Multicenter evaluation of propofol for head-injured patients in Taiwan

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Trauma

Multicenter evaluation of propofol for head-injured patients in Taiwan

Wen-Ta Chiu, MD, PhD

a

, Tien-Jen Lin, MD

a

, Jia-Wei Lin, MD

a

, Sheng-Jean Huang, MD

b

,

Cheng-Kuei Chang, MD, PhD

c

, Hsiang-Yin Chen, PharmD

d,

4

a

Department of Neurosurgery, Taipei Medical University-Wanfang Hospital, Taipei Medical University, Taipei 116, Taiwan

b_{Department of Neurosurgery, National Taiwan University Hospital, Taipei 100, Taiwan} c_{Department of Surgery, Division of Neurosurgery, Mackay Memorial Hospital, Taipei 104, Taiwan}

d_{Department of Pharmacy, Taipei Medical University-Wanfang Hospital and School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan}

Received 12 April 2006; accepted 21 August 2006

Abstract Background: The present study was a multicenter, retrospective study which aimed to evaluate the efficacy of propofol, a new choice of pharmacotherapy in head-injured patients.

Methods: Head-injured patients admitted to 3 hospitals during the period from January 2003 to December 2004 were included in this clinical trial. Data on patients’ demographics, laboratory data, GCS score, ICP, CPP, concurrent medications, and therapeutic outcomes were collected.

Results: Among the 104 patients included, only 44 were given propofol. The average age was 40.8 F 22 years for all patients, with 41.91 F 20.41 and 43.48 F 23.19 years for the propofol group and nonpropofol group, respectively ( P = .097). There was no significant difference in baseline GCS score between the 2 groups (5.86 F 1.84 vs 5.66 F 1.59, P = .729). Mean ICP for the first 3 days in the ICU was 17.23 F 9.0 mm Hg in the propofol group and 33.19 F 32.56 in the nonpropofol group, respectively ( P = .017). Mean CPP for the first 5 days in the ICU was 71.10 F 15.32 mm Hg in the propofol group and 43.20 F 29.92 mm Hg in the nonpropofol group ( P b .001). A higher survival rate was found in the propofol group (81.8% vs 46.7%, P b .001).

Conclusions: The present study demonstrated that propofol improved the outcome in recovery phase of head-injured patients.

Keywords: Propofol; Head injury; Head trauma; Intracranial pressure; Sedatives

1. Introduction

Evidences on the use of sedatives in the management of head-injured patients have increased in recent years. The Guidelines for the Management of Severe Head Injury have proposed new, evidence-based treatment recommendations to reduce the mortality and morbidity of head injury. Use of sedatives, as well as careful control of ICP, maintenance of CPP, and use of hyperventilation and vasopressors,

has been proposed as mainstay therapies[8]. A paper from the Society of Critical Care Medicine [38] also provided valuable guidelines on the sustained use of sedatives and analgesic agents in critically ill adults. However, there have been few studies that directly compared the effec-tiveness and adverse effects of different agents in the head-injured population. Determining the drug of choice for sedation in this group of patients warrants new studies to provide evidence.

The idea that sedatives provide advantages to the head-injured patients is based on several reasons. The general purposes of using sedatives in the ICU are to provide amnesia, hypnosis, and pain-free condition, as well as to relieve agitation and anxiety[3,8,21,37]. These agents may additionally decrease cerebral metabolism and raise ICP in head-injured patients [21]. It is suggested that an ICP greater than 20 mm Hg is a serious threat to initiate the

Abbreviations: CBF, cerebral blood flow; CMRo2, cerebral metabolic

rate for oxygen; CPP, cerebral perfusion pressure; CSF, cerebral spinal fluid; CT, computed tomography; GCS, Glasgow Coma Scale; ICP, intracranial pressure; ICU, intensive care unit; MAP, mean arterial pressure; Paco2, arterial carbon dioxide partial pressure.

4 Corresponding author. Tel.: +886 2 29307930x1157; fax: +886 2 8662 1163.

E-mail address: [email protected] (H.-Y. Chen).

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therapy, including sedatives, mannitol, diuretics, or hyper-ventilation [12,24,31,33,35,37]. Sedation also further ena-bles the manipulation of respiration, which is essential in the treatment of increased ICP [13,22]. The requirements for bidealQ sedatives are not only to put head-injured patients in a stable and peaceful phase, but also to improve the clinically important data. Thus, careful consideration is necessary to select the best regimen.

Sedation regimens for head-injured patients are quite variable [31]. Agents used in these patients include benzodiazepines, barbiturates, narcotics, and propofol. Among the above sedatives, barbiturates are recommended by the Guidelines for the Management of Severe Head Injury

[8]. However, a recent meta-analysis[32]found no evidence that barbiturate therapy in head-injured patients could improve the ultimate outcome. Thus, it is important to compare the data from other agents to determine a more ideal sedative agent than barbiturates for head-injured patients.

Propofol, a short-acting sedative-anesthetic agent which is structurally a phenolic derivative with high lipophilicity, has recently been used in head-trauma patients with increasing frequency [30]. The drug is known to induce sleep and reduce brain metabolism and CBF[23]. Propofol is fitted into a 3-compartmental pharmacokinetic model

[1,4]. Its relative short half-life allows inducing the patients into conscious sedation quickly and also arousing them quickly so that one can perform intermittent neurologic examination[3]. Because of its unique pharmacokinetic and pharmacodynamic characteristics, propofol is used in head-injured patients [15]. It also provides neuroprotection through GABA inhibition [16]. In noncomparative studies in patients with head injury, propofol has been shown to maintain a mean CPP higher than 60 mm Hg and to reduce or maintain mean ICP [3,14,30]. Use of propofol in head injury patients should be further evaluated to understand its efficacy and safety.

The objective of the present multicenter, retrospective study was to evaluate the efficacy of propofol on the survival rates in treating severe head-trauma patients in Taiwan.

2. Materials and methods

2.1. Patient population and data collection

From January 2003 to December 2004, patients who sustained traumatic head injury and were admitted to Taipei Municipal Wan Fang Hospital, National Taiwan University Hospital, and Tamshui Mackay Memorial Hospital were included in this clinical trial. Patients were selected according to the following criteria: age of more than 12 years and less than 79 years; traumatic brain injury with a post resuscitation GCS score of 3 to 13; and requirement for mechanical ventilation. Patients were excluded if treated with other sedative agents at the same time; had poor prognosis and thus aggressive treatment, except support-ive care, was not begun within 48 hours of injury, or if

propofol was not administered for a minimum of 12 hours; had spinal cord injury with paraplegia or quadriplegia, or fixed dilated pupils with a GCS score of less than 3 after initial resuscitation. The severity of head injury for the patients was classified by GCS score according to the following definitions: moderate severity, if the patients have a GCS score of between 9 and 13; severe, if GCS score is between 5 and 8; and critical, if GCS score is between 3 and 4[33].

The collected variables included age, sex, body weight, clinical symptoms, surgical date, admission date, GCS score at admission, diagnosis, complications, date of surgery, ICU length of stay, therapeutic outcome (discharge or death), and date of discharge. Clinical data collected were mean daily ICP, mean daily CPP, mean daily Paco2, mean daily fluid

balance. The required daily doses for mannitol, sedative agents, vasopressors, neuromuscular blockage agents, sys-tolic and diassys-tolic blood pressure, heart rate, respiratory rate, and body temperature were monitored and recorded. Intracranial pressure was continuously monitored and recorded every hour, and CPP was recorded every 4 hours in the ICU. Safety data were also collected. Any docu-mented severe adverse drug reaction had been included into the data collection form.

2.2. Treatment protocol

The stepwise management protocol to control ICP and CPP included CSF drainage and administration of mannitol, vasopressors, and sedatives. Drainage of CSF can reduce the volume in the cranium and promote better blood flow. Use of sedatives, including propofol, was depended on the clinical evaluation of neurosurgeons according to the clinical condition of the critical patients. The dose of propofol was initiated at 5 lg/kg per minute for 5 minutes and slowly titrated up to 100 to 150 lg/kg per minute at a rate of 12.5 lg/kg per minute every 5 minutes. The dose was increased as needed for agitation or if ICP levels persisted above 20 mm Hg. The depth of sedation targeted Ramsey Sedation Scale of 4, allowing the patient with brisk response to light glabellar tap or loud noise. Propofol was temperately discontinued to exam the muscle strength to reach grade of 3 every day. Propofol was used for at least 3 days and discontinued once the patient was extubated. Mannitol 2.5 to 5.0 g/kg was administered every 2 to 3 hours as needed to maintain an ICP of less than 20 mm Hg in all the medical centers. To keep effective CPP higher than 60 mm Hg, vasopressors were given if systolic blood pressure dropped to less than 100 mm Hg or CPP to less than 60 mm Hg. Pentobarbital, the sedative of choice among barbiturates, as well as other barbiturates, was discouraged for use in all centers in this study.

2.3. Drug administration

The sedatives used in all the hospitals were propofol (DiprivanR, containing propofol, 200 mg/20 mL per amp; Astra Zeneca Co Ltd). The vasopressors used in the trial

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included dopamine (DopminR, containing dopamine HCl 200 mg/5 mL per amp; Synmosa Biopharma Co Ltd, Taiwan), norepinephrine (LevophedR, containing norepi-nephrine bitartrate 4 mg/4 mL per amp; Abbott Laboratories Services Corp, Taiwan Branch), and epinephrine (BosminR, containing epinephrine HCl 1 mg/1 mL per amp; Daiichi Pharmaceutical Taiwan Ltd). The neuromuscular blockage agents were atracurium (TracriumR, containing atracurium besylate 25 mg/2.5 mL per amp; Glaxo Operations UK Ltd, Taiwan), pancuronium (PavulonR, containing pancuronium bromide 8 mg/2 mL per amp; Organon-Taiwan), and vec-uronium (NocuronR, containing vecvec-uronium 10 mg per amp; Organon-Taiwan).

2.4. Statistic analysis

All statistical analyses were performed using the SPSS software (version 10.0, SPSS Inc, Chicago, Ill). Statistical significance for all analyses was defined as a P value of less than .05. Quantitative variables were compared by using the independent t test, if they were normally distributed, or the Mann-Whitney U test, if they were not. Qualitative variables were compared by using the v2 test or Fisher exact test.

3. Results 3.1. Subjects

From January 1, 2004, to December 31, 2004, 151 head-injured patients were admitted to the 3 medical centers mentioned above. Of the 151 patients, 24 were excluded because their age was either less than 12 years (3 patients) or more than 79 years (21 patients). Of the remaining 127 patients, 23 patients were excluded from the present study according to the exclusion criteria. The data of the remaining 104 patients were therefore analyzed.

Baseline and interventional physiologic data are shown inTable 1. Of the 104 subjects, 71 were males and 33 were females. The mean age was 40.8 F 22 years and the median GCS score was 6 (range, 3-10) on admission. Among the

104 patients who met the inclusion criteria, only 44 were given propofol. The mean age was 41.91 F 20.41 years for the propofol group and 43.48 F 23.19 years for the nonpropofol group ( P = .097). The 2 groups did not differ significantly in age, body weight, and sex. The mean GCS scores for the 2 groups were not statistically different, and the median GCS scores at admission were 6 in both groups. The proportion of patients with a GCS score of 3 to 8 was 93.18% in the propofol group and 95% in the nonpropofol group ( P = .729).

3.2. Outcome

A higher survival rate was found in the propofol group than in the nonpropofol group (81.82% vs 46.67%, P b .001) as shown in Table 2. There was a statistically significant difference in the mean ICP for the first 3 days in the ICU (propofol vs nonpropofol group: 17.23 F 9.0 vs 33.19 F 32.56 mm Hg, P = .017, respectively). Intracranial pressure was also significantly different between the 2 groups on day 1 ( P = .009), day 2 ( P = .003), and day 3 ( P = .043) as shown in Table 3. Mean CPP for the first 5 days in the ICU was 71.10 F 15.32 mm Hg in the propofol group and 43.20 F 29.92 mm Hg in the nonpropofol group, respectively ( P b .001). The mean daily Paco2was similar

between the propofol group (30.78 F 4.07 mm Hg) and the nonpropofol group (32.00 F 6.20 mm Hg) ( P = .288). The mean GCS score within 5 days in the propofol group was significantly lower than that in the nonpropofol group (7.14 F 2.62 vs 5.66 F 2.76, P = .007), with smaller proportion of patients with a GCS score of 3 to 8 in the propofol group than in the nonpropofol group after 5 days of

Table 1 Demographics Propofol group (n = 44) Nonpropofol group (n = 60) P4 Sex Male, n (%) 31 (70.75) 40 (66.67) .832 Female, n (%) 13 (29.55) 20 (33.33) Age 41.91 F 20.41 43.48 F 23.19 .097 12-19 y, n (%) 8 (18.18) 10 (16.67) 20-39 y, n (%) 13 (29.55) 20 (33.33) 40-64 y, n (%) 13 (29.55) 11 (18.33) .811 65-79 y, n (%) 10 (22.72) 19 (31.67) Body weight (kg) 66.66 F 15.47 64.64 F 12.65 .963 Baseline GCS score4 5.86 F 1.84 5.66 F 1.59 .729

4 Statistical test by v2test ( P b .05).

Table 2

Outcomes of patients in the propofol and nonpropofol groups Propofol group (n = 44) Nonpropofol group (n = 60) P Survival rate, n (%) 36 (81.82) 28 (46.67) b .001a Mean ICP

for the first 3 d (mm Hg) 17.23 F 9.0 33.19 F 32.56 .017b Day 1 15.71 F 10.33 31.43 F 26.60 .009b Day 2 17.77 F 9.06 43.38 F 39.35 .003b Day 3 19.67 F 10.52 39.71 F 42.91 .043b Mean CPP for the first 5 d (mm Hg) 71.10 F 15.32 43.20 F 29.92 b .001b Mean GCS in the first 5 d 7.1 F 2.6 5.7 F 2.8 .007b Day 1 6.5 F 1.7 5.7 F 2.3 .041b Day 2 7.1 F 2.7 5.7 F 2.6 .013b Day 3 7.3 F 3.4 5.9 F 3.1 .026b Day 4 7.9 F 3.6 6.2 F 3.5 .027b Day 5 8.1 F 3.7 6.1 F 3.5 .027b Mean Paco2

for the first 5 d (mm Hg)

23.15 F 8.12 24.71 F 8.34 .350

a _{Statistically significant by v}2

test ( P b .05).

b

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treatment (13.5% vs 18.5%). No significant adverse drug reaction has been collected from the medical charts. 3.3. Drug administration

The mean daily dose of propofol was 1430.48 mg/d in patients of the propofol group. Vasopressors were required in 45 patients, including 12 patients (26.67%) in the propofol group and 33 patients (73.33%) in the nonpropofol group ( P b .001). The most commonly used vasopressors in the trial were dopamine and norepinephrine. Among the 45 patients using dopamine, mean dose of dopamine was statistically higher in the propofol group than in the nonpropofol group, which was 333.28 F 318.25 mg/d and 666.40 F 362.53 mg/d in the propofol and nonpropofol group, respectively ( P = .026). Mean doses of norepineph-rine were similar in the 2 groups (13.83 F 22.41 mg/d in the propofol group vs 20.28 F 14.79 mg/d in the nonpropofol group, P = .508). There were 101 patients given mannitol, including 44 (100%) in the propofol group and 57 (93.47%) in the nonpropofol group, respectively ( P = .138). 3.4. Subgroup analysis—mortality rates in injury categories

Patients were further categorized into critical (baseline GCS score of 3-4; 28 patients), severe (baseline GCS score of 5-8; 70 patients), or moderate (baseline GCS score of 9 to 13; 6 patients) subgroups based on the baseline GCS score. The mortality rate was associated with the severity of the injury of the patients, with a value of 46.43% in the critical group, 37.14% in the severe group, and 16.67% in the moderate group (Fig. 1).

The mortality rates for patients with or without propofol in the 3 subgroups are shown in Table 3. Patients using

propofol had significantly lower mortality rates than patients not using propofol in the critical subgroup ( P = .022) and severe subgroup ( P = .005). There was no difference for patients with or without propofol treatment for the moderate subgroup.

4. Discussion

The data of the present study demonstrated that the head-injured patients in Taiwan treated with propofol had a higher survival rate, decreased ICP, higher CPP, and better GCS scores. The 2 groups with or without administration of propofol did not differ in the treatment of mannitol. The percentage of patients requiring vasopressors in the propofol group was lower than that in the nonpropofol group ( P b .001). As vasopressors were administered to keep effective CPP above 60 mm Hg, the higher rate of administration indicated more unstable hemodynamics in the nonpropofol group than in the propofol group. The data showed that propofol has effectively decreased ICP to less than 20 mm Hg and maintained CPP above 70 mm Hg in the propofol group, which reached the suggested targets endorsed by current guidelines to improve the survival rate in head-injured patients.

A limitation of the present study is the nature of retrospective study. The baseline standard care might not be the same in all patients. As the criteria to give skeletal muscular blockade agents and vasopressors were the same for all surgeons in the 3 centers, the impact of the major confounding factors on the results was limited. Retrospec-tive data collection reduced the reporting rate of adverse drug reactions, as minor adverse reactions might not have been documented. The study was also limited by the nature of retrospective review which was unable to give a standard interpretation of CT data and to collect the data of postinjury assessment at 6 months or 1 year. More outcome variables need to be measured in further studies.

The efficacy of different sedatives used in head-injured patient has been investigated in few studies. The effects of barbiturates in severe head injury are controversial. Some studies showed that the use of barbiturates improved ICP control and outcomes [24,25], but this effect was not significant in a recent meta-analysis[32]. Pentobarbital has an average half-life of 15.6 hours in head-injury patients[7]

and often produces withdrawal symptoms, including

Table 3

Mortality rate for each injury category

Injury categories Propofol group (n = 44) Nonpropofol group (n = 60) P

n Mortality (%) n Mortality (%)

Critical 12 2 (16.67) 16 11 (68.75) .0224

Severe 29 5 (17.24) 41 21 (51.22) .0054

Moderate 3 1 (33.33) 3 0 (0) .64

Total 44 8 (18.18) 60 32 (53.33) b .0014

4 Statistically significant by v2test ( P b .05).

Fig. 1. The relationship between mortality rate and injury category.a_Injury

categories: critical, if GCS score was between 3 and 4; severe, if GCS score was between 5 and 8; and moderate, if GCS was between 9 and 13.

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delirium, convulsions, and possibly death, and tolerance, psychological, and physical dependence after continued use. It is also recommended to monitor blood pentobarbital concentrations frequently and regularly to adapt the dose to changes in clearance and thus increase the inconvenience of administration.

The efficacy of benzodiazepams in head-injured patients has been assessed by previous studies. Studies comparing propofol with midazolam showed that both agents equally reach the desired level of sedation and hemodynamics, but the propofol group woke up faster after discontinuation

[34,36]. Although midazolam reliably reduces CMRo2and

CBF, an increase in ICP was reported when control ICP was less than 18 mm Hg[29]. Midazolam is metabolized by the liver to its active a-hydroxy-midazolam (1-OH-midazolam [1-OH-M]), which may accumulate in patients with renal failure. It also interacts with many drugs undergoing CYP3A4 metabolism in clinically significant level[6]. For long-term sedation in the ICU, propofol has the same safety and effectiveness, but better cost-benefit ratio and quality of sedation than midazolam [5,9,10,34]. A study compared lorazepam, midazolam, and propofol in critically ill trauma patients, showed that the 3 agents provided equal efficacy on sedation. Lorazepam, although more cost-effective, caused oversedation more commonly than the 2 other agents[22].

Narcotics such as morphine, fentanyl, and sulfentanil have no effect on CMRo2 or CBF but increased ICP in

some patients [2,14,19]. The short-acting neuroprotectant etomidate is not suited for prolonged use due to its renal toxicity and adrenal suppression[20,39]. In a randomized, double-blind trial with moderately or severely head-injured patients, ICP and CPP were generally similar in groups treated with propofol or morphine [17]. Less intensive therapy for ICP control and similar long-term neurologic outcomes were obtained in the propofol group than in the morphine group.

Compared with other sedatives, several properties of propofol make it an attractive choice for head-injured patients. Propofol has no significant drug interactions or metabolites and does not require drug concentration monitoring. Its short onset of action and elimination of half-life permit frequent neurological assessments [1,4,24]. The effect of propofol on CBF, cerebral metabolism, and ICP reduction has been reliably proved in a number of studies[30].

The use of propofol is limited by some side effects in head-injured patients. The most common adverse effects associated with propofol include hypotension, hypertrigly-ceridemia, infusion syndrome, increased liver function tests, and even rhabdomyolysis [11,22,26,36,39]. Other adverse effects associated with propofol include respiratory acidosis during weaning from the ventilator, green discoloration of the urine, and rare occurrence of anaphylactic reactions

[18,39]. Hypertriglyceridemia is due to the fat emulsion formulation of propofol and is actually counterbalanced by

providing more energy source for patients under physical distress. In relatively high doses, infusion syndrome can occur and lead to mortality[18,26]. It has been discouraged to infuse propofol at rates higher than 5 mg/kg per hour in the ICU [11]. Dose-related side effects should be closely monitored and can be avoided by using appropriate titration method of administration.

Racial difference in the dose-response relationship of propofol has been discussed in the literature. Previous studies have found that there was a statistically significant difference between Caucasians and African Blacks in the arousal time from intravenous anesthesia with propofol[27]. The ratio recovery time based on the consumption of propofol was significantly lower in whites than in all the other groups [28]. The present study provides additional evidence on the use of propofol to treat head-injured patients in Taiwanese. With the profile of severe side effects, a distinct regimen of propofol use should be investigated in more detail in the future to avoid unwanted side effects in head-injured patients in Taiwan.

The data of the current study demonstrated that propofol improved the recovery phase in patients with head injury. Propofol decreased ICP to less than 20 mm Hg and main-tained CPP above 70 mm Hg. The survival rate in the propofol group was significantly higher than that in the nonpropofol group. Propofol can be suggested for use in the treatment of head-injured patients because of the beneficial clinical outcomes and unique pharmacokinetic/ pharmacodynamic characteristics. Further studies are need-ed to establish the best protocol for using propofol in head-injury patients.

Acknowledgments

The authors are grateful for the suggestions from the National Science Council, Taiwan (NSC-93-2314-B038-053, NHRI-EX94-9106PN), and the Department of Health Center of Excellence for Clinical Trial and Research (DOH94-td-b111-002) in Selected Specialty.

The authors also thank Drs Tzu-Yung Chan, Weng-Yuh Chung, Ming-Fu Chiang, Yung-Hsiao Chiung, Chih-Peng We, and Hsin-Yuan Chen for their efforts in completing this work.

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