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. 2019 Dec 12;86(1):85–92. doi: 10.1111/bcp.14137

The association of the optimal bolus of dexmedetomidine with its favourable haemodynamic outcomes in adult surgical patients under general anaesthesia

Cheng‐yu Wang 1,2, Fang Chen 1,2, Junzheng Wu 3, Shu‐ying Fu 1,2, Xi‐mou Xu 1,2, Jia Chen 1,2, Yi‐fei Jiang 1,2, Qingquan Lian 1,2,✉, Hua‐cheng Liu 1,2,✉
PMCID: PMC6983508  PMID: 31656042

Abstract

Aims

Dexmedetomidine is highly specific α2‐adrenoceptor agonist. A single bolus of dexmedetomidine can achieve clinical therapeutic effect. Therefore, it is essential to know the safety margin between the clinical effectiveness dosages of dexmedetomidine and its side effect.

Methods

A total of 42 patients who underwent elective thyroidectomy were enrolled in this study. Dexmedetomidine was given as a single bolus injection 30 min towards the end of surgery. The up‐and‐down sequential schedule was used in this study. The starting dose of dexmedetomidine was set at 0.1 μg/kg in the first patient and the next patient would then receive a dose of dexmedetomidine decremented by 0.05 μg/kg if the prior patient's baseline heart rate (HR) had a decrease of ≥20% and/or mean arterial blood pressure (MAP) increase or decrease of ≥20%, otherwise, the following patient would receive an incremental 0.05 μg/kg dose of dexmedetomidine. The analytic techniques of linear, linear‐logarithmic, exponential regressions and centred isotonic regression were used to determine the ED50 of dexmedetomidine and the residual standard errors were calculated for the comparison of goodness of fit among the different models.

Results

The median (interquartile range [range]) lowest HR was 57 beats/min (53–63.3[46–76]) with an average HR decrease of 8.0 beats/min (5–13 [4 to 23]). The median (interquartile range [range]) highest MAP was 98 mmHg (91.8–105 [83–126]) with a MAP increase of 10.0 mmHg (6.8–18.0 [2–24]). The ED50 (95% confidence interval) from 4 different statistical approaches (linear, linear‐logarithmic, exponential regressions and centred isotonic regression) were 0.262 μg/kg (0.243, 0.306), 0.252 μg/kg (0.238, 0.307), 0.283 μg/kg (0.238, 0.307), and 0.278 μg/kg, respectively. Among the 4 models, the exponential regression had the least residual standard error (0.03618).

Conclusion

The ED50 derived from 4 statistical models for an intravenous bolus of dexmedetomidine without significant haemodynamic effects was distributed in a narrow range of 0.252–0.283 μg/kg, and the exponential regression was the model to best match the study data.

Keywords: adult, dexmedetomidine, general anaesthesia, haemodynamic

What is already known about this subject

  • Some authors have reported cases of single rapid bolus of dexmedetomidine (ED50) without significant haemodynamic changes in children.

What this study adds

  • This study was designed to investigate how well the optimal single bolus dose of dexmedetomidine correlate to its favourable haemodynamic stabilities (ED50) in adults who underwent elective thyroidectomy under general anaesthesia. No similar studies are found in adults under general anaesthesia.

1. INTRODUCTION

https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=521 (DEX) is a highly selective https://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=4 agonist widely used in clinical practice; it produces sedative, anxiolytic, analgesic, anti‐sympathetic and neuroprotective effects.1, 2, 3, 4, 5 A single bolus dose without subsequent infusion has been shown to reduce postoperative analgesic requirements,6 mitigate emergence agitation,7, 8 provide smoother extubation conditions,9 and treat emergence delirium10 and postoperative shivering11 effectively. Sedative effects without respiratory depression may be a particular advantage in adults who are at particular risk of opioid‐ and anaesthetic‐induced respiratory complications postoperatively.12

A loading dose of DEX infused over 10 min has been routinely administrated to mitigate side effects such as of hypertension and bradycardia.13 However, this method goes with some obvious disadvantages, such as inconvenient preparation and time‐consuming, which may dramatically affect the efficiency of surgical turn‐over in case‐loaded busy operating rooms. ED50 is a commonly used important index for determination of the therapeutic level and toxic effects of a drug; it is defined as the dose or amount of a drug that produces a desired response or effect in 50% of the patients taking it. In our study, ED50 means that at the target dose of DEX, 50% of patients had favourable haemodynamic response (<20% of baseline fluctuation) as we desired. It has been reported that ED50 for a single dose14 of DEX does not show significant haemodynamic changes in paediatric patients. However, no similar studies are found in adults under general anaesthesia. The purpose of this study was to investigate the correlation between the optimal single bolus dose of DEX and its favourable haemodynamic stabilities (ED50) in adult surgical patients who underwent elective thyroidectomy under general anaesthesia.

2. METHODS

This study was approved by the Ethics Committee of The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University and registered at http://ClinicalTrials.gov (NCT03655847). Each patient participating in the study gave written informed consent.

Patients who underwent elective and 2 hours less thyroidectomy under general anaesthesia, with American Society of Anesthesiologists physical status I or II, body mass index 18–28 kg/m2 and age 18–55 years, were enrolled in this study. The exclusion criteria included patients with suspected difficult airway, cardiopulmonary dysfunction (e.g. bronchial asthma, chronic obstructive pulmonary disease and restrictive pulmonary disease), liver or kidney dysfunction, neuromuscular diseases, and allergic to active ingredients. Patients who had received DEX or any other α1 or α2 adrenergic receptor agonist or antagonist in the last 3 months were also excluded from this study.

No premedication was given. On arriving in the operating room, all patients were monitored with electrocardiography, noninvasive blood pressure, pulse oximetry and bispectral index. Anaesthesia was induced with intravenous propofol 2–2.5 mg/kg, fentanyl 3–5 μg/kg and cisatracurium 0.2 mg/kg. Patients were mechanically ventilated after tracheal intubation and anaesthesia was maintained with 1.1–1.3 minimum alveolar concentration sevoflurane in 60% oxygen throughout the surgery.

Patients' haemodynamics were monitored with PHILIPS‐IntelliVue MX550 monitor. Electrocardiogram and pulse oximetry were continuously observed and noninvasive blood pressures were intermittently taken every 5 min for the most time of surgical procedure. The DEX study started about 40 min from the end of surgery. For the baseline establishment, the patient's heart rates (HRs) were collected in an interval of 2 min synchronized with the recordings of measured blood pressure in every 2 min. Five paired data of HR and blood pressure were obtained during the period of 10 min and the medians of HRs and blood pressures were calculated separately as baselines. Then, DEX (10 μg/mL by diluting 200 μg/2 mL into 18 mL normal saline) was intravenously administrated over 60 s approximately 30 min after the thyroid gland was removed, and the HR and blood pressure were registered every minute for 10 min. For the dose schedule, the first patient received 0.1 μg/kg DEX, and the dose for each subsequent patient was decided on the previous patient's haemodynamic response which was determined by the modified Dixon's up‐and‐down method (UDM: see below). The study was completed after DEX administration followed by 10‐min data collection. Then, noninvasive blood pressure, HR and pulse oximetry readings were registered every 5 min for the rest of the surgery and in the postanaesthesia care unit per standard protocol.

Rescue medications (glycopyrrolate 10 μg/kg, atropine 20 μg/kg, ephedrine 5 mg/mL and epinephrine 10 μg/mL) were prepared prior to the start of surgery. Bradycardia (absolute HR ≤45 beats/min) with hypotension (mean arterial blood pressure [MAP] decrease ≥30% of baseline) were required to be treated with glycopyrrolate 10 μg/kg or atropine 20 μg/kg, and more treatments could be given if the haemodynamic parameters did not return to the preset limits in subsequent reassessment. Other interventions would be taken at the anaesthesiologist's discretion, including adjustment of minimum alveolar concentration or intravenous ephedrine 0.1 mg/kg. Bradycardia (absolute HR ≤45 beats/min) accompanied with an increased blood pressure (MAP increase of ≥30% of baseline) was observed for 1 min, and the clinical management was left to the clinician's discretion if this situation existed persistently.

2.1. UDM

The dose schedules for each subsequent subject were determined based on the haemodynamic responses according to UDM result from the previous patient. HR decrease of ≥20% and/or MAP increase or decrease of ≥20% (unfavourable haemodynamic response) compared to pre‐DEX baseline values during the 10‐min observation period would prompt a dose reduction (0.05 μg/kg as 1 step size) and if the changes of those haemodynamic parameters were <20% (favourable haemodynamic response) off the baseline would prompt a dose increase of 0.05 μg/kg in the following patient. Haemodynamic data were recorded every minute for 10 min after DEX was given.

Our preliminary work found that 0.1 μg/kg of DEX will not cause significant haemodynamic changes, while the doses up to 0.4 μg/kg could result in severe haemodynamic alterations. Therefore, we selected 0.1 μg/kg as the starting dose and the up‐or‐down step sizes of doses were set at 0.05 μg/kg.

2.2. Sample size

In most cases, the exact sample size for Dixon's UDM could not be determined in advance. Patient recruits were ceased when 6 crossovers (conversion from favourable haemodynamic response to unfavourable response or vice versa) had occurred.14, 15 Our simulation studies in anaesthesia trials using the Dixon's UDM suggested that at least 20–40 patients will be required to provide reliable estimates of the target dose.16 The goal was reached when 42 patients were recruited in our study.

2.3. Statistical analysis

A case report form was designed on paper for registration of all patient's clinical data and study results, and all of information were transferred to Excel spreadsheet (Microsoft Corporation, Redmond, WA, USA) after the study was over. The guideline of good clinical practice was closely followed during the study. One study team member was specifically assigned to the job of data collection, filing and transfer, ensuring the data's accuracy, as well as safety and patient privacy. The haemodynamic data were visualized and estimated using R (R Foundation for Statistical Computing, Vienna, Austria) while model building.

Four statistical approaches were used to explore the target dose ED50, including 3 parametric estimates of dose responsive curve16: linear, linear‐logarithmic and exponential regressions, and 1 nonparametric model: the centred isotonic regression, which was only for assuming a nondecreasing dose and response relationship.17

Residual standard errors, a statistical tool to determine the goodness of fit, which analyses how well a set of data points fit with the actual model, were calculated for all 4 statistical approaches.

2.4. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY,18 and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16.19

3. RESULTS

A total of 42 patients were recruited and completed the study successfully. The study protocol was carried out by a total of 5 trained anaesthetists. The median age (interquartile range [IQR]) for 42 subjects (9 males) was 45.50 (42.55–47.17) years, median weight (IQR) 59.50 (56.73–62.06) kg, median height (IQR) 160 (159.23–162.66) cm and median duration of surgery (IQR) 57 (56.35–64.37) min. The final crossover was reached at when the 42nd patient's data were finalized (Figure 1).

Figure 1.

Figure 1

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Study trajectory of haemodynamic response to a dexmedetomidine bolus, starting at a dose of 0.1 μg/kg and concluding at 0.35 μg/kg. Heart rate decrease of ≥20% and/or mean arterial blood pressure increase or decrease of ≥20% (unfavourable haemodynamic response) compared to pre‐dexmedetomidine baseline values during the 10‐min observation period would prompt a dose reduction (0.05 μg/kg as 1 step size) and if the changes of those haemodynamic parameters were <20% (favourable haemodynamic response) off the baseline would prompt a dose increase of 0.05 μg/kg in following patient

The maximum HR changes occurred at 60s after a single bolus of DEX administration; the median (IQR [range]) lowest HR was 57 (53–63.3 [46–76]) beats/min accompanied by HR decrease of 8.0 (5–13 [4–23]) beats/min. The maximum MAP changes were as follows: the median (IQR [range]) highest MAP was 98 (91.8–105 [83–126]) mmHg with a MAP increase of 10.0 (6.8–18.0 [2–24]) mmHg occurring at 156 s (Figure 2).

Figure 2.

Figure 2

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Hemodynamic response to dexmedetomidine bolus. The top plot shows the relative heart rate (HR) changes (beats/min), normalized to each patient's baseline value; (0 = baseline HR) similarly, the relative mean noninvasive blood pressure (MAP) changes (mmHg), normalized to each patient's baseline value, (0 = baseline MAP) are shown on the bottom plot. The raw data are superimposed by population percentiles (5th, 50th and 95th centiles) in blue lines, green lines and red lines, respectively and measurements violating the ±20% MAP baseline and HR ≤20% baseline are highlighted with large grey dots

By analysing the results from the full dataset of continuous haemodynamic values, we found that 26 subjects (62%) had developed bradycardia (HR <60 beats/min) and 5 subjects had their absolute MAP <70 mmHg; however, none of subjects had both. Those patients did not receive any treatment with rescue medications because their haemodynamic fluctuations were deemed as nonharmful events by the attending anaesthesiologist. Figure 3 shows the lowest values of HR and MAP for each subject vs DEX dose.

Figure 3.

Figure 3

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Lowest recorded mean arterial blood pressure (MAP) and lowest recordedHeart rate (HR). Data are split by dexmedetomidine dose. Each plot shows raw data as a dot plot overlaid with quartile boxes (1st quartile, median value and 3rd quartile)

The linear model estimator led to an ED50 of 0.262 μg/kg, the linear‐logarithmic model resulted in an ED50 value of 0.252 μg/kg, the exponential regression gave an ED50 of 0.283 μg/kg, and the centred isotonic regression (a nonparametric method) yielded an ED50 of 0.278 μg/kg (see Figure 4). The 95% confidence intervals for the 3 parametric models (linear, linear‐logarithmic and exponential) were 0.243, 0.306; 0.238, 0.307; and 0.238, 0.307 μg/kg, respectively (Table 1) and they showed similar fitted probabilities within the range of the ED50, and the 95% confidence intervals from these models successfully covered all observed data except for dose level 0.35 μg/kg or above with all 5 subjects presenting unfavourable haemodynamic responses.

Figure 4.

Figure 4

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Estimated dexmedetomidine–haemodynamic response relationship for a given dose level and probability of unfavourable haemodynamic response pair. Median estimators for each model are plotted. The numbers of measurements at each dexmedetomidine dose are represented by numbered triangles

Table 1.

The ED50 and 95% confidence interval (CI) of different models

Model ED50 (μg/kg) 95%CI (μg/kg) Residual standard error
Centred isotonic
Regression 0.278
Linear 0.262 0.243, 0.306 0.1311
Linlog 0.252 0.238, 0.307 0.2041
Exponential 0.283 0.238, 0.307 0.03618
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The results of residual standard deviations for goodness of fit of each model were showed in Table 1. The exponential regression has the least residual standard error (0.03618) among the all models.

3.1. Adverse events

Among the 19 subjects with their HR decrease of ≥20% and/or MAP increase or decrease of ≥20% as responses to the DEX bolus, 10 had bradycardia (HR ≤ 20% baseline), 16 had hypertension (MAP ≥20%baseline), 3 had hypotension (MAP ≤20%baseline), 9 had bradycardia and hypertension, and 1 had hypotension and bradycardia (Table 2). The highest MAP observed was 126 mmHg (22% increase from baseline) and the lowest HR was 46 beats/min (21% decrease from baseline). No intervention was taken for those events since the patients' pulses and peripheral perfusions remained consistently adequate throughout the study time and all of the haemodynamic changes were considered as benign alterations by the anaesthesiologist. There were no other adverse events such as drowsiness prior to discharge.

Table 2.

Adverse events

Adverse event Number
Bradycardia 10
Hypertension 16
Hypotension 3
Bradycardia and hypertension 9
Hypotension and bradycardia 1
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4. DISCUSSION

We have used UDM to study the ED50 of a single intravenous bolus injection of DEX without significant haemodynamic compromise in adult surgical patients under general anaesthesia. The study results showed that the values of ED50 among the all statistical models stayed in a very narrow range of 0.252–0.283 μg/kg, and the exponential regression model, which had the best goodness of fit in this study, yielded an ED50 of 0.283 μg/kg.

In comparison to controlled studies, 1 advantage of UDM is that it offers a simpler and more practical way to obtain an accurate ED50 with lower patient requirement. UDM was chosen as dose‐finding technique in our study over continuous reassessment methods (CRMs) because CRM is a model‐based design and more suitable to estimate the maximal tolerance dose (ED95) while UDM is more suitable for ED50 calculation with its advantages of simplicity and lower sample requirement. Therefore, we selected UDM.

All patients had preoperative diagnosis of benign thyroid adenoma, which was consistent with postoperative pathological findings. A euthyroid status was confirmed by laboratory tests to rule out hyper‐ and hypothyroidism prior to surgical procedure. Patients were scheduled for elective subtotal thyroidectomy once diagnosis was made.

DEX (0.5–1 μg/kg) in a single bolus20, 21, 22 was well tolerated in adults, and it blunts haemodynamic and hormonal responses to tracheal intubation, reduce opioid and anaesthetic requirements, and improve the quality of postoperative analgesia. The use of lower doses (0.3 μg/kg) infused over 10 min is associated with insignificant haemodynamic changes.22 According to our preliminary study results, we set the starting dose of DEX at 0.1 μg/kg with rapid injection over 60 s.

Three parametric statistical models (linear, linear‐logarithmic and exponential) were used to determine ED50 and 95% confidence interval and 1 nonparametric method (centred isotonic) was also used to calculate ED50 to provide the extra layer of comparison. The centred isotonic regression is a commonly used, simple and fast statistical approach for nonparametric estimation in dose–response and dose‐finding studies. It does not require a specific form of the relationship, and is more suitable for analysing study data than the UDM. Results showed that the values of ED50 from 4 models were distributed in a narrow range of 0.252–0.283 μg/kg. The 95% confidence intervals for 3 parametric models had similar fitted probabilities within the range of the ED50, and the 95% confidence intervals from those models covered all observed data in a dose range of 0.1–0.35 μg/kg.

In reality, different models may not universally fit well to a certain study. Maybe only 1 of a few statistic techniques will match study data more perfectly than others. The test of goodness of fit would help to solve the dilemma. For the next step, we calculated the residual standard deviation to analyse how a group of variables fit well with the actual model and to assess the strength of goodness of fit for each model. The results showed that the exponential regression model had the least residual standard error (0.03618); that is, this statistical model fitted the study data better than our other statistical models. This phenomenon can be easily identified in Figure 4.

DEX has a biphasic effect on haemodynamics, which is mainly dependent on plasma drug concentration and intravenous injection rate. A rapid bolus of DEX would cause peripheral vasoconstriction and bradycardia. Our study results showed that a median absolute HR reduction (8.0 beats/min) occurred at 60 s, and HR persistently remained at a low level during the 10‐min observation period. Apart from sinus bradycardia, no other cardiac dysrhythmias were observed. The decreases of HR after rapid injection of a bolus of DEX in our study were brief and transient. One study showed that the peak of HR decrease occurred at 3 min and lasted for 11 min after giving 0.25–2 μg/kg of DEX over 2 min in healthy adult volunteers.23 Another study reported that after receiving a rapid DEX boluses (0.25 or 0.5 μg/kg over 5 s), children developed sustained decreases in HR (in the 0.5 μg/kg group) for 10 min.24 The sympathetic suppression seen with such low doses would be considered a desirable clinical effect during surgical stimulation. The trend toward a sustained decrease in HR should be investigated in future studies. The causes for bradycardia are likely to be multifactorial. Particularly in patients under general anaesthesia, anaesthetic drugs and agents, such as opioids and sevoflurane may play synergistic roles with DEX.

A median absolute MAP increase of 10.0 mmHg was observed at 156 s, and these values returned to baseline after 7 min. It is uncertain whether the decrease in MAP following the initial increase is due to biphasic blood pressure effect of the DEX or the operation factors. These MAP changes were short lived and no treatment was required. Other studies in adults4 also described biphasic responses to a single DEX bolus. The effect of DEX on haemodynamics is mainly dependent on plasma drug concentration and intravenous injection rate.25 A biphasic cardiovascular response has been reported for DEX with a transient hypertension followed by hypotension.26, 27 The transient hypertension can be avoided by a slow infusion.28, 29 DEX causes peripheral vasoconstriction and bradycardia when the plasma concentration exceeds 1000 pg/mL.30, 31 The initial BP elevation is thought to be due to stimulation of peripheral postsynaptic α2‐adrenergic receptors resulting in vasoconstriction with the subsequent decrease in BP due to central presynaptic α2A‐adrenergic receptor‐stimulated sympatholysis.32 It is believed that another potential cause for the elevated MAP might be function of thyroid hormone released from thyroid glands during the surgeon's manipulation. In our study, we can rule out the involvement of thyroid hormone in the haemodynamic changes since all of our patients had benign thyroid mass with normal thyroid function.

One subject (age 40 years, 50 kg) experienced significant bradycardia of 47 beats/min and hypotension of 63 mmHg following 0.2 μg/kg DEX bolus, the baseline of HR and MAP were 63 beats/min, 78 mmHg, respectively. The attending anaesthesiologist (J.M.A.) chose not to treat this bradycardia and hypotension and the HR recovered to 60 beats/min within 60 s. Bradycardia and hypotension following DEX bolus were frequently treated in early studies,33 but a recent report34 based on clinicians' experiences suggested that the pretreatment and treatment of bradycardia and hypotension are not mandatory because they tend to be very brief and self‐limiting events without clinical sequelae.

4.1. Limitations

UDM allows determination of an ED50 for a clinical variable with a binary outcome,35 in a smaller sample size. It is also known that the UDM is not reliable for calculating small or large percentage points, such as the ED95,36 which is a more relevant indicator for clinical application. Although the ED95 level may be more useful for clinical purposes, the results of our simulation calculations in 42 small samples were significantly less accurate.

When ED50 is calculated using the UDM, the premise is that the dose‐effect relationship is the traditional s‐shaped curve, which may be incorrect. It is not accurate to speculate the ED95.

4.2. Future study design

This study provides preliminary data that could be used to determine the ED95 (safe level) of bolus DEX. Other study designs, such as biased coin design (BCD) and CRM, may be more appropriate for an ED95 study. BCD is used on the outcome of the preceding subject. Simulated BCD with 2000 iterations suggests that 153 subjects (step size 0.01 μg/kg) or 140 subjects (step size 0.025 μg/kg) are necessary. The CRM method uses the outcomes from previous subjects together with clinical experience; therefore, it only requires a smaller sample size than BCD.37 The rule of thumb formula suggests that 52 subjects are necessary for CRM.

In summary, the study has investigated the correlation between a single bolus of DEX and the prompting haemodynamic response in adult surgical patients under general anaesthesia. The values of ED50 analysed by 4 different statistical models fell in a close range of 0.262–0.283 μg/kg. The exponential regression fitted the data best in this study, with ED50 of 0.283 μg/kg. Future studies will focus on single bolus of DEX to achieve safe and effective clinical outcome, using well‐defined clinical endpoints.

COMPETING INTERESTS

There are no competing interests to declare.

CONTRIBUTORS

F.C., S.F and X.X. contributed to the data collection. J.C. and Y.J. contributed to Statistical analysis. C.W. and J.W. contributed to the statistical analysis and writing of the article. Q.L. and H.L. Liu contributed to the study design.

ACKNOWLEDGEMENTS

The research was funded by Zhejiang Provincial Natural Science Foundation (LY17H310006) and Clinical Research Foundation of the Second Affiliated Hospital of Wenzhou Medical University (SAHoWMU‐CR2018‐03‐126).

Wang C‐y, Chen F, Wu J, et al. The association of the optimal bolus of dexmedetomidine with its favourable haemodynamic outcomes in adult surgical patients under general anaesthesia. Br J Clin Pharmacol. 2020;86:85–92. 10.1111/bcp.14137

The authors confirm that the Principle Investigator for this paper was Dr Huacheng Liu who had direct clinical responsibility for patients.

Contributor Information

Qingquan Lian, Email: lianqingquanmz@163.com.

Hua‐cheng Liu, Email: huachengliu@163.com.

DATA AVAILABILITY STATEMENT

Publicly available datasets were analysed in this study. These data can be found here: https;//www.clinicaltrials.gov (NCT03655847).

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Publicly available datasets were analysed in this study. These data can be found here: https;//www.clinicaltrials.gov (NCT03655847).

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

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