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Anesth Analg 2002;94:1212-1216
© 2002 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Target-Controlled Versus Manually-Controlled Infusion of Propofol for Direct Laryngoscopy and Bronchoscopy

Sylvie Passot, MD*, Frédérique Servin, MD{dagger}, René Allary, MD*, Jean Pascal, MD*, Jean-Michel Prades, MD PhD{ddagger}, Christian Auboyer, MD*, and Serge Molliex, MD PhD*

*Département d’Anesthésie-Réanimation, {ddagger}Service d’ORL et de Chirurgie Cervico-Faciale et Plastique, Hôpital Bellevue, Saint-Etienne Cedex 2, France; and {dagger}Département d’Anesthésie-Réanimation, Hôpital Bichat, Paris, France

Address correspondence and reprint requests to Sylvie Passot, Département d’Anesthésie-Réanimation, Hôpital Bellevue, 42055 Saint-Etienne Cedex 2, France. Address e-mail to sylvie.passot{at}chu-st-etienne.fr


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Few studies have compared the clinical profile of target-controlled infusions of propofol with that of manually-controlled infusions. Fifty-four ASA physical status I or II patients scheduled for an elective otorhinolaryngology endoscopy performed under general anesthesia with spontaneous ventilation were enrolled in this prospective randomized study to compare the clinical outcome of such administrations. Before induction, all patients received a single alfentanil bolus dose (10 µg/kg). Propofol administration was adapted to maintain absence of movement, hemodynamic stability, and efficient spontaneous ventilation. When compared with the Manually-Controlled Infusion group, in the Target-Controlled Infusion group there were fewer movements at insertion of the laryngoscope (14.8% vs. 44.4%), improved hemodynamic stability (largest variations of mean arterial blood pressure <10% of control values, versus 20%), fewer episodes of apnea, and less respiratory acidosis after endoscopy (pH = 7.37 ± 0.05 and PaCO2 = 50 ± 7 mm Hg versus pH = 7.28 ± 0.06 and PaCO2 = 58 ± 9 mm Hg); the recovery was also shorter (time to opening eyes or verbal response, 4.6 ± 2.0 min and 6.8 ± 2.5 min versus 10.8 ± 7.3 min and 15.7 ± 7.1 min). Propofol consumption was comparable in the two groups. Targeting the effect-site concentration improved the time course of the propofol drug effect during direct laryngoscopy performed during spontaneous ventilation when compared with manual infusion.

IMPLICATIONS: This study compares the clinical profile of propofol anesthesia for direct laryngoscopy with spontaneous ventilation when the drug is administered either as a manually controlled infusion or by targeting the effect-site concentration through a target-controlled infusion (TCI) device. TCI improves the time course of propofol effects.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Target-controlled infusions (TCI) of propofol are now often used in Europe for the induction and maintenance of anesthesia, with the introduction of a specific device for propofol TCI. A careful titration of propofol concentration should decrease the incidence of unwanted effects, such as apnea in spontaneously ventilating patients, reactions to painful stimuli, and hemodynamic changes, but only a few studies (1–3) have compared the clinical profile of TCI with that of manually controlled (MAN) infusions, and even fewer have demonstrated a clinical advantage for TCI (4).

Direct laryngoscopy and rigid bronchoscopy, increasingly used in the diagnosis of neoplastic otorhinolaryngology lesions, produce brief but intense nociceptive stimuli. They require general anesthesia and sufficient analgesia, but airway control remains a problem. When endotracheal intubation is performed, the tube impairs the surgeon’s vision, and intercricothyroid jet ventilation is not devoid of intrinsic morbidity and requires a deep level of anesthesia with muscle relaxation. In most patients, spontaneous ventilation is a good alternative that secures against hypoxemia but involves the acceptance of some degree of acute respiratory acidosis (5). In this situation, apneas should be avoided, as should disturbing responses to nociceptive stimuli, and IV anesthesia is recommended (6,7). Propofol infusions are therefore routinely used to achieve these goals, and it is hypothesized that a tight control over propofol effect-site concentration might decrease the incidence of apneas and movements and improve control over respiratory depression and hemodynamic responses.

This study was thus designed to compare the clinical profile of propofol anesthesia for direct laryngoscopy with spontaneous ventilation when the drug is administered either as a MAN infusion or by targeting the effect-site concentration with a TCI device.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After institutional approval and written informed consent, 54 ASA physical status I or II patients aged 18–80 yr and weighing 40 to 90 kg were allocated to one of two groups to receive either a TCI or a MAN propofol infusion. All were scheduled for an elective direct laryngoscopy and rigid bronchoscopy under general anesthesia. Patients with unstable cardiac conditions, severe liver disease, pregnancy, or known allergy to propofol or its lipid emulsion were excluded from the study.

Our routine anesthetic protocol for these procedures consists of a propofol infusion with small opioid concentration supplementation with alfentanil or remifentanil to ensure that spontaneous ventilation is preserved throughout the procedure. Oxygen is delivered through a nasal cannula, the tip of which is sited in front of the glottis.

Patients were orally premedicated with hydroxyzine (1.5 mg/kg) and 800 mg of effervescent cimetidine 1 h before surgery. After preoxygenation (5 min), anesthesia was induced with a single alfentanil bolus dose (10 µg/kg), and a propofol infusion was started 2 min later, according to the randomization schedule.

Patients in the TCI group received a propofol infusion driven by a computer-controlled Graseby 3400 syringe pump (Graseby Medical, Watford, UK) with use of the STANPUMP software (S. Shafer, Stanford University, Palo Alto, CA), implemented with a pharmacokinetic model developed in the absence of opioids (8). The initial effect-site target concentration of propofol was 2.5 µg/mL, and this was titrated upward by 0.5 µg/mL steps every 2 min to ensure a stepwise increase in propofol effect-site concentration until loss of verbal contact, which ended the induction period. In the MAN group, propofol was infused at a rate of 600 mL/h with use of a Graseby 3400 syringe pump until loss of loss of verbal contact; thereafter, the propofol was administered at a rate of 6 mg · kg-1 · h-1.

During the procedure, effect-site concentration (TCI group) or infusion rates (MAN group) were adjusted to maintain adequate anesthesia, estimated on clinical grounds (absence of movement during laryngoscopy and bronchoscopy, stable hemodynamic variables [±15% of preinduction values], and efficient spontaneous ventilation without a decrease in oxygen saturation). Electroencephalogram monitoring of the depth of hypnosis was not used during those procedures because the surgeon frequently manipulated the patient’s head, thus precluding any sustained, reliable recording of the electroencephalogram.

Throughout the procedure, all patients breathed 100% oxygen, spontaneously or assisted in case of apnea. Topical anesthesia with 5% lidocaine was applied to the pharynx, the larynx, and the lower part of the tongue under laryngoscopic control before insertion of the Portmann-Prades laryngoscope. Then the patients breathed spontaneously and received a continuous oxygen flow (6 L/min) via a nasal cannula or the lateral part of the rigid bronchoscope during bronchoscopy. In case of apnea lasting more than 2 min or if SpO2 decreased to <90%, ventilation was manually assisted.

The electrocardiogram, heart rate, and SpO2 were monitored throughout the procedure. Noninvasive blood pressure was measured every 3 min from induction to complete recovery. Cough or movements at any time during the surgical procedure were recorded, as were apneic episodes lasting more than 10 s. An arterial line was inserted before the induction of anesthesia, and arterial blood samples were drawn for blood gas measurements before induction (i.e., baseline), during laryngoscopy just before rigid bronchoscopy (i.e., bronchoscopy), and at the time of propofol infusion discontinuation (i.e., infusion end). The surgeon performing the endoscopy assessed the operating conditions with use of a subjective score ranging from 0 to 3 (0= bad, 1= poor, 2= fair, 3= excellent). The total amount of propofol infused was recorded, and the average infusion rate was calculated. Times from induction to loss of verbal contact and from the end of propofol infusion to opening eyes on verbal command and to orientation (giving date of birth) were recorded. In the MAN group, the achieved effect-site concentrations were retrospectively estimated by using the same set of pharmacokinetic variables as in the TCI group.

Before the study, the sample size was determined. In a preliminary investigation, we evaluated the mean PaCO2 increase after laryngoscopy as 10 ± 5 mm Hg (mean ± SD). The estimated sample size was 22 patients per group to detect, with a power of 90% and an {alpha} = 0.05, a difference of at least 50% in PaCO2 increase, which we defined as clinically relevant. The statistical analysis included data from all patients according to intention to treat. A two-sided {chi}2 test or a Fisher’s exact test were used to compare TCI and MAN for qualitative variables, and Student’s t-test was used for quantitative variables. Results are expressed as mean ± SD unless otherwise stated. A value of P < 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Fifty-four patients were included in the study: 27 in the TCI group and 27 in the MAN group. There was no difference between the groups as far as patient characteristics (Table 1). No patient was withdrawn from the study because of an adverse event or impossible operating conditions.


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  		Table 1. Patient Characteristics
 
Loss of consciousness was achieved in 141 ± 75 s in the TCI group and 116 ± 21 s in the MAN group (not significant) and required significantly different amounts of propofol (127 ± 57 mg versus 169 ± 37 mg for the TCI and MAN groups, respectively). The total amount of propofol infused was 391 ± 165 mg/kg and 383 ± 186 mg/kg, respectively, in the TCI and MAN groups (not significant) for an infusion duration of 23 ± 9 min in the TCI group and 19 ± 7 min in the MAN group (P < 0.05). This corresponded to an average infusion rate, respectively, of 288 ± 106 µg · kg-1 · min-1 and 328 ± 137 µg · kg-1 · min-1 (not significant). Despite similar propofol consumptions, recovery times were shorter in the TCI group (time to opening eyes: TCI, 4.6 ± 2.0 min [median, 5 min] versus MAN, 10.8 ± 7.3 min [median, 9 min]; time to stating date of birth: TCI, 6.8 ± 2.5 min [median, 8 min] versus MAN, 15.7 ± 7.1 min [median, 14 min]).

The predicted blood propofol concentrations were more than two times larger in the MAN group at loss of consciousness (12.5 ± 2.8 µg/mL versus 5.8 ± 2.1 µg/mL), and they remained so throughout the procedure (6.6 ± 1 µg/mL versus 4 ± 1.2 µg/mL just before bronchoscopy and 5.5 ± 2.4 µg/mL versus 3.1 ± 0.7 µg/mL at the end of propofol infusion). The predicted effect-site concentrations were statistically smaller in the TCI group at laryngoscopy and at the end of infusion, whereas they were similar at times to loss of consciousness, opening eyes, and orientation (Fig. 1). The maximal predicted effect-site concentration obtained during the procedure was significantly larger in the MAN group (6.7 ± 1.1 µg/mL) than in the TCI group (4.1 ± 1.2 µg/mL).



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  		Figure 1. The changes over time of the predicted effect-site propofol concentrations. The box represents the 25th–75th percentiles, the dark line is the median, the extended bars represent the 10th–90th percentiles, and the circles represent values outside this range. The notches correspond to the 95% confidence interval around the median. *P < 0.05 versus manual infusion. LOC = loss of consciousness; TCI = target-controlled infusion; MAN = manually controlled infusion.

 
Surgeons’ assessments of operating conditions were not significantly different between the two groups (Fisher’s exact test; P = 0.67) (Table 2). However, the incidence of movements or coughing at insertion of the Portmann-Prades laryngoscope was significantly less in the TCI group (Fisher’s exact test; P < 0.05) (Table 2).


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  		Table 2. Quality of Operating Conditions (n [%])
 
Hemodynamic stability was best achieved in the TCI group. The largest variations of mean arterial blood pressure (MAP), estimated in percentage of control values, were <10% both when MAP increased (6.8% ± 1.4%) and when MAP decreased (8.9% ± 1.2%), whereas they were approximately 20% in the MAN group both when MAP increased (19% ± 2.5%) and when MAP decreased (20.9% ± 1.7%) (P < 0.05 versus TCI). Significant tachycardia was recorded in both groups during endoscopy, and the largest variations of heart rate, expressed in percentage of control values, were 16.9% ± 16.8% and 21% ± 21.4% for the TCI and MAN groups, respectively (not significant).

The changes over time in the respiratory depression assessed by arterial blood gases in both groups of patients are displayed in Table 3. In the TCI group, patients experienced fewer episodes of apnea than in the MAN group (4 vs 23), and the mean cumulated duration of apneas was shorter (14 ± 40 s versus 191 ± 150 s). All the apneas were central, and most were observed before endoscopy. Four patients in the MAN group experienced more than one episode of apnea, compared with none in the TCI group.


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  		Table 3. Evolution over Time of Arterial Blood Gases
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our results demonstrate the efficacy of TCI in controlling anesthesia depth during direct suspension laryngoscopy performed in spontaneous ventilation. The use of TCI was associated with an infrequent incidence of responsiveness, an increased hemodynamic stability, a decreased respiratory depression, and a shorter recovery than the MAN infusion of propofol. These results concern surrogate end points rather than actual end points such as morbidity or mortality. However, the demonstration of consequential differences in outcomes between the two techniques of propofol administration would require a massive sample, rending such a study unrealistic in clinical practice.

Bolus injections of propofol are frequently associated with apneas (9,10). Peacock et al. (11) have shown that, in older patients, the induction of anesthesia by a continuous propofol infusion of 600 mL/h resulted in an infrequent incidence of apneas and threatening respiratory depression. Accordingly, this technique was chosen for MAN administration of propofol in our study. This technique is satisfactory for the maintenance of spontaneous ventilation (1,12), and it also results in induction times suitable for standard anesthetic practice.

Low-opioid/high-propofol anesthesia with a single bolus of alfentanil and no reinjection minimizes respiratory depression and reduces the influence of opioid supplementation on the propofol concentration required. When spontaneous breathing is mandatory, smaller than optimal effect-site opioid concentrations in the presence of correspondingly larger than optimal effect-site propofol concentrations should be given (13). Although alfentanil affects the propofol concentration at which patients awake after surgery, it did not interfere in our study, because retrospectively estimated plasma alfentanil concentrations (with use of the STANPUMP software and the pharmacokinetic model developed by Maitre et al.) (14) were <25 ng/mL at the end of the procedure (15).

All clinical effects were well correlated with effect-site, but not with plasma, concentrations. During induction in the MAN group, the infusion rate of propofol led to a large initial blood concentration, which was maintained until loss of verbal contact. This created a large blood/effect-site concentration gradient and resulted in an overshoot of effect-site concentration, thus causing an increased incidence of adverse effects such as initial apneas. It may also have contributed to the delayed decreases in MAP observed during surgery, because the propofol time to hemodynamic peak effect was longer than the time to hypnosis peak effect (16). The 20% decrease in MAP in the MAN group is common during propofol induction (17), but it was significantly different from that in the TCI group. When targeting the effect-site concentration in the TCI group, the initial calibrated bolus provided a large but brief initial plasma concentration to drive the drug into the effect-site, allowing quicker equilibration of the compartments, and was calculated to achieve the targeted effect-site concentration and no more. The clinical effect of the selected target concentration could be observed and the target concentration titrated to the required end point, avoiding overshoot. Induction was therefore prolonged but was achieved with a smaller dose and fewer initial adverse effects (3,18). Targeting the effect-site concentration improved the time course of the propofol drug effect at induction and also throughout the direct suspension laryngoscopy, as demonstrated by fewer movements during surgery; reduction of respiratory depression, leading to less acidosis; less hypercapnia at the end of the case; better hemodynamic stability; and, finally, faster recovery.

In our study, the predicted effect-site concentrations at major clinical end points, such as loss of consciousness and recovery, were similar whatever the propofol administration mode. This confirms the results of Wakeling et al. (19), that effect-site concentration is a better predictor of loss of consciousness than predicted plasma concentration. This study was not designed to compare effect-site with plasma-controlled TCI. However, simulating both techniques shows that variations in effect-site concentrations are more rapid and precise with effect-site-controlled TCI. Targeting the effect site rather than the blood propofol concentration results in a more rapid loss of consciousness without increasing the risk of hypotension (18,19), reduces variability in the time to loss of consciousness (20), and allows easy achievement and maintenance of a specified effect-site drug concentration as rapidly as possible without overshooting (21). It can therefore be speculated that with otorhinolaryngology endoscopies associated with brief but major variations in the level of stimulation, effect-site control would be the best technique to administer propofol.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Russell D, Wilkes MP, Hunter SC, et al. Manual compared with target-controlled infusion of propofol. Br J Anaesth 1995; 75: 562–6.[Abstract/Free Full Text]
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  7. Cavaliere S, Venuta F, Foccoli P, et al. Endoscopic treatment of malignant airway obstructions in 2,008 patients. Chest 1996; 110: 1536–42.[Abstract/Free Full Text]
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Accepted for publication January 9, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press