|Year : 2016 | Volume
| Issue : 1 | Page : 108-115
Outcome of sedation therapy using midazolam or propofol continuous infusion in patients with severe traumatic brain injury
Mohamed Amr Shabana
Department of Anesthesia and Intensive Care, Faculty of Medicine, Al Azhar University, Cairo, Egypt
|Date of Submission||24-Dec-2014|
|Date of Acceptance||24-Dec-2015|
|Date of Web Publication||17-Mar-2016|
Mohamed Amr Shabana
Department of Anesthesia and Intensive Care, Faculty of Medicine, Al Azhar University, Cairo
Source of Support: None, Conflict of Interest: None
The aim of this study was to compare the sedative effect of midazolam and propofol alone or in combination on hemodynamic stability and subsequent intracranial pressure (ICP) changes in adults with severe traumatic brain injury.
Patients and methods
All patients received fentanyl continuous infusion and were randomly divided into three groups: group I received midazolam continuous infusion, group II received propofol continuous infusion, and group III received midazolam and propofol combination at half the dose used for groups I and II. Doses were titrated with gradual increments until the patients were well-sedated irrespective of the upper-dose limit as long as hemodynamic stability was maintained. Intraventicular ICP sensor was inserted at the end of the surgery for patients who underwent surgical interference or through Kocher's pathway at the right frontal lobe for patients did not undergo surgical interference. Patients were monitored to maintain mean arterial pressure at 80 mmHg or greater and cerebral perfusion pressure and ICP in the range of 50-70 and 18-21 mmHg, respectively. Sedation was judged according to the behavioral pain scale and Bispectral Index.
Intraoperative catheter was applied in 72 patients and through Kocher's pathway in 48 patients. The catheter was removed without complications in 104 patients (86.7%). The applied therapeutic strategies provided a significant reduction in ICP compared with baseline measures, but with significantly lower ICP in group III compared with other groups. The number of patients who had an ICP less than 21 mmHg was significantly higher in group III compared with other groups. Nineteen patients required mannitol therapy and 20 patients required muscle relaxant infusion, with a significant difference in favor of group III. The mean total Glasgow Coma Scale of patients in group III was significantly higher compared with groups I and II, with a significantly higher difference in favor of group II.
Midazolam-propofol combination in the used dosage allowed proper control of hemodynamic changes and improved cerebral perfusion pressure with reduction in ICP and minimizing the need for additional therapy.
Keywords: intracranial pressure, sedative therapy, severe traumatic brain injury
|How to cite this article:|
Shabana MA. Outcome of sedation therapy using midazolam or propofol continuous infusion in patients with severe traumatic brain injury
. Ain-Shams J Anaesthesiol 2016;9:108-15
|How to cite this URL:|
Shabana MA. Outcome of sedation therapy using midazolam or propofol continuous infusion in patients with severe traumatic brain injury
. Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2019 Jun 25];9:108-15. Available from: http://www.asja.eg.net/text.asp?2016/9/1/108/178889
| Introduction|| |
Traumatic brain injury (TBI) is defined as an impact, penetration, or rapid movement of the brain within the skull that results in altered mental state. TBI affects all age groups and both sexes. In the USA and Europe, the magnitude of this epidemic has drawn national attention owing to the publicity received by injured athletes, military personnel, and civilians during street fights , .
TBI, alone or in combination with trauma of other body regions, still represents a major challenge despite the advances in field emergency care and in modes of transport to the hospital and account for a high mortality rate among other forms of trauma. Moreover, most patients with severe traumatic injury have a prolonged stay in the ICU, the outcome being a long-term disability or death, with a minority of patients (20-30%) achieving a functionally independent outcome ,, .
Several studies have documented an association between disturbed post-traumatic cerebrovascular autoregulation and unfavorable outcome after TBI. After TBI, systemic hypotension can compromise cerebral hemodynamics and cause cerebral ischemia. Vasoparalysis caused by ischemia has been shown to abolish autoregulation. Thus, a vicious circle occurs with hypotension, decreased cerebral perfusion pressure (CPP), cerebral ischemia, vasoparalysis, and re-ends in more hypotension. The resultant uncoupling of cerebral blood flow and metabolism can trigger secondary brain lesions, particularly during the early phases, consequently worsening the patient's outcome ,, .
Increased intracranial pressure (ICP) due to traumatic intracranial or intracerebral hematoma or due to the presence of depressed fracture of the skull, or simply diffuse brain edema, all of these sequences of TBI lead to increased ICP with concomitant decrease in CPP, which was already compromised by hemodynamic dysregulation, and thus increases the deleterious effects of neuronal integrity, thereby worsening outcome ,, .
Several different classes of sedative agents are used in the management of patients with TBI. These agents are used for induction of anesthesia, to maintain sedation, to reduce elevated ICP, to terminate seizure activity, and facilitate ventilation. The intent of their use is to prevent secondary brain injury by facilitating and optimizing ventilation, reducing cerebral metabolic rate, and reducing ICP. There is limited evidence available as to the best choice of sedative agents in TBI, with each agent having specific advantages and disadvantages , .
The current study aimed to compare the sedative effect of midazolam or propofol alone or in combination on the hemodynamic stability and subsequent ICP changes in adults with severe TBI.
| Patients and methods|| |
The current prospective randomized comparative study was conducted since April 2011 up to June 2013 at Qatar in Hamad Medical Corporation. After approval of the study protocol by the Local Ethical Committee and obtaining a written fully informed consent signed by the nearest relative, adult patients with severe isolated TBI or TBI as a part of body polytrauma were enrolled in the study. All patients were immediately admitted to the ICU for determination of baseline data and to receive first-aid management. The severity of head injury was categorized according to the postresuscitation Glasgow Coma Scale (GCS)  and first computed tomography (CT) scan was categorized according to Traumatic Coma Bank data  . Patients with GCS of 7 or less, CT category of 2 or greater, and requiring ICP monitoring were enrolled in the study.
Patients were randomly divided using sealed envelopes into three study groups to receive sedation with midazolam, propofol, or combination of midazolam and propofol. All patients received fentanyl as a fixed analgesic as a continuous infusion at a rate of 1-3 μg/kg/h. In addition, patients in group I received a continuous infusion of midazolam at a rate of 0.05 mg/kg/h and the dose rate was increased according to the patient's level of sedation, up to a maximal dose of 0.15 mg/kg/h. Patients in group II received propofol as a continuous infusion at a rate of 0.5 mg/kg/h and the dose rate could be increased according to the patient's level of sedation up to a maximal dose of 4 mg/kg/h. In group III, the patients received midazolam and propofol combination but at half the dose used for groups I and II. All doses were titrated on the basis of the behavioral pain scale and Bispectral Index values; doses reflect a general association between clinical state and BIS values.
General management included the following: intubation, ventilation, oxygenation, head elevation, fluid resuscitation with normal saline, sedation, analgesia, muscle relaxation, mild hyperventilation for PaCO 2 of 30-35 mmHg, and normothermia. All patients received norepinephrine as a continuous infusion at a rate of 0.05-0.3 μg/kg/min. However, the dose was not recorded in each group for statistical analysis, to maintain an optimal CPP by keeping mean arterial pressure (MAP) in targeted number that was determined by means of continuous invasive monitoring.
After general condition stabilization, all patients underwent radiological workup for evaluation of the extent of skull and brain injuries, and patients who had definite intracranial pathology necessitating surgical interference were prepared for surgery with insertion of the intraventicular ICP sensor (Codman Microsensor, ICP Transducer; Codman & Shurtleff, Raynham, Massachusetts, USA) at the end of surgery. Patients free of definite intracranial pathology had intraventricular ICP sensor insertion through Kocher's pathway at the right frontal lobe. Catheters were removed when ICP and CCP remained controlled for 2-3 days.
All patients underwent monitoring for heart rate, invasive blood pressure, and MAP, central venous pressure, ICP, and CPP. The BIS (40-60), arterial hemoglobin oxygen saturation, end-tidal fraction of CO 2 , and body temperature (36.2-37.9°C) were also monitored. PaCO 2 was maintained between 31 and 35 mmHg. Hemodynamic variables were defined according to Brain Trauma Foundation guidelines for the management of TBI, including maintaining MAP at 80 mmHg or greater  , CPP in the range of 50-70 mmHg  , and ICP in the range of 18-21 mmHg  . Additional therapy for management of refractory ICP included mannitol or intravenous infusion of muscle relaxant. For resistant cases, CT imaging was repeated for a possibility of recent changes. Sedation was considered efficient on fulfillment of the five criteria of the behavioral pain scale [Table 1]  , followed by BIS.
Sample Power was calculated as described by Kraemer and Thiemann  using their proposed figure, which showed that the sample size for 60% power would require an N of 31/group and 80% power would require an N of 51/group. This hypothesis was documented by Murphy and Myors  . Considering ICP changes as being a frequent event with traumatic head injuries, especially if associated with brain injury, from a standard nomogram, a sample size greater than 31 patients per group was determined to be sufficient to give the trial a power ranging between 60 and 80% to detect a difference at the 5% significance level between studied procedures. Obtained data were presented as mean ± SD, ranges, numbers, and ratios. The results were analyzed using the Wilcoxon ranked test for unrelated data (Z-test) and using the χ2 -test paired t-test for variability between groups. Statistical analysis was conducted using the statistical package for the social science, (SPSS version 15, 2006) (Chicago, IL) for Windows statistical package. A P value less than 0.05 was considered statistically significant.
| Results|| |
The study included 120 trauma patients, 87 male and 33 female, with a mean age of 39.2 ± 14.8 years (range: 19-71 years). Forty-two patients (35%) had isolated TBI, whereas 78 patients (65%) had TBI as a part of multiple body trauma. The mean GCS at admission was 4.8 ± 1.2 (range: 3-7).
The mean Injury Severity Score at admission was 30.8 ± 11 (range: 15-65). The results of radiological examination of the skull were as follows: 45 cases had skull fracture, 31 patients had subdural hematoma, 24 patients had extradural hematoma, 20 patients had intracerebral hematoma, and 64 patients had diffuse cerebral edema. There was a nonsignificant difference between the studied groups as regards enrollment data [Table 2].
Seventy-two patients (64.2%) required surgical interference for their TBI, for either hematoma evacuation or reduction of skull fracture. Intraoperative catheter application was conducted at end of surgery for these patients, whereas in the other 48 patients (35.8%), the catheter was applied through Kocher's pathway. Bleeding during catheter insertion was encountered in seven patients (5.8%) and the catheter was removed immediately and these seven patients were excluded from the study. Catheter-related infection was the only complication that occurred during ICU stay and was encountered in nine patients (7.5%); the catheter was removed on the third day in four patients and on the fourth day in five patients, and these nine patients were also excluded from the study. The catheter was maintained until removed by a neurosurgeon without complications in 104 patients (86.7%). There was a nonsignificant difference between study groups as regards the frequency of surgical interference and catheter-related complications.
Throughout the ICU stay, 29 patients (27.9%) died either because of the inflected trauma, additional morbidities developed during ICU stay, or due to complications secondary to surgical interference. Other 25 (24%) survivors developed neurologic deficits and were considered as unfavorable outcome. Fifty patients (48.1%) were discharged alive and free of neurologic deficits and were considered as favorable outcome. There was a nonsignificant (P > 0.05) difference between the studied groups as regards outcome [Table 3].
|Table 3 Patients' distribution according to outcome as regards survival and neurological outcome|
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At admission, hemodynamic measures showed a nonsignificant (P>0.05) difference among studied patients. The applied therapeutic strategies enabled restoration of average measures of blood pressures, with significantly (P < 0.05) higher blood pressure measures at 24 h compared with corresponding baseline blood pressure measures in all studied groups. However, group III showed significantly (P < 0.05) higher MAP compared with measures reported in groups I and II, with nonsignificantly (P > 0.05) higher measures in group II compared with group I. Subsequently, CPP was significantly (P < 0.05) higher at the end of 24 h compared with baseline CPP, with significantly (P < 0.05) higher CPP in group III compared with groups I and II and nonsignificantly (P > 0.05) (CPP = MAP-ICP) higher CPP in group II compared with group I [Table 4] and [Figure 1].
|Figure 1: The mean cerebral perfusion pressure (CPP) determined in the studied groups at baseline and 24 h after therapy|
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|Table 4 Mean baseline and 24-h levels of hemodynamic parameters and CPP and ICP with percentage of ICP change|
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The majority of patients had increased ICP at admission with a mean of 26.8 ± 4.1 mmHg (range: 19-35 mmHg). The applied therapeutic strategies provided successful control of ICP manifested as a significant (P < 0.05) reduction in ICP in comparison with their respective baseline measures. Patients in group III showed pronounced improvement, with significantly (P < 0.05) lower ICP compared with that in groups I and II and nonsignificantly (P > 0.05) lower ICP measures in group II compared with group I. However, the percentage of decrease in ICP was nonsignificantly (P > 0.05) different between the studied groups, but in favor of group III [Table 4] and [Figure 2].
|Figure 2: The mean intracranial pressure (ICP) determined in the studied groups at baseline and 24 h after, with the recorded percentage of change|
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Among the enrolled patients (n = 104), the number of patients who had an ICP less than 21 mmHg was significantly higher in group III compared with their number in groups I (P = 0.007) and II (P = 0.021), whereas it was nonsignificantly (P = 0.598) higher in group II compared with group I [Figure 3]. Thirty-nine patients required additional therapies more than sedation and mild hyperventilation for control of ICP; 19 patients responded to mannitol therapy, and 20 patients responded to intravenous infusion of muscle relaxant, with a significantly higher frequency of patients responding to mannitol infusion in group III compared with groups I (P = 0.004) and II (P = 0.034) and nonsignificantly higher frequency of patients in group II compared with groups I and II (P = 0.493) [Table 5]. Fifteen patients required decreased dose of sedation for maintenance of ICP in the range of 19-21 mmHg and CPP in the range of 50-70 mmHg without shooting of ICP, with a nonsignificant (P > 0.05) difference between the studied groups [Table 5].
|Figure 3: Patients'distribution according to at 24-h intracranial pressure (ICP) recorded in the studied groups|
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|Table 5 Patients' distribution according to ICP strata and additional therapies required for ICP control|
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Control of hemodynamic status and surgical interference for hematoma evacuation or elevation of depressed bones allowed improvement of consciousness, manifested as improved GCS reported on the fifth day of intervention, before ICP measurement catheter removal. Forty-two patients (40.4%) had a GCS of 10-12 and 24 patients (23.1%) had a GCS of 8-9, whereas 38 patients (36.5%) still had a GCS of 7 or less. Despite the nonsignificantly (P = 0.109) higher frequency of improved patients in group III compared with other groups, the mean total GCS of patients in group III was significantly higher compared with groups I (P = 0.001) and II (P = 0.041), with significantly (P = 0.040) higher mean total score in group II compared with group I [Table 6] and [Figure 4].
|Figure 4: The mean ± SD Glasgow Coma Scale (GCS) determined at 24 h of therapy|
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|Table 6 Patients' distribution according to GCS strata and additional therapies required for ICP control|
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| Discussion|| |
The current study illustrated an important fact that no single therapeutic modality could allow by its virtue controlling elevated ICP secondary to severe TBI. All enrolled patients were subjected to mild hyperventilation to maintain PCO 2 in the range of 30-35 mmHg and received fentanyl as a fixed analgesia in addition to either midazolam (group I), propofol (group II), or combined (group III).
The applied therapeutic strategies provided successful control of ICP, manifested as a significant reduction in ICP in comparison with their respective baseline measures. Both groups I and II provided comparable effect, manifested as nonsignificant difference as regards hemodynamic variables and improvement in GCS, despite the difference being in favor of propofol-fentanyl combination.
In line with these data Kelly et al.  suggested that a propofol-based sedation and an ICP control regimen is a safe, acceptable, and, possibly, desirable alternative to an opiate-based sedation regimen in intubated head-injured patients. Sandiumenge Camps et al.  found that, in traumatized critically ill patients, sedation adequacy was similar, patient behavior after drug discontinuation was not different, and that hemodynamic or neuromonitoring variables were also similar for both midazolam and 2% propofol groups.
However, patients in group III showed a significant improvement compared with the other groups in terms of control of systemic hemodynamic changes, improvement in CPP, and reduction in ICP. In addition, group III showed a significantly lower frequency of patients having resistant high ICP that required additional therapies for ICP control. Moreover, GCS of patients in group III at the end of 24 h of therapy was significantly higher than that in those who received either drug alone, despite the reduced dose of both drugs.
In support of the strategy of using a combination of midazolam and propofol, multiple studies evaluated the use of such combinations during various anesthetic and ICU situations. Richman et al.  found that, in mechanically ventilated patients, sedation with midazolam and fentanyl by means of constant infusion provides more reliable sedation and is easier to titrate compared with midazolam alone, without a significant difference in the rate of adverse events. Cho et al.  reported that, during endoscopic submucosal dissection, treatment with propofol and a low dose of midazolam for sedation provides a greater satisfaction for endoscopists compared with midazolam alone. Ueno et al.  found that intravenous sedation using midazolam and propofol reduces hypertensive risks during implant surgery. Li et al.  documented that combination sedatives appear to be safe when administered intravenously in the emergency department and are more effective compared with single-agent sedatives in agitated patients.
For control of increased ICP, multiple studies tried either propofol or midazolam in combination with various drugs and both propofol and midazolam proved to be effective. Coles et al.  found that remifentanil an appreciate opioid to use in combination with propofol during anesthesia for supratentorial craniotomy. Bourgoin et al.  suggested that midazolam in combination with ketamine is comparable to a combination of midazolam-sufentanil in maintaining ICP and CPP of severe head injury patients placed under controlled mechanical ventilation.
Recently, Kataoka and Ueno  found butorphanol-midazolam combination therapy may be useful for intracranial hypertension leading to downregulation of headache with sedation not accompanied by amnesia or impaired psychomotor function and concluded that such combination might be an option for the management of intracranial hypertension in central nervous system infections.
In line with the use of reduced dose of both drugs, Xu et al.  studied the medical records of 68 patients treated in the emergency ICU receiving mechanical ventilation and sedation care using either midazolam or propofol or a combination of both and found that the drug dosage in the combination group was decreased significantly compared with propofol alone and midazolam alone, but there was no significant difference in sedation time and duration of mechanical ventilation among all groups, but emergency ICU stay days in combination group was shortened significantly compared with other groups. Calver et al.  used high-dose parenteral sedation defined as 10 mg or greater midazolam, droperidol, or haloperidol (alone or in combination) in comparison with using the normal dose of 10 mg or less and found that high-dose sedation did not result in more rapid or effective sedation but was associated with more adverse effects.
The current study was designed as a pilot study presenting personal experience for dealing with such cases; the doses of the studied drugs were titrated with gradual increments until the patients were well-sedated irrespective of the upper-dose limit as long as hemodynamic stability was maintained. The obtained results allowed concluding that midazolam-propofol combination in the used dosage allowed proper control of hemodynamics and improved CPP, with reduction in ICP and minimizing the need for additional therapy with significant improvement in conscious state.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]