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The Influence of Age on Sensitivity to Dexmedetomidine Sedation During Spinal Anesthesia in Lower Limb Orthopedic Surgery

Xu, Bo MD*; Li, Zhitao MS; Zhou, Dongxu MS; Li, Liuxun MS*; Li, Pingyue MD§; Huang, Huayang MS§

doi: 10.1213/ANE.0000000000002531
Anesthetic Clinical Pharmacology
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To investigate the influence of age on sensitivity to dexmedetomidine sedation in adult patients, we selected 79 patients scheduled for lower limb orthopedic surgery under spinal anesthesia to identify the dexmedetomidine ED50 for adequate sedation among different age groups. After a spinal anesthetic was placed, a dose of dexmedetomidine determined by the Dixon up–and–down method was administered over 15 minutes. The ED50 in the elderly group was lower than in the other 2 groups (elderly: 0.88 ± 0.07; middle aged: 1.16 ± 0.08; young: 1.21 ± 0.06 µg/kg; both P < .001). There was no difference between the young and middle-aged groups (P = .160).

Published ahead of print October 5, 2017.

From the *Department of Anesthesiology, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, China

Department of Anesthesiology, Peking University Shenzhen Hospital, Shenzhen, China

Department of Anesthesiology, Xiangyang Central Hospital, Xiangyang, China

§Department of Arthrosteopedics, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, China.

Published ahead of print October 5, 2017.

Accepted for publication August 23, 2017.

Funding: This work was supported by the National Natural Science Foundation of China (Grant No. 61773130), the Special Project for Medical Science Development of PLA (Grant No. CGZ15C003), and the Foundation for Science and Technology Planning Project of Guangdong Province, China (Grant No. 2014A020215026).

The authors declare no conflicts of interest.

The authors B. Xu and Z. Li contributed equally to this work.

Institutional review board: Guangzhou General Hospital of Guangzhou Military Command Medical Ethics Committee. E-mail: gzjqzyy@163.com.

This manuscript describes human research. This study was conducted with written informed consent from the study subjects and was registered before patient enrollment. This report describes an observational clinical study and case–control observational clinical study. The authors state that the report includes every item in the Strengthening the Report of Observational Studies in Epidemiology (STROBE) checklist for case–control observational clinical studies.

Registry URL: http://www.clinicaltrials.gov/ct2/show/NCT02099253?term=NCT02099253&amp;rank=1. Identifier: NCT02099253.

Reprints will not be available from the authors.

Address correspondence to Bo Xu, MD, Department of Anesthesiology, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou 510010, China. Address e-mail to xubo333@hotmail.com.

Compared to younger patients, elderly patients often require lower doses of sedatives to achieve the same level of sedation compared with younger patients.1 Dexmedetomidine has minimal effect on respiratory drive, is a mild analgesic, and decreases airway secretions, making it ideal for sedation.2 However, minimal information is available about the influence of age on dexmedetomidine.1 The aim of this study was to investigate the influence of age on sensitivity to dexmedetomidine sedation in adult patients, we selected 79 patients scheduled for lower limb orthopedic surgery under spinal anesthesia to identify the dexmedetomidine ED50 (Dixon up-and-down method3) for adequate sedation among different age groups. We hypothesize that elderly patients will require less dexmedetomidine to achieve a near-equivalent level of sedation compared to younger patients.

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METHODS

This study was approved by the local ethics board (Guangzhou General Hospital of Guangzhou Military Command Medical Ethics Committee: February 3, 2014) and registered at ClinicalTrials.gov (NCT02099253 on March 26, 2014). Written informed consent was obtained from patients scheduled for elective lower limb orthopedic surgery. Exclusion criteria were a history of neurologic deficits, coagulation disorders, congestive heart failure or arrhythmias, bundle-branch block, severe liver and kidney dysfunction, pregnancy, allergy to dexmedetomidine, chronic alcohol use or abuse, sensory block level over T10,4 patients who had recently received antidepressant treatment, or dementia. Patients were divided into 3 groups based on age: young group, patients 18–39 years of age; middle-aged group, patients 40–64 years of age; and elderly group, patients 65–79 years of age.

Atropine 0.5 mg was injected intramuscularly 30 minutes before surgery as premedication. No sedative or analgesic was administered before dexmedetomidine. On arrival in the operating room, an intravenous (IV) cannula was inserted in the dorsum of a hand and Ringer’s lactate infusion was started. Electrocardiogram, blood oxygen saturation (Spo2), and noninvasive blood pressure were monitored. After the spinal anesthetic with 0.5% bupivacaine was administered, the dermatomal extension of block was determined by cutaneous finger pinching every 5 minutes and the patient’s position was adjusted to ensure that the upper block level was between T12 and T10. Supplemental oxygen via a Venturi mask (Guangzhou Weili Medicine Co Ltd, Guangzhou, China) at 3 L/min was administered throughout surgery. The observer’s assessment of alertness/sedation (OAA/S) scores were evaluated on a scale from 1 (no response to mild prodding or shaking) to 5 (responds readily to name spoken in a normal tone). All patients were fitted with a pair of antinoise earplugs to minimize the influence of auditory stimuli in the operating room during the study period. The OAA/S assessment was carried out by an independent observer, blinded to the dexmedetomidine dose.

Dexmedetomidine was prepared as a 50 mL solution of 4 µg/mL in 0.9% saline (Jiangsu Hengrui Medicine Co Ltd, Lianyungang, China). The dexmedetomidine solution was administered as continuous infusions using a syringe pump (Injectomat TIVA Agilia syringe pump; Fresenius Kabi Laboratories, Brezins, France) over 15 minutes. A single investigator was designated to prepare the solution of dexmedetomidine for all patients.

The initial dexmedetomidine dose was 1.0 μg/kg in the young and middle-aged groups and 0.7 μg/kg in the elderly group. Different doses were used because of safety issues in the elderly group, but these differences should not affect the results because the doses are adjusted according to the actual patients’ reactions. It was administered by the anesthetist responsible for the patients during surgery.

Based on pilot testing and other previous study5 that showed when dexmedetomidine, as dosed, was expected to have a maximal effect around 26 minutes, the 26-minute time point was selected to assess the effect of dexmedetomidine. Adequate sedation was defined as an OAA/S <3 (responsive after mild prodding and shaking).6 If the adequate sedation level was not achieved, the dose for the next patient was increased by an increment of 0.05 μg/kg. If the desired sedation was achieved, a decrease of 0.05 μg/kg was made. According to the Dixon up–and–down method, this process was repeated until the seventh crossover point was achieved in each group.7 The midpoint was defined as the mean crossover concentration. The ED50 was defined as the mean crossover midpoint in each group.

Bradycardia was defined as heart rate <50 bpm and treated with atropine 0.5 mg IV. Ephedrine 5 mg and Ringer’s lactate 5 mL/kg were administered IV for hypotension (mean blood pressure below 50 mm Hg). Hypertension was defined as a systolic blood pressure >160 mm Hg or a diastolic blood pressure >100 mm Hg, and treated with 10–50 mg urapidil IV. Rescuing procedures were reassessed every 1 minute. If Spo2 dropped below 90%, rescue was accomplished by lightly tapping on the shoulder or mild shaking with a verbal prompt. A laryngeal mask would be inserted to maintain ventilation when the patient did not respond to the stimulation.

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Statistical Analysis

Data were shown as mean ± standard deviation, median (range), or number of patients (decided by the Dixon up–and–down method). Statistical analyses were performed using SPSS 13.0 (SPSS Inc, Chicago, IL). P < .05 was considered statistically significant. The 3 age groups were compared. Continuous data that were normally distributed were compared by 1-way analysis of variance (age, weight, height, and albumin level). The Kruskal-Wallis H test was used to detect significant differences in ranked categorical variables (sensory block level and baseline OAA/S). Frequency data (eg, gender) were analyzed with the χ2 test. If there was no heterogeneity of variance across the 3 groups (based on the Levine test), the doses of 3 independent pairs were analyzed with the Bonferroni of the Tukey honestly significant difference method. Otherwise, Dunnett’s T3 was used for post hoc analysis.

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RESULTS

A total of 79 patients were enrolled. Four patients were excluded: 3 patients were inadvertently awakened before the assessment of the OAA/S and 1 patient developed an upper sensory level at T6. Therefore, 75 patients were included in the final analysis: 25 in the young group, 26 in the middle-aged group, and 24 in the elderly group. Except for age, there were no significant differences in gender, height, weight, sensory block level, albumin concentration, and baseline OAA/S scores among groups (Table).

Table.

Table.

Figure.

Figure.

Figure presents the responses of 75 consecutive patients in the 3 groups according to Dixon up–and–down method and the dose of dexmedetomidine. The dexmedetomidine ED50 estimate using the midpoint analysis was 1.21 ± 0.06, 1.16 ± 0.08, and 0.88 ± 0.07 μg/kg for the young, middle-aged, and elderly groups, respectively. There was no evidence of heterogeneity of variance of dexmedetomidine dose among the age groups (P = .451). The analysis of variance of the mean dose of dexmedetomidine revealed a significant difference among the 3 groups (P < .0001). Post hoc analysis revealed that the dexmedetomidine ED50 for the elderly group was less than that of the other 2 groups (versus the young group, P < .001; versus the middle-aged group, P < .001). There was no significant difference in the dexmedetomidine ED50 between the young and middle-aged groups (P = .160).

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Adverse Events

One patient in the middle-aged group and 2 in the elderly group had to be treated with atropine because of bradycardia. One patient in the middle-aged group and 2 in the elderly group were treated with urapidil because of hypertension. Ephedrine was used to treat 1 patient with hypotension in the elderly group. Placement of a supraglottic airway was not needed in any patient.

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DISCUSSION

We assessed the ED50 of dexmedetomidine as a sole sedative agent based on OAA/S observations in 3 different age groups undergoing lower limb surgery with a bupivacaine spinal. The dexmedetomidine ED50 for providing adequate sedation was lower in elderly patients (≥65 years) compared to younger patients. With the absence of marked alterations in dexmedetomidine pharmacokinetics with aging,1 the age-related increases in pharmacodynamic sensitivity to dexmedetomidine may be because neuronal composition, neuron number, and neuronal regeneration capacities diminish in the central nervous system with age. In addition, the number of α2-adrenoceptors in the locus ceruleus or other related receptors, the composition of these receptors, and the propagation of dexmedetomidine could be decreased in elderly patients.8 Ko et al9 showed that the ED50 of dexmedetomidine was 0.29 µg/kg (95% confidence interval, 0.14–0.44) for elderly patients, though they used different drug administration paradigm and scoring criteria. We administered the drug over a constant 15 minutes, which will induce a more gradual increase in the hemodynamics. Considering the potential risks of higher dexmedetomidine on the heart rate and blood pressure in the elderly group, our administration regimen is safer for the elderly group. Kim et al10 showed that the administration of dexmedetomidine (0.4 μg·kg−1·hr−1) decreased the emergence agitation after orthopedic surgery in elderly patients. Nevertheless, the present study shows that different doses of dexmedetomidine are necessary to achieve the same level of sedation between elderly and younger patients. In addition, there are some limitations in our study. The time point of 26 minutes we selected to determine dexmedetomidine’s efficacy might not represent the peak effect time in all patients. This time point was based on pilot testing and other previous study5 which showed that dexmedetomidine reached its peak effect plateau around 26 minutes. No other time point was used because repeatedly arousing the patient could affect the level of sedation. Another was this study performed in healthy patients and sick elderly patients who could respond differently to dexmedetomidine. Of note, differences have been reported in the Asian versus Non-Asian populations with regard to the age of patients and pharmacokinetics of dexmedetomidine.11 It should be pointed out that all subjects recruited in this study are Chinese. In summary, among patients having lower extremity surgery under a bupivacaine spinal anesthetic, we found that elderly patients (≥65 years) are more sensitive to the sedating effects of dexmedetomidine compared to younger patients.

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DISCLOSURES

Name: Bo Xu, MD.

Contribution: This author helped design and conduct the study, write the manuscript, see the original study data, review the analysis of the data, and read and approve the final manuscript.

Name: Zhitao Li, MS.

Contribution: This author helped design and conduct the study, analyze the data, write the manuscript, see the original study data, review the analysis of the data, read and approve the final manuscript, and archive the study files.

Name: Dongxu Zhou, MS.

Contribution: This author helped conduct the study, write the manuscript, see the original study data, review the analysis of the data, and read and approve the final manuscript.

Name: Liuxun Li, MS.

Contribution: This author helped design and conduct the study and read and approve the final manuscript.

Name: Pingyue Li, MD.

Contribution: This author helped conduct the study and read and approve the final manuscript.

Name: Huayang Huang, MS.

Contribution: This author helped conduct the study and read and approve the final manuscript.

This manuscript was handled by: Ken B. Johnson, MD.

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REFERENCES

1. Iirola T, Ihmsen H, Laitio R, et al.Population pharmacokinetics of dexmedetomidine during long-term sedation in intensive care patients. Br J Anaesth. 2012;108:460–468.
2. Ok HG, Baek SH, Baik SW, Kim HK, Shin SW, Kim KHOptimal dose of dexmedetomidine for sedation during spinal anesthesia. Korean J Anesthesiol. 2013;64:426–431.
3. Pace NL, Stylianou MPAdvances in and limitations of up-and-down methodology: a précis of clinical use, study design, and dose estimation in anesthesia research. Anesthesiology. 2007;107:144–152.
4. Ben-David B, Vaida S, Gaitini LThe influence of high spinal anesthesia on sensitivity to midazolam sedation. Anesth Analg. 1995;81:525–528.
5. Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MDThe effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology. 2000;93:382–394.
6. Chen Z, Shao DH, Hang LHEffects of dexmedetomidine on performance of bispectral index as an indicator of loss of consciousness during propofol administration. Swiss Med Wkly. 2013;143:w13762.
7. Park HJ, Lee JR, Kim CS, Kim SD, Kim HSRemifentanil halves the EC50 of propofol for successful insertion of the laryngeal mask airway and laryngeal tube in pediatric patients. Anesth Analg. 2007;105:57–61.
8. Samuels ER, Szabadi EFunctional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part II: physiological and pharmacological manipulations and pathological alterations of locus coeruleus activity in humans. Curr Neuropharmacol. 2008;6:254–285.
9. Ko KH, Jun IJ, Lee S, Lim Y, Yoo B, Kim KMEffective dose of dexmedetomidine to induce adequate sedation in elderly patients under spinal anesthesia. Korean J Anesthesiol. 2015;68:575–580.
10. Kim DJ, Kim SH, So KY, Jung KTEffects of dexmedetomidine on smooth emergence from anaesthesia in elderly patients undergoing orthopaedic surgery. BMC Anesthesiol. 2015;15:139.
11. Weerink MAS, Struys MMRF, Hannivoort LN, Barends CRM, Absalom AR, Colin PClinical pharmacokinetics and pharmacodynamics of dexmedetomidine. Clin Pharmacokinet. 2017;56:893–913.
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