Cerebral Microdialysis Effects of Propofol versus Midazolam in Severe Traumatic Brain Injury

Abstract

Propofol, an anesthetic agent acting as an analogue of vitamin E, has been advocated to be an ideal neuroprotective agent both in animal models and in clinical practice, due to its positive effects on oxidative stress. Nevertheless, no studies have compared this agent to another sedative agent used for sedation after traumatic brain injury (TBI). The objective was to compare the effects of propofol to midazolam on cerebral biomarkers at the acute phase of severe TBI patients. Thirty patients aged 35±18 years were prospectively randomized to receive propofol or midazolam and 29 were analyzed (n=15 for propofol, and n=14 for midazolam). A cerebral microdialysis catheter was used to measure the lactate:pyruvate (L:P) ratio, glutamate, glycerol, and glucose for 72 h. No difference between groups was observed for the L:P ratio (time effect p=0.201, treatment effect p=0.401, time×treatment interaction p=0.101). Similarly, no difference was observed for glutamate (time effect p=0.930, treatment effect p=0.651, time×treatment interaction p=0.353), glycerol (time effect p=0.223, treatment effect p=0.922, time×treatment interaction p=0.308), or glucose (time effect p=0.116, treatment effect p=0.088, time×treatment interaction p=0.235). These results do not support a difference between propofol and midazolam for sedation for the cerebral metabolic profile in severe TBI.

Introduction

T here is growing evidence that the damaged permeability of mitochondria in response to post-traumatic oxidative stress plays a pivotal role in the metabolic crisis observed after a severe traumatic brain injury (TBI) (Jayakumar et al., 2008; Mustafa et al., 2010). This mitochondrial dysfunction leads to apoptotic cerebral cell death, especially when oxidative stress is strongly expressed (i.e., in brain areas with higher neuronal content and respiratory rate), and may affect neuronal recovery after TBI (Marcoux et al., 2008; Mazzeo et al., 2009). Microdialysis analysis assessment in vivo at the early phase post-TBI has advanced our understanding, and has increased interest in several biomarkers. Notably, elevations of the lactate:pyruvate (L:P) ratio appear to be a key marker of this cascade of events (Vespa et al., 2005). Several pharmacological means of neuroprotection have been explored (Jayakumar et al., 2008; Mazzeo et al., 2008; Mustafa et al., 2010; Singh et al., 2006). Propofol, an anesthetic agent acting as an analogue of vitamin E, has been advocated as an ideal neuroprotective agent both in animal models and in clinical practice, due to its positive effects on oxidative stress (Nakahata et al., 2008; Tsuchiya et al., 2001, 2002). Nevertheless, no studies have compared this agent to another sedative agent used for post-TBI sedation. The main objective of this study was to compare the effects of propofol to midazolam on the cerebral L:P ratio in TBI patients during the first 72 h after surgical intensive care unit (SICU) admission. The effects of these agents on other cerebral biomarkers, outcome at 12 months assessed by the Glasgow Outcome Scale (GOS), and memory tests were also evaluated.

Methods

This prospective, randomized, single-blinded study was performed in a SICU of a university hospital from June 2006 to September 2008. This unit acts as a referral center and receives severe TBI patients from local and regional institutions. The protocol was approved by the Comité de Protection des Personnes of Rennes, France on March 8, 2006, and written informed consent was obtained from each patient's next of kin.

The main objective of this study was to compare the effects of propofol versus midazolam on the cerebral L:P ratio in TBI patients during the first 72 h after SICU admission. Secondary objectives were to evaluate the effect of these drugs on cerebral glutamate, glycerol, and glucose. Moreover, GOS and memory tests were evaluated at 12 months.

Patients

All adult patients (age ≥18 years) with a severe and isolated closed head injury (Glasgow Coma Scale [GCS] score ≤8) requiring sedation, ventilation, and intracranial pressure (ICP) monitoring were eligible. Patients who had major focal injuries (>25 cc), and/or who required neurosurgery for epidural and/or subdural hematomas, and/or who had coagulation disorders and/or delayed admission to the SICU (>12 h) were excluded.

All candidates were managed according to standardized protocols in order to maintain a mean arterial pressure (MAP) ≥85 mm Hg, an ICP ≤20 mm Hg, and a cerebral perfusion pressure (CPP) ≥65 mm Hg (Vincent and Berre, 2005). Other types of therapy to avoid secondary insults were applied as recommended (Vincent and Berre, 2005).

Data collection

The following data were recorded at inclusion: general characteristics (age and sex), severity of illness as assessed by the Simplified Acute Physiologic Score II (SAPS II) and GCS, core body temperature, vital signs (mean arterial pressure and oxygen saturation), blood glucose, carbon dioxide tension, and hemoglobin level. Cerebral hemodynamic parameters including ICP and CPP were noted, and computed tomography (CT) scan classification according to the Traumatic Coma Data Bank (TCDB) was recorded (Marshall et al., 1992). During the study, core body temperature, MAP, cerebral hemodynamic parameters (ICP and CPP), arterial oxygen tension, arterial carbon dioxide tension, and blood glucose were recorded every 4 h.

At 12 months, a structured interview was used either with the patient or with a caregiver or relative to allocate patients as assessed by the GOS into two outcome categories: A, good recovery or moderate disability; and B, death, vegetative state, or severe disability. A cognitive difficulties scale was also used to assess memory complaints (Derouesné et al., 1993).

Investigated variables

All patients had an arterial catheter placed (Plastimed Division, Prodimed, Le Plessis-Bouchard, France) to allow continuous measurements of systemic arterial pressure. At the bedside of every patient a cerebral pressure sensor (Codman Microsensors ICP transducer; Codman & Shurtleff, Raynham, MA), and a cerebral microdialysis catheter (CMA 70; CMA/Microdialysis, Stockholm, Sweden) were inserted through a burr-hole into the frontal lobe and secured with a triple bolt. The pressure sensor allowed us to continuously monitor the ICP. The microdialysis catheter was infused with Ringer's Hartmann solution at a rate of 0.3 μL/min via a pump (CMA 106; CMA/Microdialysis). The L:P ratio, glutamate, glycerol, and glucose were measured using a CMA 600 bedside Microdialysis Analyser (CMA/Microdialysis). The limit of detection was 0.1 mmol/L for lactate, 1 μmol/L for glutamate, 10 μmol/L for pyruvate and glycerol, and 0.1 mmol/L for glucose. The normal values of the L:P ratio, glutamate, glycerol, and glucose were 23.0±4.0, 16.0±16.0 μmol/L, 82±44 μmol/L, and 1.7±0.9 mmol/L, respectively (Reinstrup et al., 2000).

Study protocol

After baseline data were taken, thee patients were randomized to receive propofol or midazolam. In the absence of recommendations concerning sedation in TBI, our objective was to obtain a persistent Ramsay sedation level of 4–5 (Bratton et al., 2007; Ramsay et al., 1974). Accordingly, propofol was infused at an initial rate of 1 mg/kg.h⁻¹, and increased if necessary by increments of 1 mg/kg.h⁻¹, with an upper limit of 5 mg/kg.h⁻¹. Midazolam was infused at an initial rate of 0.03 mg/kg.h⁻¹, with increments of 0.01 mg/kg.h⁻¹, to obtain the objective level. Both groups received fentanyl, infused at a rate of 1–3 μg/kg.h⁻¹. Concerning the microdialysis analysis, the first dialysate sample was obtained before the sedation was started. Thereafter, microvials of the microdialysis analyzer were changed every 120 min, and samples were analyzed every 120 min for L:P ratio, glutamate, glycerol, and glucose for 72 h. If refractory high cerebral pressure requiring thiobarbiturate or craniectomy occurred, the microdialysis analysis was stopped.

Statistical analysis

We planned to enroll 24 patients (12 per group). This sample size allowed us to detect, in a two-sided test with a Type I error of 5% and a power of 95%, a 30% decrease in the dialysate L:P ratio with propofol, assuming a mean reference value of 36±8 (Hutchinson et al., 2000). Due to the possible variability of the L:P ratio, a safety margin of 6 patients was scheduled. Data are presented as mean±standard deviation (SD) unless otherwise noted for continuous variables, and as the number (corresponding percentage) for categorical variables. Statistical analysis was performed with SAS software version 9.2 (SAS Institute, Cary, NC). Comparison of the evolution of the cerebral biomarkers between the two groups was performed using a two-way (time×treatment) analysis of variance (ANOVA; mixed models). All other comparisons between the two groups were performed using the Student's t-test or the Wilcoxon rank-sum test when needed for continuous variables, and the chi-square test or the Fischer's exact test as appropriate for categorical variables. For all analyses, p values <0.05 were considered significant.

Results

During the study period 94 adult patients with isolated closed severe head injury were admitted to the SICU. Fifty-three patients met exclusion criteria (emergent neurosurgery [n=20], major hematoma [n=6], imminent brain death [n=19], contraindications to monitoring [n=5], and other [n=3]), and 11 patients could not be monitored due to technical problems. Thirty patients aged 35±18 years were randomized, but in one patient we could not insert the microdialysis catheter due to technical problems. Therefore 29 patients were analyzed (n=15 for the propofol group, and n=14 for the midazolam group). There were no significant differences between the two groups at baseline for general characteristics, severity, and cerebral hemodynamics (Table 1), as well as for microdialysis parameters (Table 2).

Table 1.

Baseline Demographic and Clinical Characteristics in the Propofol and Midazolam Groups

	Propofol (n=15)	Midazolam (n=14)	p Value
Age, years	37±20	33±18	0.645
Sex, male/female	10/5	13/1
SAPS II score	39±12	42±10	0.525
GCS score	5±2	5±2	0.687
Core body temperature, °C	37.0±1.3	37.7±1.3	0.167
MAP, mm Hg	91±11	100±16	0.072
Spo ₂, %	97±2	98±1	0.082
Paco ₂, mm Hg	38±7	35±10	0.388
Blood glucose, mmol/L	8±2	8±4	0.633
Hemoglobin, g/dL	12±2	13±2	0.280
ICP, mm Hg,	19±12	20±12	0.759
median [range]	17 [2–45]	18 [5–40]
CPP, mm Hg,	71±14	73±11	0.645
median [range]	68 [49–105]	77 [48–93]
TCDB CT scan class
II	11	7
III	3	5	0.408
IV	1	2

Data are expressed as mean±standard deviation for continuous variables, and as number for categorical variables, unless otherwise noted.

SAPS II, Simplified Acute Physiologic Score II; GCS, Glasgow Coma Scale; MAP, mean arterial pressure; Spo ₂, oxygen saturation; Paco ₂, arterial carbon dioxide tension; ICP, intracranial pressure; CPP, cerebral perfusion pressure; TCDB, Traumatic Coma Data Bank; CT, computed tomography.

Table 2.

Baseline Levels of Cerebral Microdialysis Biomarkers

	Propofol (n=15)	Midazolam (n=14)	p Value
Lactate:pyruvate ratio	53±38 (47)	57±53 (40)	0.844
Glucose, mmol/L	0.8±0.7 (0.6)	0.6±0.5 (0.6)	0.544
Glycerol, μmol/L	105±117 (77)	90±56 (82)	0.743
Glutamate, μmol/L	38±35 (33)	43±45 (27)	0.948

Data are expressed as mean±standard deviation (median).

Figure 1 shows the evolution over time of the L:P ratio, glutamate, glycerol, and glucose. No difference between propofol and midazolam was observed for the evolution of the L:P ratio during the 72-h follow-up period (time effect p=0.201, treatment effect p=0.401, time×treatment interaction p=0.101). Similarly, no significant difference was observed between the two groups for glutamate (time effect p=0.930, treatment effect p=0.651, time×treatment interaction p=0.353), glycerol (time effect p=0.223, treatment effect p=0.922, time×treatment interaction p=0.308), and glucose (time effect p=0.116, treatment effect p=0.088, time×treatment interaction p=0.235). Although not significant, mean cerebral glucose concentrations tended to be higher with propofol, ranging between +37% and +114% between 6 and 24 h after the start of treatment. During the study period, no difference was observed between the two groups for core body temperature, MAP, ICP, CPP, arterial oxygen and carbon dioxide tension, blood glucose, and catecholamine and mannitol use. Moreover, the number of patients who received barbiturates and/or decompressive surgery was no different between the two groups.

FIG. 1.

Changes seen over time for the cerebral lactate:pyruvate ratio, glutamate, glycerol, and glucose. Data are mean±standard deviation.

Eleven patients (n=7 for propofol, and n=4 for midazolam) died during their SICU stay (p=0.316). All but two died secondary to their brain trauma. One more patient died in hospital after SICU discharge in the midazolam group. One patient was lost to follow-up at 12 months in the propofol group. The GOS score at 12 months did not differ between the two groups (propofol group A=5 patients, B=2 patients; midazolam group A=6 patients, B=3 patients; p=1.000). Similarly, memory complaints at 12 months were no different between the two groups (9±11 in the propofol group, and 16±15 in the midazolam group; p=0.440).

Discussion

The main result of this study is that in severe TBI patients with a high L:P ratio, the variations in the extracellular L:P ratio were no different for the propofol and midazolam groups over a 72-h period. This trial is, to the best of our knowledge, the first to compare the effects of these sedative agents on cerebral biomarkers in TBI.

This prospective and comparative study was undertaken to detect a putative neuroprotective effect of propofol in severe TBI. Indeed, the protective effects of propofol have been reported in numerous in vitro and in vivo models, due to its effects on oxidative stress which are related to propofol's phenolic chemical structure, similar to that of vitamin E, which is a major natural free radical scavenger (Kobayashi et al., 2008; Nakahata et al., 2008; Tsuchiya et al., 2001, 2002).

Post-TBI increases in free radical generation have recently received considerable attention (Awasthi et al., 1997, Tyurin et al., 2000). Their proposed mechanisms include the arachidonic acid cascade, the increased leakage of superoxide from mitochondrial electron transport, enhanced activity of xanthine oxidase, auto-oxidation of catecholamines, activation of neutrophils, and breakdown of hemoglobin with release of iron (Awasthi et al., 1997). The brain contains a large amount of antioxidants. Lipophilic vitamin E acts at the cytoplasmic and membrane levels and is recycled by ascorbate (Li et al., 2003). Oxidative stress post-TBI may be synergistic or additive with glutamate excitotoxicity (Peters et al., 2001; Sitar et al., 1999; Velly et al., 2003). Under normal circumstances neurons are exposed to very brief pulses of glutamate, a major excitatory neurotransmitter. In TBI the interstitial compartment is at risk of glutamate flooding due to the inhibition of glutamate reuptake carriers by oxidative stress (Peters et al., 2001; Sitar et al., 1999; Velly et al., 2003). This leads to the destructive processes of the excitotoxic cascade, with excessive intracellular Ca²⁺-induced mitochondrial dysfunction and activation of pro-apoptotic mechanisms. Direct quantification of cerebral oxidative stress has been conducted in experimental and animal studies (Awasthi et al., 1997; Tyurin et al., 2000). However, it is assumed that cerebral microdialysis can be indirectly used to assess oxidative stress (Vespa et al., 2005), and in a recent study performed in TBI patients, a close relationship was demonstrated between a direct marker of oxidative stress and the routine microdialysis markers of the post-TBI metabolic crisis (Clausen et al., 2011).

A clear link exists between severe TBI and a high L:P ratio in extracellular cerebral fluid (Hutchinson et al., 2000; Kerr et al., 2003; Vespa et al., 2005). In recent years the hypoxia/ischemic insult was thought to be the cause. This hypoxia/ischemic insult takes place after brain herniation, a pre-terminal event with major metabolic failure in which a marked increase in the L:P ratio and a near-zero level of intracerebral glucose are present. But in more common types of head trauma such as those explored here, the elevation of the L:P ratio may have another explanation (Hlatky et al., 2004; Vespa et al., 2005). Indeed, it could be related to the mitochondrial alterations present after severe TBI, with causatives roles for oxidative stress and glutamate excitotoxicity. Consequently, the L:P ratio and extracellular glutamate kinetics appear to be relevant factors to use to compare the effects of propofol and midazolam on cerebral oxidative stress.

Our data do not support the view that cerebral oxidative stress would be better controlled with propofol than midazolam. The L:P ratio, a marker of mitochondrial dysfunction, as well as glutamate, demonstrated similar levels in the two sedation groups. Finally, with regard to the putative neuroprotective effect of propofol, the only biomarker that showed a positive effect was cerebral glucose. Extracellular brain glucose tended to be better preserved with propofol during the first 24 h. This could be indirect evidence of a lower exposure to glutamate with propofol.

The accuracy of glycerol as a microdialysis marker in TBI is a matter of debate. It is an end product of membrane phospholipid degradation, and favorable effects have been shown of antioxidant molecules on glycerol liberation after TBI (Hillered et al., 2005; Peerdeman et al., 2003). In our study, however, no difference between propofol and midazolam was observed for glycerol release. In addition to the absence of acute effects on biochemical markers, we did not find any differences between the two studied groups for GOS score and memory complaints at 1 year. Nevertheless, the number of patients analyzed was clearly too small to draw definitive conclusions about these outcomes.

Our study has several limitations. First, it was a single-blinded trial, but therapeutic goals and sedation levels were independent from microdialysis biomarkers, because the physicians were unaware of the biochemical values. Second, the ability of microdialysis to analyze these effects is obviously limited, and oxidative stress is predominantly present in areas with high neuronal content and O₂ demands. Thus we cannot exclude that a beneficial effect of propofol might be observed in these areas. The concentration of propofol used may have been insufficient to produce antioxidant effects; however, higher dosages are not recommended. Indeed, it is well known that propofol can induce propofol infusion syndrome in head trauma patients receiving the drug for prolonged periods (Smith et al., 2009). In our study, we used a level of sedation that did not induce EEG suppression, so the infusion rate was limited to 5 mg/kg.h⁻¹, as recommended. Third, a 30% reduction in the L:P ratio planned in our statistical methods may have been too large and negatively impact our results. Finally, it could be argued that midazolam possesses itself neuroprotective effects. Nevertheless, the antioxidant effect of midazolam is weak, and is largely inferior to that reported for propofol (Tsuchiya et al., 2001), although it has recently been shown that benzodiazepines may exert a mitochochondrial protective effect through other mechanisms. In consequence, they may interfere with the biomarkers we have chosen to study (Sarnowska et al., 2009; Tanabe et al., 2011).

In conclusion, our results indicate that there is no difference between the effects of propofol and midazolam sedation on the cerebral metabolic profile during the acute phase of severe TBI. Accordingly, the use of propofol as a sedative agent in TBI and its neuroprotective effects warrant further investigation.

Footnotes

Acknowledgments

The study was supported by a grant from Programme Hospitalier de Recherche Clinique (PHRC) of Rennes, October 2005 (R0903).

Author Disclosure Statement

No competing financial interests exist.

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