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A Comparison of Target- and Manually Controlled Infusion Propofol and Etomidate/Desflurane Anesthesia in Elderly Patients Undergoing Hip Fracture Surgery

Passot, Sylvie MD; Servin, Frédérique MD*; Pascal, Jean MD; Charret, Françoise MD; Auboyer, Christian MD; Molliex, Serge MD, PhD

doi: 10.1213/01.ANE.0000149542.04833.55
Anesthetic Pharmacology: Research Report

Elderly patients have a higher risk of developing adverse drug reactions during anesthesia, especially anesthesia affecting cardiovascular performance. In this prospective randomized study we compared quality of induction, hemodynamics, and recovery in elderly patients scheduled for hip fracture surgery and receiving either etomidate/desflurane (ETO/DES) or target-controlled (TCI) or manually controlled (MAN) propofol infusion for anesthesia. Sixteen patients were anesthetized with ETO (0.4 mg/kg) followed by DES titrated from an initial end-tidal concentration of 2.5%. Eighteen patients received propofol TCI at an initial plasma concentration of 1 μg/mL and titrated upwards by 0.5-μg/mL steps. Fifteen patients received a bolus induction of propofol 1 mg/kg over 60 s followed by an infusion initially set at 5 mg · kg−1 · h−1. All received a bolus (20 μg/kg) followed by an infusion of 0.4 μg · kg−1 · min−1 alfentanil. According to hemodynamics, concentrations of DES or propofol (TCI group) and propofol infusion rate (MAN group) were respectively adjusted by a step of 20% and 50%. In the TCI and ETO/DES groups, the time spent at a mean arterial blood pressure within 15% and 30% of baseline values was more than 60% and 80% of anesthesia time, whereas in the MAN group it was <30% and 60%, respectively. In the MAN group more anesthetic drug adjustments were recorded (6.4 ± 2.8 versus 2.5 ± 1.2 [ETO/DES] and 2.6 ± 1 [TCI]). TCI improves the time course of propofol's hemodynamic effects in elderly patients.

IMPLICATIONS: The combination etomidate/desflurane resulted in better hemodynamic stability than a manually controlled infusion of propofol in elderly patients undergoing hip fracture surgery. Target-controlled infusion of propofol improved the time course of propofol's hemodynamic effects.

Département d'Anesthésie-Réanimation, Hôpital Bellevue, Saint-Etienne, France; *Service d'Anesthésie-Réanimation Chirurgicale, Hôpital Bichat, Paris, France

Accepted for publication October 19, 2004.

Address correspondence and reprint requests to Sylvie Passot, MD, Département d'Anesthésie-Réanimation, hôpital Bellevue, 42055 Saint-Etienne cedex 2, France. Address e-mail to sylvie.passot@chu-st-etienne.fr.

Hip fracture is common among elderly patients. Although chronological and biological age may differ considerably, advanced age is always accompanied by a general decline in organ function and especially by alterations in structure and function of the heart and vasculature that affect cardiovascular performance (1). Coexisting medical disease makes elderly patients a surgical high-risk group, and mortality and morbidity after orthopedic emergency surgery are frequent (2). When choosing the anesthetic technique one has to consider physiological changes of aging and frequently associated diseases. Elderly patients have a diminished reserve to withstand complications.

Etomidate (ETO) and desflurane (DES) are often used because of their hemodynamic stability (3) or for the ability to control hemodynamic responses (4) they respectively convey. In contrast, the cardiovascular effects of propofol, particularly its vasodilator properties, limit its use in this population despite its titrability and the quality of anesthetic induction and recovery it produces. As target-controlled infusion (TCI) results in better hemodynamic stability than manual infusion (MAN) (5,6), propofol TCI may be an alternative to ETO/DES anesthesia in this population. The aim of this study was to compare the hemodynamic changes during anesthesia with ETO and DES or propofol administered by TCI or MAN in elderly patients scheduled for hip fracture surgery.

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Methods

After Institutional Ethics Committee approval and individual written informed consent, patients older than 80 yr scheduled for hip fracture surgery under general anesthesia were included in a prospective, randomized study. Exclusion criteria included weight less than 40 kg, known allergy to propofol or its lipid emulsion, general anesthesia 7 days before surgery, or ASA physical status III or over. Patients were randomly allocated into three groups to receive either ETO for induction and DES for maintenance of anesthesia (ETO/DES group) or propofol for both induction and maintenance of anesthesia, administered either as a TCI (TCI group) or as a MAN controlled infusion (MAN group). All other aspects of anesthetic management were standardized in the three groups. Baseline values of noninvasive mean arterial blood pressure (MAP) and heart rate (HR) were defined as the average of three repeated measurements taken on the day before surgery. All patients received hydroxyzine 1 mg/kg orally 1 h before induction of anesthesia. An 18-gauge catheter was inserted in a large forearm vein for fluid and drug administration. Patients received 10 mL/kg Ringer's lactate solution and in the propofol groups the drug infusion was connected as close as possible to the IV catheter to minimize dead space. Electrocardiogram, HR, pulse oxygen saturation (Spo2), and end-tidal CO2 (ETco2) were monitored throughout the procedure, as were end-tidal concentration of DES and predicted concentration of propofol. MAP was measured every 5 min from anesthetic induction to complete recovery. After breathing 100% oxygen for 5 min, anesthesia was induced with the hypnotic drug according to the randomization schedule.

Patients in the ETO/DES group received 0.4 mg/kg ETO and 20 μg/kg alfentanil 1.5 min later. If laryngoscopy could not be performed 1.5 min after alfentanil injection, a second bolus dose of 0.2 mg/kg ETO was given and tracheal intubation was attempted 3 min later.

Patients in the TCI group received a propofol infusion driven by a computer-controlled Graseby 3400 syringe pump (Graseby Medical, Watford, UK) with the STANPUMP software (STANPUMP is freely available from the author Steven Shafer at http://anesthesia.stanford.edu/pkpd) implemented with a pharmacokinetic (PK) model developed by Dyck and Shafer (7) targeting the plasma concentration. This model is age- and weight-adjusted and used a time to peak effect of 2.3 min. The initial target concentration (TC) of propofol was 1 μg/mL and it was titrated upwards by 0.5-μg/mL steps every 3 min until loss of eyelash reflex. Then 20 μg/kg alfentanil was administered. Tracheal intubation was attempted 1.5 min later; if unsuccessful, the TC propofol was increased by 0.5 μg/mL and intubation was performed 3 min later.

Patients in the MAN group received a bolus induction dose of propofol 1 mg/kg over 60 s, followed by 20 μg/kg alfentanil 1.5 min later. If necessary to achieve tracheal intubation, additional boluses of 10 mg propofol were administered every 3 min.

In the three groups, laryngoscopy was attempted 1.5 min after the alfentanil bolus dose and 5% lidocaine was applied topically on the glottis before tracheal intubation. The lungs of all patients were ventilated with a mixture of 60% oxygen and 40% nitrous oxide (N2O), and ventilation was adjusted to maintain ETco2 between 33 and 36 mm Hg. All patients received an infusion of alfentanil 0.4 μg · kg−1 · min−1. Blood loss was compensated volume for volume by Ringer's lactate solution.

In the ETO/DES group, DES was administered for maintenance of anesthesia from tracheal intubation to end of surgery, titrated from an initial end-tidal concentration of 2.5% according to hemodynamic variables. If the systolic arterial blood pressure (SAP) and HR increased or decreased by more than 20% from baseline values, the inspired concentration of DES was adjusted to change the end-tidal concentration by 20%. If SAP and HR had not returned to within 20% of baseline after 3 min, the end-tidal concentration was changed again. If SAP or HR remained increased after 2 successive increases in concentration, an extra bolus of alfentanil 10 μg/kg was given and the alfentanil infusion rate was increased upwards by 0.10 μg · kg−1 · min−1.

In the TCI group, if the SAP and HR increased or decreased by more than 20% from baseline values propofol TC was changed by 20%. If SAP and HR had no return to within 20% of baseline after 3 min, the TC was changed again. If an increase in SAP or HR still remained after 2 successive increases in propofol TC, alfentanil was given as in the ETO/DES group.

In the MAN group, the infusion of propofol, initially set at 5 mg · kg−1 · h−1, was titrated according to SAP and HR changes. Increases or decreases more than 20% of baseline values resulted in a propofol infusion rate change by 50%. If no normalization occurred after 3 min, the infusion rate was changed again. If an increase in SAP or HR still remained after 2 successive increases in the propofol infusion rate, alfentanil was given as in the 2 other groups.

In all patients, from anesthetic induction to end of surgery, a decrease in SAP of more than 30% less than baseline values was treated with ephedrine 6 mg every 3 min until return to baseline value and a down titration of the hypnotic involved as described above. The alfentanil infusion was stopped at the beginning of skin closure and the DES, propofol, and N2O administration at completion of skin closure. Postoperative analgesia was standardized and included propacetamol 2 g and tramadol 100 mg 1 h before the end of surgery.

The time to loss of eyelash reflex, time to tracheal intubation, and number of intubation attempts were recorded for each patient. The doses and mean infusion rates of all IV drugs and duration of anesthesia and surgery were recorded. From the hemodynamic measurements, the time spent with a MAP value within 15% and 30% of baseline values and the largest variation in MAP from the baseline values were calculated. Ephedrine consumption and the amount of intravascular fluid administration and all the intraoperative drug dose adjustments were recorded. The predicted blood and effect-site propofol concentrations at the main clinical end-points were recorded in the TCI group. Times to spontaneous breathing, to eyes opening, and to tracheal extubation were recorded, as were postoperative nausea and vomiting occurrences in the recovery room. These variables were evaluated by a physician unaware of allocated treatment.

The number of patients was calculated using the results of a preliminary investigation in which propofol was administered MAN to elderly people scheduled for hip fracture surgery. We measured the MAP decrease after induction of anesthesia and tracheal intubation to be 34% ± 13% of the preinduction value (mean ± sd). The required sample size was therefore calculated to be 15 patients per group to detect with a power of 90% and an adjusted α = 0.028 (3 groups) a difference of at least 50% in MAP decrease. Power and sample calculations were made using the Power™ program (8). Data are presented as means ± sd or median values (minimum–maximum). The statistical analysis included data from all patients according to intention-to-treat and was performed using the Statview™ package (Abacus Concepts Inc., Berkeley, CA). A 2-sided χ2 test or Fisher's exact test were used to compare the ETO/DES, TCI, and MAN groups for qualitative variables and a Kruskal-Wallis analysis of variance was used for quantitative variables. Post hoc analysis using the Bonferroni correction of the Mann-Whitney U-test was performed in case of significant differences. P < 0.05 was considered statistically significant.

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Results

Fifty-two patients scheduled for hip fracture surgery were included in the study, 17 in. the ETO/DES group, 18 in. the TCI group and 17 in. the MAN group. One patient in the ETO/DES group and two in the MAN group were excluded from the study because of missing data. The three groups were comparable with respect to age, weight, height, ASA class and sex (Table 1). All the patients were treated by internal fixation with a dynamic screw-intramedullary nail.

Table 1

Table 1

Time to loss of eyelash reflex was longer in the TCI group than in the ETO/DES group (Table 2). Mean time to tracheal intubation was less in the ETO/DES group compared with the propofol groups. Eight patients in the ETO/DES group required additional boluses of etomidate to allow tracheal intubation versus four in the TCI and five in the MAN group (the difference was not significant). No hemodynamic events occurred before tracheal intubation in any of the groups. In the TCI group, duration of anesthesia was longer than in the MAN group (Table 2), but the propofol consumption was identical.

Table 2

Table 2

The three groups were similar with respect to alfentanil doses used during anesthesia.

There were significant hemodynamic profile differences between the MAN group and the ETO/DES and TCI groups. In the TCI and ETO/DES groups, the time spent at a MAP within 15% and 30% of baseline values was more than 60% and 80% of total anesthesia time, whereas in the MAN group it was <30% and 60%, respectively (Fig. 1). Difficulties in maintaining hemodynamic stability in the MAN group led to more corrective actions for hypotension (i.e., intraoperative hypnotic and analgesic adjustments) (Table 3). The total ephedrine dose was larger in the MAN group but the difference did not reach statistical significance (Table 3). Similarly, the largest decrease in MAP expressed in percentage of baseline value was observed in this group (50%) (Table 3). No increases in MAP occurred in any group. The crystalloid intravascular volume administration was the same in the three groups.

Figure 1

Figure 1

Table 3

Table 3

Immediate recovery assessed through time to spontaneous breathing, eyes opening, and time to tracheal extubation was comparable (Table 2). Early recovery was more comfortable in the propofol groups because of a significantly infrequent postoperative nausea and vomiting (Table 2).

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Discussion

As the elderly population continues to increase, more aged patients will undergo surgical procedures and anesthesia techniques must be adapted to ensure hemodynamic stability and adequate tissue oxygen supply. The present study demonstrated that in this population, the combination ETO/DES ensured better hemodynamic stability than the MAN controlled infusion of propofol and also that propofol TCI reduced this difference. Anesthetic induction times were longer with propofol compared with ETO. Recovery times were similar among the three groups with less nausea and vomiting in patients receiving propofol.

ETO and DES have been proposed for many years in geriatric patients because of their pharmacodynamic (PD) and PK properties (3,9–11). The hypnotic and electroencephalographic (EEG) effects of propofol are enhanced in the elderly (12), and they occur more rapidly than changes in SAP, which decreases to a larger degree but more slowly with increasing age (13). Thus, any overshoot in propofol concentration may result in a delayed but increased decline in MAP. In our study, the variations in MAP were mainly corrected by boluses of ephedrine and hypnotic adjustments so that alfentanil consumption was comparable in all groups. The fact that in the TCI group hemodynamic stability was similar to that observed in the ETO/DES group highlights the use of the infusion technique in propofol administration. The TCI technique allowed a better titration (thus fewer overshoots) and improved the time course of propofol effects without modification of overall propofol consumption (5). On the other hand, titrating delayed time to loss of eyelash reflex and time to tracheal intubation. During MAN controlled infusions, it is very difficult to calibrate boluses to reach the desired anesthesia level, and when a reduction in concentration is warranted, the infusion rate is decreased but never stopped; therefore the concentration decreases more slowly than with TCI. This probably explains the better hemodynamic stability obtained in the TCI group. However, we cannot exclude that a reduction in propofol induction dose and infusion rate during anesthesia maintenance in the MAN group would have induced lesser hemodynamic consequences. One limitation concerning our study results is the absence of anesthesia depth monitoring. Hemodynamic effects could have been different if drug dosing had been guided by hypnotic effect monitoring targeting a similar hypnotic depth, as suggested by recent studies (14,15).

In the postanesthesia care unit, propofol anesthesia was considered beneficial mainly because of the lack of postoperative nausea and vomiting. We had expected greater differences in time to early recovery as previously shown when desflurane was compared with propofol (16) and propofol TCI with MAN controlled infusion (5). This lack of difference in early recovery times is probably multifactorial. Coadministered drugs may have blunted differences among groups. Titration of anesthetic drugs using hemodynamic variables is particularly difficult in elderly patients inducing excessive adjustments that might be avoided by titrating to EEG effects (17). Finally, in a study that showed a shorter recovery time with TCI (5), the effect site rather than the plasma was targeted and propofol was titrated on several clinical end-points, both points possibly allowing a finer tuning of anesthesia.

As aging delays the onset of action of propofol, targeting a small initial effect-site concentration titrated upwards by 0.5-μg/mL steps could help to achieve the desired effect without overshooting, provided that the PK model implemented in the TCI device incorporates age as a covariate (18). Previous studies have described a more rapid loss of consciousness when targeting the effect site rather than the plasma concentration without increasing the risk of hypotension (19,20). Nevertheless, only young patients were included in those studies and further investigations in elderly patients are required.

This study confirms previous findings that the combination of ETO and DES allows rapid anesthetic induction, excellent intraoperative control of anesthesia, and rapid emergence and recovery from anesthesia in geriatric patients. It demonstrates that propofol administered by TCI also provides cardiovascular stability and ensures smooth induction and fast recovery, in contrast with MAN controlled infusion, which leads to larger changes in MAP and thus potentially deleterious effects. TCI retains all of propofol's beneficial properties while attenuating its hypotensive effects provided PK and PD changes in this population are considered (choice of an appropriate model). Future studies, using PK-PD modeling would provide accurate dosing guidelines for the delivery of anesthetics to the elderly, increase the margin of safety, and improve the quality of anesthesia in this fast-growing population.

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