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PEDIATRIC ANESTHESIA

Remifentanil Requirements During Propofol Administration to Block the Somatic Response to Skin Incision in Children and Adults

From the Departamento de Anestesiología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

Address correspondence and reprint requests to Hernán R. Muñoz, MD, Departamento de Anestesiología, Universidad Católica de Chile, Marcoleta 367, Santiago, Chile. Address e-mail to hmunoz{at}med.puc.cl.

	Abstract

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BACKGROUND: During sevoflurane administration, children require a remifentanil infusion rate twofold higher than adults to block responses to skin incision. Similar data concerning remifentanil requirements are unavailable during total IV anesthesia.

METHODS: We prospectively determined the infusion rate (IR) of remifentanil necessary to block the somatic response to skin incision in 50% (IR₅₀) of adults (n = 20, aged 20–60 yr) and children (n = 20, aged 3–11 yr) during propofol anesthesia. In each patient undergoing lower abdominal surgery, a remifentanil infusion was initiated, followed by target-controlled infusion of propofol set at a plasma concentration of 6 µg/mL. After tracheal intubation, propofol was reduced to 3 µg/mL until the end of the study. Remifentanil IR was determined according to Dixon's up-and-down method, with the first patient in each group receiving 0.2 µg · kg^–1 · min^–1 followed by the consecutive patient receiving 0.02 µg · kg^–1 · min^–1 modifications according to the response of the previous patient. The remifentanil IR was kept unchanged for at least 20 min before surgery. At the beginning of surgery, only the skin incision was performed, and the somatic response was observed. If there was any gross movement of extremity the response was considered positive.

RESULTS: The IR₅₀ (CI_95%) was 0.08 (0.06–0.12) µg · kg^–1 · min^–1 in adults and 0.15 (0.13–0.17) µg · kg^–1 · min^–1 in children (P < 0.001).

CONCLUSION: These results demonstrate that, similar to sevoflurane anesthesia, during total IV anesthesia with propofol, children require a remifentanil IR almost twofold higher than adults to block the somatic response to skin incision.

	Introduction

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The effective concentration 50% (EC₅₀) is the steady-state plasma concentration of a drug necessary to prevent (or elicit) a given response in half of the population. It is a useful parameter to determine equipotency of different drugs or, alternatively, to compare the requirements of a given drug among different populations. In addition, the EC₅₀ can be used as a general guide for administering anesthetic drugs. In this context, using the MAC (analog to the EC₅₀), the requirements of inhaled anesthetics have been shown to be higher in children compared with adults (1–4). In the case of drugs administered by continuous infusion, the infusion rate (IR) to prevent responses in 50% of patients (IR₅₀) can also be used to compare requirements among different age groups. For example, during the administration of 1 MAC awake of sevoflurane, the IR₅₀ of remifentanil required to block both the somatic and cardiovascular responses to skin incision are twofold higher in children than in adults (5). Remifentanil is also a useful adjunct when infused as a component of propofol total IV anesthesia (TIVA); however, there are no reports on the requirements of this opioid to block the response to a surgical stimulus when combined with propofol in the pediatric population. This information can be a useful guide to administer this opioid with this technique.

The aim of this study was to test the hypothesis that during TIVA with propofol, the IR of remifentanil to block the somatic response to skin incision in 50% of children (IR₅₀) is higher than in adults.

	METHODS

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After obtaining institutional ethics committee approval (School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile) and informed consent from patients or parents, 20 adults and 20 children were enrolled. Inclusion criteria included: age 20–60 yr in adults and 3–11 yr in children, ASA physical status I, a weight within ±20% of the ideal body weight for height, and a scheduled first time surgery in the inguinal region under general anesthesia. Exclusion criteria included pregnancy, chronic or acute (within the last 48 h) intake of any sedative or analgesic drug, and any known adverse effect to the study drugs. Lidocaine and prilocaine cream were applied to the skin on puncture sites to facilitate the insertion of a peripheral IV catheter in children.

In the operating room, routine noninvasive monitoring of arterial blood pressure, electrocardiogram, and pulse oximetry were initiated. In all patients, induction of anesthesia was with remifentanil at an infusion rate previously determined followed by a target-controlled infusion of propofol set at a plasma concentration of 6 µg/mL. Tracheal intubation was facilitated with mivacurium 0.1 mg/kg, and the lungs were mechanically ventilated with O₂ 100% and adjusted to maintain the end-tidal CO₂ at 30–35 mm Hg. After intubation, anesthesia was maintained with remifentanil and the propofol concentration reduced to 3 µg/mL in all patients.

For the first patient in each group, the remifentanil infusion rate was 0.2 µg · kg^–1 · min^–1, and in the consecutive patients, this rate was modified in 0.02 µg · kg^–1 · min^–1 increments/decrements according to the Dixon's up-and-down method (6). This infusion rate was kept unchanged during the whole study period and for at least 20 min before skin incision. Target-controlled infusion of propofol was performed by a computer-controlled continuous infusion device with a Pilot Anesthesia 2-syringe infusion pump (Fresenius Vial S.A., Brezins, France) and a Toshiba Satellite 330 CDS laptop computer using Stanpump software (Stanford University, Anesthesiology Service, Palo Alto, CA) to maintain a constant predicted plasma concentration. The propofol pharmacokinetic parameters used were those determined by Marsh et al. (7) in adults, or those by Kataria et al. (8) in children.

A train-of-four stimulation on the cubital nerve at the level of the wrist was applied at least 5 min before skin incision to assure the recovery of neuromuscular function after mivacurium administration. The intensity of stimulation was 35 mA in children and 55 mA in adults. The presence of four similar movements of the thumb in response to the stimulation was considered as adequate recovery. At the beginning of surgery, only skin incision with a scalpel was performed, and the somatic response was observed for 90 s. The somatic response was evaluated by two surgeons blinded to the remifentanil infusion rate and was considered positive if there was any gross movement of an extremity. The IR₅₀ (CI_95%) was determined for each group with the method described by Dixon and Massey (6). The probability of no response to skin incision (E) was related to the remifentanil IR (R_IR) using a sigmoid E_max model:

where E₀ is the baseline effect, E_max is the maximal drug effect, R_IR50 is the remifentanil IR that produces 50% of the maximal effect, and describes the sigmoidicity of the relation. Using the parameters obtained with the sigmoid E_max model the dose–response curves were calculated in both groups. IR₅₀ was compared between groups using the unpaired Student's t-test. A P < 0.05 was considered significant.

	RESULTS

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The demographic and anesthetic data for both groups are shown in Table 1. All subjects had recovered from mivacurium neuromuscular blockade before skin incision. All subjects in each group had a propofol predicted plasma concentration of 3 µg/mL for at least 10 min before skin incision.

To block somatic response to skin incision, the IR₅₀ (CI₉₅) was 0.149 (0.130–0.172) µg · kg^–1 · min^–1 in children and 0.080 (0.055–0.116) µg · kg^–1 · min^–1 in adults (P < 0.001) (Fig. 1). The parameters of the E_max model were R_IR50 of 0.147 µg · kg^–1 · min^–1 and of 10.8 in children, and R_IR50 of 0.074 µg · kg^–1 · min^–1 and of 4.9 in adults. The dose–response curves of both groups are shown in Figure 2.

View larger version (15K): [in this window] [in a new window]   Figure 1. This figure shows the individual responses to skin incision at the different infusion rates of remifentanil in both groups. The black symbols represent patients who had a positive response to skin incision, and the white symbols represent those with negative response. The calculated IR50 (dashed lines) were significantly different between groups.

View larger version (14K): [in this window] [in a new window]   Figure 2. This figure shows the relationship between the probability of no response to skin incision and infusion rate of remifentanil determined by the sigmoid Emax model (dashed and continuous lines). The squares and circles represent the actual ratio of patients who did not move at the corresponding infusion rate.

	DISCUSSION

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The main finding of this study is that, during TIVA with propofol, the IR of remifentanil necessary to block the somatic response to skin incision is almost twice as high in children aged 3–11 yr compared with that in adults.

The quality of anesthesia resulting from different combinations of propofol and opioids has been widely studied in adults. This has allowed the determination of the optimal dose combinations of propofol and opioids to obtain adequate anesthesia with the fastest recovery in this population (9). Because clinically relevant differences between children and adults have been found in the requirements of remifentanil during inhaled anesthesia (5), the recommended doses of propofol and opioids derived from adult studies cannot be extrapolated a priori to the pediatric population. This is demonstrated in this study by the clinically significant higher requirements of remifentanil in children during skin incision. Similar to the increased needs for remifentanil during sevoflurane anesthesia in children, this factor should be considered when using remifentanil with propofol in this population.

The findings of this study may be secondary to remifentanil pharmacokinetic and/or pharmacodynamic differences between these two age groups. In pediatric patients from 2 to 10 yr, Ross et al. (10) found a volume of distribution for remifentanil of 234.8 ± 110.0 mL/kg, clearance of 69.4 ± 21.8 mL · kg^–1 · min^–1, and an elimination half-life of 4.1 ± 1.7 min. When these values are compared with a volume of distribution of 300–400 mL/kg, a clearance of 40–60 mL · kg^–1 · min^–1, and an elimination half-life of 8 min in adults (11), it is not possible to exclude pharmacokinetic differences as an explanation for the higher requirements of remifentanil in children. In addition, a clear increase in sensitivity with age (i.e., a pharmacodynamic effect) to remifentanil (12) and other opioids (13) has been demonstrated in adults aged 20 to >80 yr of age. If this age-effect is also present in children, this population might also be more resistant than adults to remifentanil.

In this study, a propofol plasma concentration of 3 µg/mL was used in both groups. This concentration was chosen because it is frequently recommended for children (14–17) and is common during TIVA with propofol and remifentanil in adults. However, the possibility that the pharmacodynamics of propofol are different in children compared with that in adults, thus resulting in a different effect at the same concentration, cannot be excluded. If the effects of propofol were less pronounced in children, this could be an additional explanation for their higher remifentanil requirements. Alternatively, if pediatric patients experienced deeper hypnosis than adults, the actual requirements of remifentanil would be even more than those observed in this study. A recent study (18), however, using the Paedfusor's pharmacokinetic model and the Bispectral Index monitor suggests that 3 µg/mL of propofol might be equipotent in both populations.

Target-controlled infusion of propofol was used in all patients to maintain a predicted plasma concentration of 3 µg/mL. The pharmacokinetic models were chosen because Marsh's model for adults has been validated prospectively (19,20). In children, Kataria et al. (8) model has not been validated prospectively; however, this model was used by the authors who recommend or use a propofol concentration of 3 µg/mL in this population (14–17). By using average pharmacokinetic parameters, target-controlled infusion systems cannot account for individual kinetic variability and lead to an unavoidable variability in the actual plasma concentrations. In a study like ours, this is particularly relevant when measured plasma levels are biased to higher or lower concentrations than those predicted because this can result in a systematic error in determining the dose of the second (coadministered) drug (i.e., remifentanil). Although with Marsh's model, this potential bias seems to be negligible (19,20), the degree to which this phenomenon occurs in children with Kataria et al. model is unknown. The same previous considerations are valid for remifentanil as, with certainty, different plasma levels at the same IR were obtained in the different subjects. The only way to circumvent this problem for obtaining an accurate pharmacodynamic study is by measuring plasma concentrations of drugs, and this was not done in our study. Because the clinician must work with predicted concentrations and IRs, rather than plasma concentrations of drugs, the lack of plasma levels does not invalidate the message of our study. During the use of clinically useful predicted concentrations of propofol, children require higher IRs of remifentanil than adults to block the somatic response to skin incision.

An additional factor that has to be considered is the degree of propofol and remifentanil equilibrium that was achieved before skin incision. The time that patients had a propofol plasma concentration of 3 µg/mL before skin incision ranged from 10 to 22 min. The half-time k_e0's of propofol of 0.6 min in adults (21) and 1.7 min in children (22) suggest that, from a practical point of view, the equilibrium between plasma and the effect site had been reached in both groups at the moment of skin incision. In the case of remifentanil, a constant rate infusion period of at least 20 min before surgery should have allowed for more than 90% of the final steady-state plasma concentration to be reached in adults (23). Because the pharmacokinetics of remifentanil in children do not seem to be extremely different from adults (10,11), it is likely that the 20 min infusion period also allowed a high degree of equilibrium in this group. Unfortunately, the lack of complete knowledge about the pharmacokinetics and pharmacodynamics of remifentanil and propofol in children precludes definitive conclusions for several aspects of this study. Clearly, more studies that include determination of the concentration–effect curves and the pharmacodynamic interaction of propofol and remifentanil are needed in this population.

Finally, although the up-and-down study design is a very accurate method to determine IR₅₀ and its variability, it is weak for the determination of extreme values of dose–response curves. Therefore, the dose–response curves obtained with the sigmoid E_max model must be interpreted with caution.

In conclusion, during TIVA with propofol using the current clinically recommended predicted plasma concentration, children aged 3–11 yr require a remifentanil IR twice as high as adults to block the somatic response to skin incision. These differences should be considered when using this anesthetic technique in children.

	ACKNOWLEDGMENTS

 
We greatly thank Dr. Stephen Klein, MD, Associate Professor, Department of Anesthesiology, Duke University Medical Center for his help in the writing of the manuscript.

	Footnotes

 
Accepted for publication October 12, 2006.

Part of this study was presented as a poster at the ASA Annual Meeting, 2005.

	REFERENCES

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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