods. J Neurotrauma 2007;24(Suppl. 1):S3–6. [5] Wang JW, Li JP, Song YL, Tan K, Wang Y, Li T, et al. Decompressive craniectomy in neurocritical care. J Clin Neurosci 2016;27:1–7.
[6] Wang R, Li M, Gao WW, Guo Y, Chen J, Tian HL. Outcomes of early decompressive craniectomy versus conventional medical management after severe traumatic brain injury: a systematic review and meta-analysis. Medicine (Baltimore) 2015; 94:e1733. [7] Tang A, Pandit V, Fennell V, Jones T, Joseph B, O'Keeffe T, et al. Intracranial pressure monitor in patients with traumatic brain injury. J Surg Res 2015;194: 565–70. [8] Han J, Yang S, Zhang C, Zhao M, Li A. Impact of intracranial pressure monitoring on prognosis of patients with severe traumatic brain injury: a PRISMA systematic review and meta-analysis. Medicine (Baltimore) 2016;95:e2827. [9] Kelts EA. Traumatic brain injury and visual dysfunction: a limited overview. NeuroRehabilitation 2010;27:223–9. [10] Stocchetti N, Zanaboni C, Colombo A, Citerio G, Beretta L, Ghisoni L, et al. Refractory intracranial hypertension and “second-tier” therapies in traumatic brain injury. Intensive Care Med 2008;34:461–7. [11] Kahveci FS, Kahveci N, Alkan T, Goren B, Korfali E, Ozluk K. Propofol versus isoflurane anesthesia under hypothermic conditions: effects on intracranial pressure and local cerebral blood flow after diffuse traumatic brain injury in the rat. Surg Neurol 2001; 56:206–14. [12] Lyeth BG, Jiang JY, Liu S. Behavioral protection by moderate hypothermia initiated after experimental traumatic brain injury. J Neurotrauma 1993;10:57–64. [13] Dietrich WD, Busto R, Halley M, Valdes I. The importance of brain temperature in alterations of the blood-brain barrier following cerebral ischemia. J Neuropathol Exp Neurol 1990;49:486–97. [14] Marion DW, Obrist WD, Carlier PM, Penrod LE, Darby JM. The use of moderate therapeutic hypothermia for patients with severe head injuries: a preliminary report. J Neurosurg 1993;79:354–62. [15] Popugaev KA, Savin IA, Oshorov AV, Kurdumova NV, Ershova ON, Lubnin AU, et al. Postsurgical meningitis complicated by severe refractory intracranial hypertension with limited treatment options: the role of mild therapeutic hypothermia. J Neurol Surg Rep 2014;75:e224–9. [16] Polderman KH. Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet 2008;371:1955–69. [17] Andrews PJ, Harris BA, Murray GD. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J Med 2016;374:1385. [18] Konstantinidis A, Inaba K, Dubose J, Barmparas G, Talving P, David JS, et al. The impact of nontherapeutic hypothermia on outcomes after severe traumatic brain injury. J Trauma 2011;71:1627–31. [19] Kramer C, Freeman WD, Larson JS, Hoffman-Snyder C, Wellik KE, Demaerschalk BM, et al. Therapeutic hypothermia for severe traumatic brain injury: a critically appraised topic. Neurologist 2012;18:173–7. [20] Burger R, Bendszus M, Vince GH, Solymosi L, Roosen K. Neurophysiological monitoring, magnetic resonance imaging, and histological assays confirm the beneficial effects of moderate hypothermia after epidural focal mass lesion development in rodents. Neurosurgery 2004;54:701–11 [discussion 711-702].
Contents lists available at ScienceDirect
Journal of Critical Care journal homepage: www.jccjournal.org
Mild induced hypothermia for patients with severe traumatic brain injury after decompressive craniectomy Chunhai Tang, MD, PhD a,b, Yun Bao, MD, PhD a,1, Min Qi, MD, PhD a,c, Lizhi Zhou, MD, PhD a,d, Fan Liu, MD, PhD a, Jian Mao, MD, PhD a, Qingmei Lei, MD, PhD a,e, Songtao Qi, MD, PhD a,⁎, Binghui Qiu, MD, PhD a,⁎ a
Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China Department of Neurosurgery, Tenth Affiliated Hospital, Guangxi Medical University, Guangdong Province, China First College of Clinical Medicine, Southern Medical University, Guangzhou City, Guangdong Province, China d Department of Biostatistics, school of biostatistics, Southern Medical University, Guangzhou City, Guangdong Province, China e Department of Nursing, Nanfang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China b c
a r t i c l e
i n f o
Keywords: Traumatic brain injury Hypothermia Craniectomy Intracranial pressure Outcome
a b s t r a c t Purpose: To evaluate the efficacy and safety of mild induced hypothermia for intracranial hypertension in patients with traumatic brain injury after decompressive craniectomy. Methods: A total of 60 adults with intracranial pressure (ICP) of more than 20 mm Hg after decompressive craniectomy were randomly assigned to standard care (control group) or hypothermia (32°C-35°C) plus standard care. Then, ICP, cerebral perfusion pressure, Glasgow Outcome Scale score, and complications were assessed. Results: There was a significant difference in ICP and cerebral perfusion pressure between the 2 groups. Favorable outcomes occurred in 12 (40.0%) and 7 (36.5%) patients in the hypothermia and control groups, respectively (P = .267). Kaplan-Meier curves revealed a marked difference in survival between the hypothermia and control groups (P = .032). There were significant differences in pulmonary infection and electrolyte disorders between the hypothermia and control groups (P = .038 and .033, respectively). Conclusion: Mild induced hypothermia can reduce intracranial hypertension after decompressive craniectomy, decreasing patient mortality. Hypothermia should be considered one of the main treatments for intracranial hypertension after decompressive craniectomy in patients with traumatic brain injury. © 2016 Elsevier Inc. All rights reserved.
1. Introduction About 1 million people die annually, whereas 10 million are seriously injured in accidents, which constitute the primary cause of traumatic brain injury (TBI). Low-income and industrial countries have the highest mortality and disability rates, respectively, in patients with severe closed TBIs [1-3]. To improve patient outcomes, several options are available, including decompressive craniectomy, hyperosmolar therapy, prophylactic hypothermia, cerebrospinal fluid drainage, sedation and analgesia, muscle relaxants, pentobarbital treatment, and hyperventilation [4]. Decompressive craniectomy provides satisfactory intracranial pressure (ICP) control and a favorable outcome in neurocritical care patients with refractory intracranial hypertension, and has been used for the treatment of intracranial hypertension associated with TBI [5,6]. However, with secondary causes of injury, a subset of patients still have intracranial hypertension after decompressive craniectomy, ⁎ Corresponding authors at: Guangzhou Dadao Bei Street 1838#, Guangzhou, PR China. Tel.: +86 20 61641801; fax: +86 20 61641806. E-mail address: [email protected] (S. Qi). 1 Yun Bao is a co-first author of this article.
http://dx.doi.org/10.1016/j.jcrc.2016.12.012 0883-9441/© 2016 Elsevier Inc. All rights reserved.
which is more difficult to treat. Whether hypothermia can also be used to reduce intracranial hypertension in such patients remains unknown. The aim of this study was to evaluate the efficacy and safety of mild induced hypothermia for intracranial hypertension in patients with severe TBI after decompressive craniectomy.
2. Methods 2.1. Study design This was a randomized, controlled, double blind trial; informed consent was obtained from patients' families. Each subject was assigned to 1 of 2 treatment groups in the neurologic intensive care unit of our brain center, using a randomization table. Allocation and randomization were concealed to blind study investigators for patient grouping, and the allocation sequence was protected until assignment. The attending physicians were not involved in data collection, and the nursing staff and surgical team were not aware of the patient grouping. Therefore, biased grouping was avoided. This study was approved by the medical ethics committee of Nanfang Hospital, Southern Medical University.
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C. Tang et al. / Journal of Critical Care 39 (2017) 267–270
2.2. Patients From January 2012 to January 2016, 60 patients admitted to the intensive care unit in our department after TBI showed elevated ICP (N20 mm Hg) after decompressive craniectomy within 24 hours. All patients met the following criteria: (1) primary, closed TBI; (2) ICP N20 mm Hg after decompressive craniectomy, with no overt reversible cause; (3) N16 years of age; (4) men or nonpregnant women; (5) clear history of head injury; (6) GCS 3-8 on admission or after resuscitation; (7) availability of a cooling device or technique for more than 72 hours; and (8) brain injury confirmed by sequential computed tomography scanning within 6 hours of trauma. Patients were excluded with one or more of the following criteria: (1) pregnancy; (2) younger than 16 years or older than 70 years; (3) multiple injuries, hemorrhagic shock, or no bilateral pupil fixed on initial examination; (4) no spontaneous breathing; (5) bilateral hemi-craniectomy or bifrontal craniectomy selection; (6) external ventricular drainage for ICP control or monitoring; and (7) history of serious heart, lung, brain and other diseases. The participants were randomly assigned to standard (control group, ≥36°C) and hypothermia plus standard (hypothermia group, 32°C-35°C) treatment groups. Randomization was performed by the method of minimization for allocation to balance assignments according to gender, age, Glasgow Coma Scale (GCS) motor score, causes of injury, and pupillary response. The control group comprised 30 patients with 28 men and 2 women; meanwhile, the hypothermia group was composed of 30 patients, including 23 men and 7 women. General patient characteristics were similar between the 2 groups. All patients were administered routine treatments in the intensive care unit of the neurosurgery department according to “Guidelines for the management of severe traumatic brain injury,” published by the American Brain Injury Association in 2007. Unilateral hemi-craniectomy was performed within 6 hours of injury. For ICP monitoring, Codman Micro Sensor (Codman & Shurtleff Inc, Raynham, Mass) was used. Postoperative ICP was recorded every hour, with intracranial hypertension managed according to the Brain Trauma Foundation guidelines. Hypothermia was induced with a water-circulating cooling blanket (Blanketro II 222R, Cincinnati, USA). Rewarming was considered after 48 hours at a rate of 0.25°C per hour, provided that ICP was 20 mm Hg or less for more than 24 hours. In the control group, patient body temperature was maintained in the normal range, between 36°C and 37°C. Cooling in patients with body temperature lower than 38.5°C was carried out with an ice bag; antipyretic analgesics were used with body temperature higher than 38.5°C. Active anti-infective treatment was administered when infection was suspected. 2.3. Data collection The following data were recorded: baseline demographic characteristics; Glasgow Outcome Scale (GOS) score at 6 months after injury; ICP at randomization; temperature at randomization; mean arterial pressure, cerebral perfusion pressure (CPP), and temperature measured hourly on days 1 through 5; and complications such as intracranial infection, pulmonary infection, electrolyte imbalance, hyperglycemia, stress ulcer, and renal malfunction. Electrolyte disorders are defined as follows: hypernatremia (serum sodium N145 mmol/L), hyperkalemia (serum potassium N5 mmol/L), hyponatremia (serum sodium b135 mmol/L), and hypokalemia (serum potassium b3. 5 mmol/L). Unfavorable and favorable outcomes were defined at 6 months after injury by GOS scores of 1-3 and 4-5, respectively. 2.4. Statistical analysis Data were analyzed with SPSS version 20.0. (IBM Corp, Armonk, NY). Descriptive statistics were presented as frequency (percentage) or
mean ± SD. Categorical variables were compared by the χ2 test or Fisher exact test. Kaplan-Meier survival curves were generated and compared by the log-rank test. P b .05 was considered statistically significant. 3. Results The 60 patients who underwent primary decompressive craniectomy for TBI included 51 men and 9 women. Mean age was 41.07 ± 14.56 years (range, 18-63 years). Head injuries resulted from traffic accidents (n = 47), falls (n = 10), and other causes (n = 3). Neurologic assessment before decompressive craniectomy showed a mean GCS of 4.98 ± 1.57. Pupillary examination identified 31 patients with one or no nonreacting pupil, and 29 with both nonreacting pupils. Computed tomographic scan revealed 39 cases of intracranial hemorrhage, 16 of diffuse brain injury, and 5 of contusion/other anomalies. The main patient characteristics are shown in Table 1. 3.1. ICP and CPP A repeated-measures analysis was performed to compare the 2 groups from days 1 to 7 after randomization in ICP and CPP (Fig. 1). There were significant differences in ICP and CPP between the 2 groups (hypothermia vs control; P b .001). 3.2. Outcome The surviving patients were followed up at the outpatient department for a period ranging from 6 to 48 months. Six months after brain injury, no significant difference in overall neurologic outcome (GOS score) between the 2 groups was found (Table 2). Favorable outcomes occurred in 12 (40.0%) and 7 (36.5%) patients of the hypothermia and control groups, respectively (P = .267). Mortality rates were 10.0% in the hypothermia group and 33.3% in control patients (P = .057). Fig. 2 depicts Kaplan-Meier survival curves for both patient groups with or without hypothermia, revealing a marked difference (P = .032). 3.3. Complications The main complications observed in patients with TBI are summarized in Table 3. There were significant differences in pulmonary infection and electrolyte disorders between the hypothermia and control groups (P = .038 and .033, respectively). Among the 30 patients treated with hypothermia, hypernatremia occurred in 11 and hyperkalemia in 3 patients. In the control group, hypernatremia occurred in 4 and hyperkalemia in 1 patients. Hypernatremia was Table 1 Clinical characteristics of study patients with severe TBI Variable
Hypothermia (n = 30)
Control (n = 30)
P
Age (y) GCS score GCS of 5-8, no. (%) GCS of 3-4, no. (%) Pupillary response Both reacting, no. (%) Bilaterally fixed/dilated, no. (%) Unilaterally fixed/dilated, no. (%) Mechanism of injury Traffic accident, no. (%) Fall accident, no. (%) Others, no. (%) Major findings on computed tomographic scans Intracranial hematoma, no. (%) Diffuse brain injury, no. (%) Contusions and others, no. (%)
42.47 ± 13.93
39.67 ± 15.26
13 (43.4) 17 (56.7)
12 (40.0) 18 (60.0)
1.000
13 (43.3) 1 (3.3) 16 (53.3)
16 (53.3) 3 (10.0) 11 (36.7)
.327
24 (80.0) 4 (13.3) 2 (6.7)
23 (76.7) 6 (20.0) 1 (3.3)
.794
18 (60.0) 9 (30.0) 3 (10.0)
21 (70.0) 7 (23.3) 2 (6.7)
.711
.461
C. Tang et al. / Journal of Critical Care 39 (2017) 267–270
269
Fig. 2. Kaplan-Meier survival curves for TBI patients after primary decompressive craniectomy with or without hypothermia.
Fig. 1. Changes of ICP and CPP over time in the 2 groups.
more frequent in the hypothermia group than in the control group (P b .05). Meanwhile, no significant differences in the remaining complications were observed between the hypothermia and control groups (P N .05).
4. Discussion Traumatic brain injury, as a common neurocritical disease in neurosurgery, remains the leading cause of death and disability among trauma patients [7]. A severe complication of moderate or severe TBI is acute increase of ICP [8]. Elevated ICP can cause reduced perfusion pressure, brain damage, and cerebral hernia [9]. Decompressive craniectomy, a second-tier therapeutic measure for increased ICP, can effectively control ICP elevation [10]. However, some patients develop increased ICP after decompressive craniectomy. Treatment of intracranial hypertension after decompressive craniectomy counts among the most challenging neurosurgical procedures. The protective effects of profound hypothermia on the brain have been largely reported. Moderate hypothermia reduces secondary brain injury and improves behavioral outcome in animals after TBI [11]. Numerous studies have established that neuroprotective effects conferred by moderate hypothermia are multifunctional and attributed to decreased ICP, decreased overall cerebral metabolic rate, reduced cerebral blood flow, decreased cerebral metabolic requirement for oxygen, altered neurotransmitter release, and maintenance of the blood-brain barrier [12-14]. Mild induced hypothermia is effective in some patients with craniocerebral injury [7]. Can hypothermia become a treatment of choice for increased ICP after decompressive craniectomy?
Table 2 Clinical outcomes at 6 months after TBI GOS score
Hypothermia group (n = 30)
Control group (n = 30)
1 2 3 4 5
3 (10. 0) 9 (30.0) 4 (23.3) 6 (20.0) 5 (16.7)
10 (33.3) 8 (26.7) 4 (20.0) 2 (6.7) 4 (13.3)
The objective of this study was to evaluate the efficacy and safety of mild induced hypothermia for intracranial hypertension in patients with severe TBI after decompressive craniectomy. As shown above, hypothermia further lowered ICP values even after decompressive craniotomy. Furthermore, CPP in the hypothermia group was significantly higher than control values. These findings suggested that hypothermia could constitute a good option when decompressive craniectomy is unable to reduce ICP to an optimal level. It was suggested that hypothermia can be used to reduce ICP effectively and improve treatment effectiveness in TBI patients [15,16]. Meanwhile, Andrews et al [17] proposed that in patients with ICP N 20 mm Hg after TBI, therapeutic hypothermia plus standard care to reduce ICP results in improved outcomes compared with standard care alone. So far, it remains unclear which patients benefit from hypothermia. In this study, patients with intracranial hypertension and TBI after decompressive craniectomy benefited from hypothermia. These findings are different from those reported by other hypothermia trials in TBI. The discrepancy might result from a prolonged use of hypothermia (≥3 days). Furthermore, this specific TBI subgroup (patients with increased ICP after decompressive craniectomy) may benefit from hypothermia. Despite a wide scientific consensus that hypothermia can reduce ICP effectively, many controversies still exist regarding its application in TBI patients. Meanwhile, others believe that hypothermia would cause a variety of complications, such as sinus tachycardia, low blood capacity, coagulation disorders, infection, shivering, hyperglycemia, electrolyte disorders, and gastrointestinal dysfunction [18]. Indeed, the potential complications and high risk of low temperature cannot be overlooked, and hypothermia cannot be used as a routine treatment in patients with severe TBI [19]. In this research, the incidence rates of electrolyte disorders and pulmonary infection in the hypothermia group was higher than control values. Infection is considered one of the major complications associated with hypothermia, likely because hypothermia deteriorates the immune function [20]. The above complications were managed without severe sequela. However, strict monitoring of patients is important. To avoid other complications, the following
Table 3 Main complications of 2 groups of patients with severe TBI Complications
Hypothermia group (n = 30)
Control group (n = 30)
P
Intracranial infection Hyperglycemia Electrolyte disorders Hypernatremia Hyponatremia Hyperkalemia Hypokalemia Pulmonary infection Renal malfunction Stress ulcer
4 (13.3) 7 (23.3) 16 (53.3) 11 (36.7) 4 (13.3) 3 (10.0) 2 (6.7) 20 (66.7) 4 (13.3) 3 (10.0)
4 (13.3) 5 (16.7) 7 (23.3) 4 (13.3) 1 (3.3) 1 (3.3) 1 (3.3) 11 (36.7) 3 (10.0) 4 (13.3)
1.000 .748 .033 .037 .353 .612 1.000 .038 1.000 1.000
270
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strategies can be used: rapidly achieving the target temperature, avoiding temperature fluctuations during the maintenance phrase, starting rewarming until ICP falls below 20 mm Hg at least 24 hours, and rewarming slowly. 5. Conclusion Although hypothermia effects remain controversial, the current study demonstrated that hypothermia could not only reduce ICP but also decrease mortality in patients with severe TBI after craniectomy. In TBI patients with intracranial hypertension after decompressive craniectomy, hypothermia can be considered the primary treatment option. Disclosures Nothing to disclose. Acknowledgments This study was supported by key Clinical Specialty Discipline Construction Program, President Foundation of Nanfang Hospital, Southern Medical University (2015C028). Science and Technology Planning Project of Guangdong Province, China (2012B091100463, 2013B021800304). References [1] Sandestig A, Romner B, Grande PO. Therapeutic hypothermia in children and adults with severe traumatic brain injury. Ther Hypothermia Temp Manag 2014;4:10–20. [2] Georgoff P, Meghan S, Mirza K, Stein SC. Geographic variation in outcomes from severe traumatic brain injury. World Neurosurg 2010;74:331–45. [3] Hofman K, Primack A, Keusch G, Hrynkow S. Addressing the growing burden of trauma and injury in low- and middle-income countries. Am J Public Health 2005;95:13–7. [4] Carney NA. Guidelines for the management of severe traumatic brain injury. Methods. J Neurotrauma 2007;24(Suppl. 1):S3–6. [5] Wang JW, Li JP, Song YL, Tan K, Wang Y, Li T, et al. Decompressive craniectomy in neurocritical care. J Clin Neurosci 2016;27:1–7.
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