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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 6  |  Issue : 4  |  Page : 242-247

Midazolam is effective in controlling intracranial pressure in severe traumatic brain injury


1 Department of Anaesthesia, Christian Medical College and Hospital, Vellore, Tamil Nadu, India
2 Department of Neurosurgery, Aster Medcity, Kochi, Kerala, India

Date of Submission16-Jul-2018
Date of Decision06-Jan-2019
Date of Acceptance28-Jan-2019
Date of Web Publication21-Nov-2019

Correspondence Address:
Smitha Elizabeth George
Department of Anaesthesia, Christian Medical College and Hospital, Vellore, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cjhr.cjhr_111_18

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  Abstract 


Context: Traumatic brain injuries present a grave public health problem in developing countries. Guidelines suggest that neuromuscular blockade (NMB) should be avoided in severe head injury. Midazolam is an affordable option for sedation when resources are limited. Aims: We proposed to study whether midazolam as a sedative agent in severe head injury achieved adequate control of intracranial pressure (ICP) and reduced the need for NMB. Settings and Design: A prospective observational study was conducted in 96 consecutive patients with severe head injury needing ventilation in the neurosurgical intensive care unit (ICU) of our hospital. Subjects and Methods: A modification of “Guidelines for the management of severe head injury, Brain Trauma Foundation” was used to control ICP in these patients. A ventricular catheter was inserted for ICP monitoring and an ICP <20 mm Hg was targeted by cerebrospinal fluid venting, mannitol and increasing the level of sedation with midazolam up to 0.15 mg/kg/h. It was planned to monitor the ICP for a minimum of 48 hours. Results: Mean duration of ICP monitoring was 35.80 ± 23.08 hours. In 63 of the 96 patients, the ICP remained ≤20 mmHG in patients on Midazolam infusion without NMB (65.6%). Conclusions: Sedation with midazolam can be used in a severe head injury to control ICP and to reduce the need for NMB, particularly in resource-poor settings.

Keywords: Intracranial pressure control, midazolam, severe traumatic brain injury


How to cite this article:
George SE, Mathew JE. Midazolam is effective in controlling intracranial pressure in severe traumatic brain injury. CHRISMED J Health Res 2019;6:242-7

How to cite this URL:
George SE, Mathew JE. Midazolam is effective in controlling intracranial pressure in severe traumatic brain injury. CHRISMED J Health Res [serial online] 2019 [cited 2019 Dec 11];6:242-7. Available from: http://www.cjhr.org/text.asp?2019/6/4/242/271322




  Introduction Top


Traumatic brain injuries, the silent epidemic[1] of the modern world, is a grave public health problem. The resultant morbidity, mortality, and socioeconomic losses are tremendous, resulting in almost 2 million lives lost and 1.5 million neurologically disabled people every year in India.[2] According to the World Health Organization, traumatic brain injuries from road traffic accidents may become the third greatest cause of disease and injury worldwide by the year 2020.[3]

In this scenario, efficacious and timely management of brain injuries assumes prime importance to improve outcome. Therefore, protocols for traumatic brain injuries need to be evidence-based, especially when considering the effectiveness of resource utilization in developing countries.[4]

The present guidelines state that early management in a severe traumatic head injury for intubated patients in the intensive care unit (ICU) is to be accomplished with sedation alone and that neuromuscular blockade (NMB) is to be reserved for patients with raised intracranial pressure (ICP) that requires escalation of treatment intensity.[5],[6],[7]

Midazolam and propofol are the preferred drugs for sedation in the ICU as they lower the ICP by lowering the cerebral metabolism (cerebral metabolic rate of oxygen-CMRO2).[8],[9]

Midazolam is cheaper than propofol in the doses required to achieve a high level of sedation in severe head injury and hence more appropriate in a resource-constrained environment.

We proposed to study whether midazolam as a sedative agent in severe head injury achieved ventilator compliance, control of ICP and reduced the use of muscle relaxants.


  Subjects and Methods Top


The study protocol was reviewed and approved by the Institutional Review Board and ethics committee of our institution. During the study period of 15 months, 143 patients with severe traumatic brain injury (TBI) admitted in the neurosurgical ICU of our hospital were screened for the study. Severe TBI was defined as head trauma associated with a Glasgow Coma Scale (GCS) of 3–8. Ninety-six patients who fulfilled the inclusion criteria were enrolled in the prospective study. Informed consent to participate in the study was obtained from relatives of the patients.

Inclusion criteria

All severely head-injured patients who presented within 72 h following trauma with no surgical intervention, ventilated primarily for head injury were included.

Exclusion criteria

  1. Age <14 years and age >60 years
  2. Presence of systemic injury causing hypotension
  3. Inability to monitor the ICP.(Patients with deranged bleeding parameters, scalp lacerations too close to the external ventricular drain site, postoperative patients whose bone flap was not replaced and those with pneumocephalus)
  4. Other reasons for excluding patients from the study were the inability to cannulate the ventricle, brain death and patients who were ventilated for chest infections.


Study protocol

Patients found to have a severe head injury with a postresuscitation GCS score of 8 or below on admission and who did not require surgical intervention based on plain computed tomography (CT) Brain were included in the study. They were intubated using pancuronium 0.1 mg/kg, morphine 0.1 mg/kg, and midazolam 0.05–0.1 mg/kg as bolus doses. Ventilator compliance was ensured with small doses of pancuronium (1 mg) till ICP monitoring was established. A ventricular catheter was inserted, preferably on the right side, attached to an external strain gauge for monitoring ICP. We used the ventricular cannulation[10] technique described by Joseph in 2003 for all the patients. If ICP was >20 mm Hg, cerebrospinal fluid (CSF) was drained in aliquots of 2–3 ml.

Midazolam sedation was started, and all patients were given morphine analgesia at the rate of 1–3 mg/hour. General modalities in the management of head injury were followed, including maintaining normothermia, seizure prophylaxis, and head elevation to 15°. Measures were taken to prevent hypotension, hypoxia, and hyperglycemia. Stress ulceration prophylaxis was started for all patients.[11]

ICP, mean arterial pressure (MAP), and cerebral perfusion pressure (CPP) were monitored continuously and recorded hourly in all patients. End hour ICP was used for recording. The goal of therapy was to maintain the ICP <20 mmHg.

The CPP was kept >60 mmHg. The MAP was maintained using intravenous fluids and vasopressors (dopamine and adrenaline) if necessary to sustain a CPP >60 mmHg.[12] After ensuring ventilator compliance, arterial blood gas was done and ventilator adjustments made, following which repeat blood gas analysis was performed to ensure PaCO2 of 30–35 mmHg. A modification of “Guidelines for the management of severe head injury, brain trauma foundation (BTF)” was used[11] for control of the ICP as shown in [Figure 1].
Figure 1: Flow chart of escalating treatment intensity for control of raised intracranial pressure

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If ICP remained over 20 mmHg with Step 1, Step 2 was followed and so on till ICP was controlled.

Baseline infusion of midazolam at 0.03 mg/kg/h was started, and the sedation increased until the patient was adequately sedated. Mild hyperventilation was used to maintain theP CO2 between 30 and 35 mmHg on the arterial blood gas.

Ventricular CSF drainage 1–3 ml every 5 min till ICP was <20 mmHg. There was no limit to the frequency of CSF drainage.

Mannitol bolus infusions were given as standard doses. A dose of 0.25–1 g/kg was recommended If ICP remained over 20 mmHg with Step 1, Step 2 was followed and so on till ICP was controlled.

Midazolam doses for sedation was increased. Midazolam infusion was increased by 0.02 mg/kg every 20–30 min (bolus doses were given with each increase) till ICP was controlled or a maximum dose of 0.15 mg/kg/h was reached.

NMB was resorted to if all the above measures failed to control the ICP.

Sedation was considered adequate if the patient was ventilator compliant and not agitated or bucking on the ventilator.

If venting and mannitol failed to lower the ICP, sedation was gradually increased after giving a bolus dose of Midazolam each time. We waited for at least 20 min to see the response before increasing the level of sedation to a maximum of 0.15 mg/kg/h.

Ethical approval

The permission was taken from Institutional Ethics Committee prior to starting the project. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.


  Results Top


Demographic characteristics

Ninety-six patients were recruited in the study after screening 143 patients. The study was done over 15 months in a neuro ICU of a tertiary care hospital in India.

The patient population studied included 90 males and 6 females, age varying from 15 to 60, with a mean age of 34 ± 26.43 years. Etiology of the TBI was road traffic accident in 94 and fall from height in two patients.

Admission GCS in the midazolam alone group was 6.22 ± 1.73 and in the NMB group was 5.87 ± 2.36. Majority of the patients were enrolled within 12 h of the accident causing the TBI.

Control of intracranial pressure

In 63 of the 96 patients, the ICP remained ≤20 mmHg on midazolam infusion (65.6%) [Figure 2].
Figure 2: Results in patients on following the protocol

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Three patients were started on NMB because they were not compliant on the ventilator in spite of maximum dose of midazolam and adequate analgesia. These patients were excluded from the study. However, in these patients, ICP was under control.

In patients whose ICP was controlled with midazolam, the mean midazolam dose used was 0.11 ± 0.06 mg/kg/h. The mean duration of midazolam infusion was 35.80 ± 23.08 h.

There were 33 patients who had uncontrolled ICP with Midazolam sedation. NMB was started after doing a plain CT Brain and ruling out any operative lesion in these patients.

In this subset of patients, the addition of NMB lowered the ICP in only 12.5% of these patients.

Mortality

A total number of deaths were 35.

Of this, 15 belonged to the group which had ICP controlled with midazolam. So the mortality in this group was 15 out of 63, ie 25%. In the group which required the addition of NMB, the mortality was 60.6% (20 deaths in 33 patients). This was statistically significant (P = 0.0007) [Figure 3].
Figure 3: Difference in mortality during hospital stay in the two groups of patients

Click here to view


Close to 80% of patients with uncontrolled ICP (11 out of 14) died signifying a poor outcome in this group (P = 0.017). Nine out of these 11 patients who died had at least one nonreacting pupil or a motor score of 3 or less.

Complications related to intracranial pressure monitoring

None of the patients in our study developed meningitis. Two out of 96 patients (2.08%) in our study developed frontal extradural hematomas centered at the twist drill craniostomy site for insertion of the ventricular catheter.


  Discussion Top


Severe TBI has reached epidemic proportions worldwide[13] with rapid urbanization, lifestyle changes, more access to motor vehicles and poor safety protocols, together culminating in a steep rise in road traffic accidents.[14] It is the need of the hour to look at how to improve outcome in head injury, keeping in mind our resource constraints.

Management protocols for the care of the severely head injured have evolved considerably[15] in the past 35 years based on knowledge from clinical studies. The BTF published a set of guidelines in 1995, 2000 and 2007[16] for control of the ICP. The implementation of BTF guidelines is proven very effective in saving lives and decreasing overall costs[17] in the management of TBI.

NMB in severe head injury while on mechanical ventilation is an accepted practice in many centers to prevent muscle activity such as posturing, shivering, or bucking on the ventilator that raises ICP. Other than preventing a rise in ICP during routine tracheobronchial suctioning[18] when given along with sedation, there is no clear evidence on the efficacy of NMB in controlling raised ICP. In the past 30 years, evidence has emerged that NMB is associated with significant adverse effects.[19],[20] Early routine use of NMB is associated with prolonged ICU stay, prolonged paralysis, higher rates of sepsis or pneumonia, and difficulty in neurological assessment. There are no clinical trials or recommendations regarding NMB from the BTF; except that when ICP is refractory to all other agents when NMB can be tried. The present study showed that addition of NMB controls ICP at best in only 12.5% of patients in whom sedation failed to control ICP.

Sedation is an accepted practice in the management of head injury,[8],[21] as it prevents rise in ICP caused by agitation and optimizes cerebral oxygenation.[22] In severe head injury, better outcomes have been observed in sedation without the use of NMB.[7]

Propofol and midazolam are commonly used for sedating the head injured patients.[23],[24] Both reduce the cerebral metabolism and hence lower the ICP and improve cerebral oxygenation. They also improve ventilator compliance and facilitate intermittent neurological assessment.[25] Midazolam is a good anxiolytic, amnesic, anticonvulsant as well.[26]

However, propofol has shorter wake up times and shorter ICU stays as compared to midazolam in short-term sedation as demonstrated by Chamorro et al.[27]

Many comparative studies,[28],[29],[30] on propofol and midazolam have shown equal efficacy in sedating the critically ill trauma patient. However, these studies were done on patients with general trauma who required sedation for <24 h. The head injured patient presents different challenges for sedation, as the end point is not only sedation but also control of raised ICP.

In spite of superior titratability of propofol, its use must be weighed against adverse effects such as propofol infusion syndrome, hypotension that can be detrimental to CPP, and effects related to its lipid vehicle (hyperglyceridemia, infection).[31] Propofol infusion syndrome presents with hyperkalemia, hepatomegaly, metabolic acidosis, rhabdomyolysis, renal failure, myocardial dysfunction, and Brugada like ECG changes[32] that can lead to lethal malignant arrhythmias.

This entity is more common in TBI due to the high doses of propofol (>4 mg/kg/h for >48 h) used to control ICP.[33] Meta-analysis of four studies by Gu et al.[23] compared the safety and efficacy of propofol with midazolam for sedation in severe head injury, and found similar effects on ICP, CPP, GCS, and mortality in both groups. A randomized controlled trial by Tanguy et al.[34] used cerebral microdialysis catheters to check lactate to pyruvate ratio, a marker of cerebral oxidative stress and found no difference on comparing sedation with midazolam and propofol in severe TBI.

Comparing the safety and efficacy of propofol sedation for ventilating severely head injured patients with a regimen of morphine sulfate, Kelly et al.[8] found that propofol sedation controlled the ICP in 66% of patients without the use of NMB as compared to 52% in the morphine group. Similarly, in our study, midazolam was effective in achieving and maintaining a normal ICP in over 65% severely head injured patients.

We used NMB only if ICP was uncontrolled or if the patient was not compliant on the ventilator in spite of maximum dose of midazolam infusion (0.15 mg/kg/h). Out of 96 patients, 36 patients (37.5%) required the use of NMB. This was comparable with the study by Kelly et al. where they used NMB in 34% of patients in the propofol group and 66% had their ICP under control with propofol sedation.

All the patients in our study received morphine as part of the protocol. The usage of opioids in severe head injury is controversial as it can potentially increase the ICP.[35] Our rationale for using it was to decrease the pain and agitation related increase in ICP.

ICP monitoring has been shown to decrease mortality in severe TBI[36] and improve outcomes in severe TBI.[37] Complications of ICP monitoring include hemorrhage and meningitis. Published incidence of infection varies from 0% to 10.3%.[38] The incidence of infection increases with the duration of monitoring and also with breach of the closed system.[39] None of the patients in our study developed meningitis. This was probably related to the fact that ICP monitoring was restricted to <3 days in 90% of our patients.

Reports of hemorrhage also vary with an average incidence of 1.1%.[38] 2 out of 96 patients (2.08%) in our study developed frontal extradural hematomas centered at the twist drill craniostomy site for insertion of ventricular catheter. Both occurred in the early part of the study. It was probably due to attempts at inserting the brain cannula before piercing the dura, causing stripping of the dura, and accumulation of hematoma.

Overwhelming evidence in literature show that uncontrolled ICP is associated with a poor outcome. Narayan studied 207 consecutive patients who underwent ICP monitoring and found that patients with persistently elevated ICP almost always died.[38] Similarly, in our study, the subgroup that had uncontrolled ICP and received NMB had a high mortality during hospital stay (60.6% mortality) which reflected poor outcome associated with uncontrolled high ICP.

In the patients whose ICP was controlled with midazolam, the mean midazolam dose was 0.11 mg/kg/h. For an average patient weighing 60 kg, this works out to 158.4 g over 24 h. In the study by Kelly et al., the average infusion rate in the propofol group was 55 ± 42 μg/kg/min. Taking 55 μg/kg/min as the average infusion rate, this worked out to 3.3 mg/kg/h and therefore 4752 mg/day for a 60 kg patient.

Although our study was not designed to look at comparative costs of propofol and midazolam, we observed that midazolam usage, in the doses required to control the ICP costs only 1/5th that of propofol in a similar setting. We would recommend it to be the more appropriate drug for sedation in a resource constrained environment as in most developing countries like India.

Limitations of the study

This is an observational study. As midazolam was administered to all patients recruited into the study and NMB was administered only when ICP remained uncontrolled on midazolam, the difference in outcomes between the two groups is expected. The results of this study need to be confirmed in a randomized controlled trial. A randomized controlled trial with high dose Midazolam sedation in one arm without use of NMB, another arm with use of NMB and regular doses of sedation and measuring outcomes at 6 months between the two groups would provide more scientific evidence on the comparative efficacy of midazolam over NMB in severe head injury.

A study with cost benefit analysis could clearly state if midazolam is the drug to be preferred for sedation in TBI in resource constrained environments.


  Conclusions Top


Our study demonstrated that sedation with midazolam controlled ICP in over two-thirds of patients with severe TBI, helped to achieve ventilator compliance and reduced the use of muscle relaxants. Midazolam can be used as an alternative in resource constrained settings considering relative costs and the significant adverse effects of propofol.

Our study also demonstrated that patients with persistent raised ICP requiring NMB had a higher mortality rate.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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