Anesth Analg 2004;99:1193-1198
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000132546.79769.91
CRITICAL CARE AND TRAUMA
Jukka Takala Section Editor
The Effects of Remifentanil on Endotracheal Suctioning-Induced Increases in Intracranial Pressure in Head-Injured Patients
Marc Leone, MD*,
Jacques Albanèse, MD*,
Xavier Viviand, MD*,
Franck Garnier, MD*,
Aurelie Bourgoin, MD*,
Karine Barrau, MD
, and
Claude Martin, MD*
*Intensive Care Unit and Department of Anesthesiology and the
Department of Biostatistics and Epidemiology, Nord Hospital, Marseilles University Hospital System (AP-HM), Marseilles School of Medicine, Marseilles, France
Address correspondence to Marc Leone, MD, Department of Anesthesiology and Critical Care, Washington University School of Medicine, Box 8054, 660 S Euclid Ave, Saint Louis, MO 63110. Address email to leonem{at}msnotes.wustl.edu
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Abstract
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In patients with severe traumatic brain injury, bronchotracheal toilet may be accompanied by deleterious variations in intracranial pressure (ICP). To avoid these effects, IV opioids have been proposed. Twenty mechanically-ventilated patients received 3 ascending IV doses of remifentanil: dose 1 (1 µg/kg bolus, 0.25 µg/kg/min infusion); dose 2 (2 µg/kg bolus, 0.5 µg/kg/min infusion); and dose 3: (4 µg/kg bolus, 1 µg/kg/min infusion). Endotracheal suction was performed 20 min after the beginning of infusion to assess coughing. Heart rate, ICP, mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), middle cerebral artery mean flow velocity (VMCA), and bispectral index were monitored throughout the 30-min study period. Twelve, 15, and 19 patients receiving dose 1, 2, and 3, respectively, required vasopressors to maintain CPP >60 mm Hg. Suctioning resulted in coughing in 16, 15, and 5 patients receiving dose 1, 2, and 3, respectively. An increase in ICP, without change in VMCA, corresponded to the reduction in MAP consistent with the preservation of autoregulation. Remifentanil used as a continuous infusion in head-injured patients is not an effective drug to block responses to suctioning.
IMPLICATIONS: Remifentanil bolus in severe head trauma patients in the intensive care unit induces an increase in intracranial pressure related to a decrease in mean arterial blood pressure, suggesting the preservation of autoregulation. Only large doses of this opioid requiring hemodynamic support can block coughing induced by an endotracheal suction.
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Introduction
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Maintenance of cerebrovascular stability during the daily care of severe head trauma is of the highest importance, especially during the initial phase of treatment. Bronchotracheal toilet with endotracheal suction may be accompanied by deleterious variations in mean arterial blood pressure (MAP), intracranial pressure (ICP), and cerebral perfusion pressure (CPP) (1,2). To avoid these adverse events, opioids have been proposed (3,4). Remifentanil (Ultiva®, GlaxoSmithKline, Research Triangle Park, NC) is a mu-opioid agonist with a rapid onset of action and a half-life of 3 to 5 min independent of dose or administration duration (5), allowing frequent neurological examinations in a neurosurgical intensive care unit (ICU) (4). In patients undergoing supratentorial craniotomy, remifentanil does not cause a significant increase in ICP, and its profile is similar to that of alfentanil (6). Small dose remifentanil increased regional blood flow and decreased regional cerebrovascular resistance (7). Large dose remifentanil reduced cerebral blood flow velocity unrelated to any changes in systemic hemodynamics in patients undergoing cardiac surgery (8). However, the effect of remifentanil on cerebral hemodynamics of severely traumatic brain-injured patients has not been systematically investigated. As indicated by a collection of case reports, the pharmacokinetics of this drug are of interest for providing analgesia during short duration procedures in ICU patients with brain injury (4). Investigation is required to assess the efficacy of an infusion of remifentanil to block pain responses in such patients and to evaluate its impact on cerebral hemodynamics.
The primary objective of this study was to assess the effects of remifentanil on the cerebral hemodynamics of severe head trauma patients. The secondary objectives were to compare the effect on cerebral hemodynamics of three incremental doses during bolus and continuous infusion by performing endotracheal suction and to determine the concentration at which 50% of the cough responses in these patients was blunted.
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Methods
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After approval by the Ethics Committee of our institution, informed written consent was obtained from patients’ next of kin. Inclusion criteria were: severe closed-head injury (Glasgow Coma Scale score of 
8 and ICP monitoring), age older than 18 yr, and hemodynamic status stable (ICP was <25 mm Hg for 4 h and CPP >70 mm Hg for 24 h or more without any sedation consisting of a combination of midazolam and sufentanil).
Heart rate, arterial hemoglobin oxygen saturation (SpO2), end-tidal CO2 (PETCO2), and invasive MAP were continuously monitored (model 66; Hewlett-Packard, Waltham, MA). ICP was continuously monitored with a Camino Catheter System (OLM Intracranial Pressure Monitoring Kit; Camino Laboratories, San Diego, CA). A 2-MHz pulsed Doppler ultrasound device (Angiodine 2; DMS, Montpellier, France) was used to measure erythrocyte flow velocity. After identification of the right anterior cerebral artery and middle cerebral artery, the depth was adjusted by 2-mm increments to obtain signals from the proximal (M1) segment of the middle cerebral artery. The electroencephalogram (EEG) was recorded continuously using an Aspect A-1000 EEG monitor (version 3.12; Aspect Medical Systems, Newton, MA), which also computed the bispectral index (BIS) in real time. Silver/silver chloride pregelled electrodes (électrodes de diagnostic, 3MTM Red DotTM 2360, Pithiviers, France) were applied to the left and right frontal (Fp1 and Fp2) regions and referenced to a vertex electrode (CZ). Electrode impedance was maintained <5 k
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Remifentanil boluses and continuous infusions were administered by using a syringe pump (Pilote C; Fresenius, Grenoble, France). After a 5-min baseline measurement, the first IV dose (bolus dose of remifentanil 1 µg/kg over 60-s followed by a continuous infusion 0.25 µg · kg–1 · min–1, dose 1) was administered within a 30-min period. Heart rate, MAP, ICP, CPP, SpO2, PETCO2, middle cerebral artery mean flow velocity (VMCA), and BIS were recorded at 60-s intervals throughout each 30-min study period. After a stepwise order, a second dose was given as follows: bolus dose of remifentanil 2 µg/kg followed by a continuous infusion 0.5 µg · kg–1 · min–1 (dose 2). Next, a third bolus dose of remifentanil 4 µg/kg followed by a continuous infusion of 1 µg/kg/min was given (dose 3). A 60-min washout period was required between each set of measurements. Figure 1 summarizes the protocol design.
Ephedrine (9-mg repeated boluses in case of CPP decrease <20%) or norepinephrine (continuous infusion in case of CPP decrease >20%) were given to maintain CPP > 60 mm Hg. Ventilation (tidal volume or respiratory rate) was adjusted to maintain PETCO2 between 33 and 37 mm Hg. Heart rate and MAP, corrected by catecholamines, were used to evaluate systemic hemodynamics.
The endotracheal suction protocol was performed 20-min after bolus administration with increase of FIO2 to 100% for 60 s and insertion of a standardized suction catheter by the side port of the endotracheal tube for <30 s. The study was performed with patients in the supine position without saline instillation or head rotation. During the endotracheal suction, ventilatory mode and remifentanil infusion were unchanged and no further sedative or muscle relaxation drugs were given. The presence of coughing was recorded as failure. The same research nurse who was blind to the dose analyzed all responses. The period t14min–t19min was considered as the baseline value for the analysis of endotracheal suction effects.
Rescue treatment: ICP >25 mm Hg or CPP <70 mm Hg were managed sequentially as follows:
- a) hemodynamic stabilization using catecholamines to achieve a CPP >60 mm Hg;
- b) elevation of the head to a maximum of 30°;
- c) sedation with analgesic medication (sufentanil and midazolam);
- d) controlled hyperventilation (PaCO2: 32–35 mm Hg);
- e) osmotherapy with mannitol (0.25–1 g/kg IV) or 23.4% saline (30 mL IV in 20 min); and
- f) thiopental or propofol given until burst suppression EEG.
We performed separate analysis of the bolus (from t0 to t15 min) and endotracheal suction (from t19 to t30 min) periods, using repeated measurements of each variable. Data were analyzed by response feature analysis based on the calculation of the area under the curve for each patient (9). The areas under curves were assessed by the trapezoidal method and compared using Student’s paired t-test. A Bonferroni correction was applied when required to maintain the family-wise error rate in case of multiple comparisons. Qualitative data were compared using a 
2 test.
The dose response for coughing during tracheal aspiration was modeled by logistic regression with robust estimate variance estimates to take into account the repeated observations on individuals. The confidence interval for the dose required to obtain lack of cough in 50% of patients (DE50) was calculated with the formula proposed by Armitage et al. (10). To determine the concentrations at which 50% (EC50) and 90% (EC90) of the maximal effect were achieved, we performed a logistic regression from the theoretical concentrations of remifentanil using the pharmacokinetics model of Minto et al. (11). We used Stata (version 8.0, Stata Corp., College Station, TX) for statistical analysis. Results are expressed as mean ± SEM; P < 0.05 was considered statistically significant.
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Results
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The characteristics of the included patient population (16 males, 4 females) are shown in Table 1. The intracranial injuries included multiple contusions (12 patients), subarachnoid hemorrhage (5 patients), a subdural hematoma (3 patients), epidural hematoma (1 patient), and unilateral contusion (4 patients). Brain swelling defined by the absence of basal cisterns on computed tomography scan, was observed in 11 patients. No significant intra- or intergroup changes in PETCO2 (34 ± 2 mm Hg) or SpO2 (98% ± 2%) were observed during the procedure. The patients receiving dose 1 required vasopressor treatment in 12 cases: ephedrine 12 ± 8 mg in 8 cases and norepinephrine 0.010 ± 0.005 µg · kg–1 · min–1 in 4 cases. For dose 2, a vasopressor was needed in 15 cases: ephedrine 10 ± 14 mg in 4 cases and norepinephrine 0.05 ± 0.01 µg · kg–1 · min–1 in 11 cases. The patients receiving dose 3 required a vasopressor in 19 cases: ephedrine 16 mg (1 case) and norepinephrine 0.10 ± 0.02 µg · kg–1 · min–1 (18 cases). The difference was statistically significant between patients receiving doses 1 and 2 (P = 0.01) and patients receiving doses 1 and 3 (P = 0.001). No difference was observed between doses 2 and 3 (P = 0.1) (Fig. 2).
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Figure 2. Catecholamine requirement during remifentanil infusion. Results are expressed as percentage of patients (n = number of patients).
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Sixteen of 20 patients coughed in response to suctioning after receiving the smallest dose. When the second dose was administered, cough reflex was absent in 5 (25%) patients. No cough response was obtained in 15 (75%) patients when they received the third dose. The EC50 and EC90 were 17.1 ng/mL [95% confidence interval, 10.35–23.83] and 41.5 ng/mL [95% confidence interval, 34.75–48.25], respectively.
After the bolus, heart rate decreased across all three doses compared with baseline. A significant decrease was observed for patients receiving dose 3, compared with doses 1 and 2 (Fig. 3A). The decrease in MAP was significant in the three groups (Fig. 3B). ICP increased significantly to reach a maximal level of 22 ± 9 mm Hg, 19 ± 7 mm Hg, and 19 ± 8 mm Hg for doses 1, 2, and 3, respectively (Fig. 3C). CPP was decreased in patients receiving the three doses compared with baseline but no difference was observed among the doses (Fig. 3D). The minimum values reached were 61 ± 19 mm Hg, 59 ± 19 mm Hg, and 63 ± 19 mm Hg for doses 1, 2, and 3, respectively. No significant change in VMCA from baseline was observed (Fig. 3E). The effect on BIS was not significant for patients receiving dose 1, whereas a significant decrease was observed for doses 2 and 3, with no significant difference between these two doses (Fig. 3F).
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Figure 3. Changes in key variables in response to boluses, continuous infusion of remifentanil. An endotracheal suction (arrow) was performed 20 min after the beginning of infusion. (HR: Heart rate; MAP: mean arterial blood pressure; ICP: intracranial pressure; CPP: cerebral perfusion pressure; VMCA: middle cerebral artery flow velocity; BIS: bispectral index). Baseline value for bolus analysis: collection of data 5 min before starting remifentanil bolus. Baseline value for endotracheal suction analysis: collection of data during 5 min before performing the procedure. The results are represented as mean ±  (SEM). *P < 0.05 compared with baseline for the three doses; **P < 0.05 compared with baseline for dose 2 and 3.
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Heart rate, MAP, CPP, and VMCA did not differ significantly from baseline during the endotracheal suction, and no significant difference was observed among the three doses (Fig. 3). ICP increased significantly from baseline with no intergroup significant difference. Maximal ICP values were 22 ± 7 mm Hg, 22 ± 9 mm Hg, and 20 ± 8 mm Hg for doses 1, 2, and 3, respectively (Fig. 3C). The BIS did not differ from baseline for dose 1, whereas it was increased significantly for doses 2 and 3 (Fig. 3F).
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Discussion
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The present study shows that remifentanil used in patients with severe traumatic brain injury reduces the cough reflex in a dose-dependent manner. An increase in ICP occurred in all three groups, probably as a result of the reduction in MAP, which suggests that autoregulation was not impaired. In our study, for ethical reasons, the endotracheal suction was always performed under some degree of remifentanil-induced sedation. We have no data to indicate if coughing by itself (without pharmacological intervention) could result in any significant ICP increases. However, in a previous study, endotracheal suction performed in patients with brain injuries without any medication resulted in a 22 ± 3 mm Hg increase in ICP with intense coughing (3). Similar findings have been observed in other studies investigating patients with brain injury (12,13). The use of small dose remifentanil probably reduced the increase in ICP after endotracheal suction in the present study.
The effects of remifentanil on hemodynamics have been extensively evaluated. In dogs, a bolus more than 0.3 ng/kg produced dose-dependant decreases in heart rate and MAP (14). The infusion of remifentanil (1 µg/kg bolus plus 0.5 µg · kg–1 · min–1 infusion), in combination with propofol, was associated with hypotension in 10% to 30% of healthy patients (15). An experimental study performed in neuraxis intact and baro-denervated rabbits showed that remifentanil decreases MAP and heart rate by its vagotonic effect and by stimulating peripheral mu-opioid receptors. These effects were counteracted by its central sympathotonic effect and by maintaining baroreflex integrity (16). Remifentanil depressed autonomic responses to stress (17). In surgical patients undergoing laparoscopic fundoplication, a 0.39 µg · kg–1 · min–1 infusion of remifentanil depressed the epinephrine response to surgery (18). There is direct evidence for cardiovascular and autonomic uncoupling in acute brain injury (19). This would explain why, despite the use of catecholamines, we failed to maintain an adequate MAP during larger dose remifentanil infusion. These data suggest that in patients with severe traumatic brain injury, remifentanil could cause increases of ICP, probably resulting from activation of the vasodilatory cascade.
The cerebrovascular effects of remifentanil are a matter of debate. A recent study demonstrated that infusion of large-dose remifentanil (2 and 4 µg · kg–1 · min–1) in healthy male volunteers decreased cerebral blood flow (20). An experimental study simulated surgical pain in 10 conscious volunteers using increasing mechanical pressure to the tibia and measured changes in VMCA caused by the pain. Increasing doses of remifentanil (from 0.025 to 0.1 µg · kg–1 · min–1) did not affect VMCA but attenuated the pain-induced change in VMCA (21). Remifentanil (from 0.75 to 1.5 µg · kg–1 · min–1), with sevoflurane 2%, induced a greater decrease in VMCA before tracheal intubation in children than did a similar dose of fentanyl (22). Equipotent doses of fentanyl (2 µg · kg–1 · min–1) and remifentanil (1 µg · kg–1 · min–1), in combination with nitrous oxide, had similar effects on absolute cerebral blood flow in patients scheduled to undergo supratentorial tumor surgery and did not impair cerebrovascular carbon dioxide reactivity (23). In patients undergoing craniotomy for supratentorial space-occupying lesions, no difference between patients receiving equipotent doses of alfentanil, fentanyl, and remifentanil was observed with regard to ICP (24). In the present study, large dose remifentanil could have induced an increase in ICP by decreasing MAP, triggering an autoregulated cerebrovasodilation. It has been shown, with use of contrast media-enhanced perfusion magnetic resonance imaging used to measure regional cerebral blood flow, in volunteers during infusion of remifentanil (0.1 µg · kg–1 · min–1) that cerebral hemodynamics were increased significantly in areas less rich in mu-opioid receptors (7). Moreover, these areas are probably modified in patients with brain injury who have previously received sedation with opioids. In the present study, the use of transcranial Doppler was likely not specific enough to detect any change in regional cerebral blood flow. However, the absence of significant change in VMCA suggests evidence for the preservation of autoregulation in patients with traumatic brain injury receiving remifentanil.
As previously observed with fentanyl, small to moderate dose remifentanil did not prevent the cough reflex (3). The concentration of remifentanil required to blunt coughing in more than 50% of patients was estimated to be 17.1 ± 6.2 ng/mL. This concentration is 3- to 5-fold larger than the concentration used for performing general anesthesia. A concentration of 19.9 ng/mL will achieve a 50% maximal effect on EEG activity in healthy adult male volunteers (25). EEG activity was not assessed in the present study, but the BIS is an EEG indicator that measures interfrequency phase relationships in the EEG (26). In healthy volunteers, BIS values correlate with hypnotic drug concentrations, but small to moderate doses of opioids do not affect the BIS (26). The present study showed that large doses of remifentanil induce a dose-related decrease in BIS in patients with traumatic brain injury. Remifentanil without concommitant hypnotic did not prevent an increase in BIS during endotracheal suction. No data are available in the literature using opioids without hypnotic in patients with brain injury. Overall, opioids seem to blunt the cough reflex only for concentrations inducing a significant decrease in BIS and are not suitable for avoiding coughing with suctioning.
One limitation of this study is the absence of randomization for each dose. This design was used to increase the number of patients, and to determine the level required to blunt the cough reflex for each patient. According to the short context half-life of remifentanil, a 1-hour washout period was probably enough to eliminate this drug between two sets of measurements (5,11).
In conclusion, this is the first study to systematically evaluate the use of remifentanil in patients with severe traumatic brain injury in the ICU. Remifentanil did not alter autoregulation in these patients, and reduced coughing during endotracheal suctioning in a dose-dependent manner. However, the large concentrations required to achieve this objective increased ICP and decreased CPP, limiting its clinical application, and can not be recommended in patients with severe traumatic brain injury.
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Acknowledgments
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The authors thank René Tempelhoff, MD (Professor of Anesthesiology & Neurological surgery Chief, Division of Anesthesiology Barnes-Jewish Hospital south Campus, Saint Louis, MO) for his insightful comments and suggestions.
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References
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Accepted for publication April 27, 2004.
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Abstract
Introduction
