DOI: https://doi.org/10.21203/rs.3.rs-1780506/v1
Background: Sedation with dexmedetomidine is needed for patients undergoing spinal anesthesia. However, dexmedetomidine sedation increases the incidence of bradycardia. We aimed to identify and evaluate risk factors for bradycardia in patients undergoing spinal anesthesia with dexmedetomidine sedation.
Methods: The records of 91 patients who underwent spinal anesthesia with sedation using dexmedetomidine were reviewed retrospectively. For this study, we identified 15 characteristics of included patients from this group who underwent lower leg surgery and had an estimated blood loss of <300 mL. We collected details on potential risk factors for bradycardia from their clinical records. These factors included age, American Society of Anesthesiologists classification, height, weight, sensory level of spinal anesthesia, history of hypertension, diabetes mellitus, loading and maintenance dose of dexmedetomidine, tourniquet time, initial diastolic and systolic blood pressure, initial heart rate (HR), and anesthesia and surgery duration. The primary endpoint of this study was the occurrence of bradycardia. We identified potential risk factors using logistic regression analysis.
Results: The incidence of bradycardia was seen in 23 (25.3%) of 91 patients. Initial HR and tourniquet time were significant individual predictive factors for the occurrence of bradycardia. Logistic regression analysis showed that adjusted baseline HR and duration of tourniquet use were risk factors for bradycardia.
Conclusion: Patients should be monitored when undergoing spinal anesthesia with sedation using dexmedetomidine for bradycardia when they have a long tourniquet time. A low initial HR could also be a predictive factor for bradycardia.
Patients receiving spinal anesthesia are sedated to improve the patient’s experience, anesthesia compliance, and to induce anterograde amnesia.[1] Intravenous midazolam, ketamine, propofol, and dexmedetomidine are commonly used sedatives during spinal anesthesia. Dexmedetomidine is a highly selective α2-adrenoceptor agonist with anxiolytic, analgesic, sedative, and sympatholytic effects.[2] This sedative causes less hemodynamic instability and no or minimal respiratory depression.[3] Intraoperative administration of dexmedetomidine prolongs the duration of sensory and motor blockade and reduces opioid requirement in the first 24 h after surgery.[4] Dexmedetomidine is also associated with a decrease in the occurrences of postoperative shivering.[5] These advantages had led to the common use of continuous intravenous dexmedetomidine during spinal anesthesia.
However, sedation with dexmedetomidine may increase the incidence of bradycardia and hypotension, requiring treatment.[6] Dexmedetomidine has a sympatholytic action that can exacerbate hypotension and bradycardia resulting from spinal anesthesia.[7] Intraoperative hypotension is associated with postoperative mortality and organ damage, such as acute kidney injury, myocardial injury, ischemic stroke, and delirium.[8] It is important to prevent the occurrence of hypotension and bradycardia during spinal anesthesia to reduce postoperative complications. Therefore, we aimed to identify the risk factors for dexmedetomidine-associated hemodynamic instability during spinal anesthesia. This is the first study to identify these risk factors.
This retrospective study identified 91 adult patients who underwent lower-extremity orthopedic surgery under spinal anesthesia combined with sedation by intravenous dexmedetomidine at a university hospital between May 2015 and December 2016. This study was approved by Seoul Paik Hospital, Inje University Institutional Review Board (2019-07-005-003). The requirement for informed consent was waived by Seoul Paik Hospital, Inje University Institutional Review Board since we used de-identified administrative claims data. All methods were performed in accordance with the relevant guidelines and regulations.
Patients who were younger than 20 years of age or whose estimated blood loss during surgery was > 300 ml were excluded. Baseline demographics abstracted from the file included age, sex, height, weight, American Society of Anesthesiologists (ASA) classification, and past medical history. In addition, we recorded the sensory level of spinal anesthesia, loading and maintenance dose, tourniquet time, initial systolic and diastolic blood pressure (SBP and DBP, respectively), initial heart rate (HR), and duration of anesthesia and surgery. Vital signs were recorded on the anesthesia record every 5 min, but the HR at the time of the bradycardia event may not be recorded. Therefore, bradycardia was defined in this study as at least one episode in which the anesthesiologist administered a vasopressor or anticholinergic agent. We evaluated the HR between the start of anesthesia and tourniquet-off time to rule-out tourniquet-associated hemodynamic changes. If the reading of preoperative electrocardiogram(ECG) is not normal sinus rhythm, we defined it as an abnormal ECG.
At our institution, we use a standard regimen of dexmedetomidine where the loading dose is 0.6 mcg/h for 10 min, followed by the maintenance dose of 0.3 mcg/kg/h. The dose of dexmedetomidine is adjusted as needed by the anesthesiologist in charge. The recommended maximum dose is 0.7 mcg/kg/h and dose titration is aimed at a Richmond stirring sedation scale level of -2. If an adequate level of sedation is not achieved with dexmedetomidine, 1 mg of intravenous midazolam is administered. Hypotension is defined as a 30% reduction in baseline SBP or an SBP of < 90 mmHg. It is treated with 5 mg of ephedrine or 50–100 mcg of phenylephrine intravenously. Bradycardia, defined as a 30% reduction in baseline HR or an HR of < 45 beats per min (bpm), is treated with 0.25–0.5 mg of atropine or 0.2 mg of glycopyrrolate intravenously.
The statistical analysis was performed with IBM SPSS® Software for Windows, version 20 (IBM, Armonk, NY). Continuous variables are expressed with means ± standard deviations or medians with an interquartile range. The Shapiro–Wilk test was performed to test for normality for continuous variables. The Mann–Whitney U test was used to compare non-normal data, while an independent t-test was used to compare normal data. Categorical variables, expressed as frequencies and percentages, were analyzed using the chi-square test. We applied logistic regression analysis to analyze the risk factors associated with development of bradycardia during anesthesia. We selected variables with P < 0.2 from the univariate analysis to include in the multivariate analysis. Independent risk factors are presented as odds ratios (OR) with 95% confidence intervals (CIs). Receiver operating characteristic (ROC) curves were used to evaluate the sensitivity and specificity of risk factors. The cutoff value for each risk factor was determined by the maximum area under the curve (AUC) of the ROC curve. We defined statistical significance at P < 0.05 for all analyses.
The baseline clinical characteristics of the patients are presented in Table 1. Twenty-three (25.3%) patients experienced bradycardia during their surgery using spinal anesthesia and intravenous dexmedetomidine. The remaining 68 patients were included in the comparison group.
Table 1. Univariable analysis of baseline characteristics
|
|
Bradycardia (n=23) |
Without bradycardia (n=68) |
P value |
|
Sex Male Female |
13 (56.5%) 10 (43.5%) |
45 (66.2%) 23 (33.8%) |
0.561 |
|
Age (years) |
30 [25; 55] |
47.5 [33; 56] |
0.059 |
|
BMI (kg/m2) |
25.2±3.1 |
24.9±3.0 |
0.647 |
|
ASA PS 1 2 |
19 (82.6%) 4 (17.4%) |
47 (69.1%) 21 (30.9%) |
0.326 |
|
Previous medical history Hypertension Diabetes Liver disease |
1 (4.3%) 1 (4.3%) 4 (17.4%) |
11 (16.2%) 5 (7.4%) 8 (11.8%) |
0.274 0.987 |
|
Abnormal ECG |
5 (21.7%) |
17 (25.0%) |
0.973 |
|
Baseline SBP (mmHg) |
125.0 [116.5; 132.5] |
130.0 [122.5; 140.0] |
0.051 |
|
Baseline DBP (mmHg) |
75.0 [67.5; 82.0] |
80.0 [73.5; 85.0] |
0.123 |
|
Baseline HR (bpm) |
65.0 [56.5; 69.5] |
75.0 [65.0; 82.0] |
0.000 |
|
Sensory level >T6 level <T7 level |
5 (21.7%) 18 (78.3%) |
8 (11.8%) 60 (88.2%) |
0.403 |
|
Duration of surgery (min) |
85.0 [60.0; 105.0] |
65.0 [40.0; 97.5] |
0.144 |
|
Duration of anesthesia (min) |
130.0 [107.5; 155.0] |
107.5 [82.5; 145.0] |
0.104 |
|
Tourniquet time (min) |
85.0 [60.0; 107.5] |
62.5 [35.0; 87.5] |
0.004 |
|
Recovery time (min) |
35.0 [27.0; 61.0] |
42.0 [32.0; 56.0] |
0.483 |
|
Dexmedetomidine Loading dose (mcg/kg) Maintenance dose (mcg/kg/h) Total infused dose (mcg/kg) |
0.7 [ 0.7; 0.7] 0.3 [ 0.3; 0.3] 28.6 [20.8; 37.4] |
0.7 [ 0.7; 0.7] 0.3 [ 0.3; 0.3] 23.4 [14.7; 33.0] |
0.724 0.507 0.191 |
Values are presented as numbers (%), medians with [interquartile ranges], or mean±standard deviation. BMI, body mass index; ASA PS, American Society of Anesthesiologists physical status; ECG, electrocardiography; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; bpm, beats per minute
In univariate analysis, there were no differences in sex; age; body mass index; ASA physical status; previous medical history of hypertension, diabetes, or liver disease ECG abnormality; baseline SBP and DBP; sensory blockade level; surgery and anesthesia duration; recovery time; and loading, maintenance, or total infused dose of dexmedetomidine between patients with and without bradycardia. A significant difference was observed in the baseline HR and tourniquet time between patients with and without bradycardia (P<0.05).
In addition to these two significant variables, six additional variables were identified as potential effect modifiers in a multivariable logistic regression analysis model (Table 2). Only baseline HR and tourniquet time were found to be significant independent risk factors of bradycardia during spinal anesthesia combined with dexmedetomidine infusion. The lower the baseline HR, the greater the risk of developing bradycardia (OR 0.89, 95% CI 0.82–0.96, P=0.005). A longer tourniquet time was a significant risk factor for bradycardia (OR 1.06, 95% CI 1.02–1.1, P=0.004).
Table 2. Logistic regression analysis of selected variables
|
|
Odd ratio (95% CI) |
P value |
|
Age |
0.97 (0.92–1) |
0.099 |
|
Baseline SBP |
0.98 (0.92–1.03) |
0.388 |
|
Baseline DBP |
1.01 (0.93–1.09) |
0.871 |
|
Baseline HR |
0.89 (0.82–0.96) |
0.005* |
|
Duration of surgery |
1.05 (0.99–1.13) |
0.118 |
|
Duration of anesthesia |
0.97 (0.94–1) |
0.061 |
|
Tourniquet time |
1.06 (1.02–1.1) |
0.004* |
|
Total infused dose of dexmedetomidine |
0.88 (0.75–1.04) |
0.123 |
SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; CI, confidence interval
Our study also showed a correlation between low baseline HR and bradycardia development. In terms of age, patients who developed bradycardia had a median age of 30 years, which was lower than that of patients who did not develop bradycardia; however, the difference was not statistically significant. High sensory block levels >T6 were identified in 21.7% and 11.8% of patients with and without bradycardia, respectively, but there was no statistical significance.
Patients with bradycardia had longer surgery and anesthesia duration than those who did not develop bradycardia, but the difference was not statistically significant. The total infused dose of dexmedetomidine was higher in patients with bradycardia than in those without.
In this study, a long tourniquet time was demonstrated to be a significant risk factor for the development of bradycardia during spinal anesthesia combined with dexmedetomidine sedation (OR 10.6, P=0.004).
We performed a receiver operating curve analysis and found that the optimal baseline HR threshold for predicting bradycardia was < 73 bpm (sensitivity, 91.3%; specificity, 57.4%). The AUC for a cutoff value of 73 bpm was moderately accurate for predicting bradycardia (AUC, 0.764; 95% CI 0.663–0.865, P<0.001) (Figure 1). The tourniquet time threshold for estimating the development of bradycardia was >72.5 min (sensitivity 69.6%; specificity 61.8%). A cut-off value of 72.5 min was moderately accurate for estimating the risk of bradycardia (AUC, 0.701; 95% CI 0.577–0.826; P=0.004) (Figure 2).
In this study, we aimed to identify risk factors for dexmedetomidine-associated bradycardia during spinal anesthesia. Baseline HR and tourniquet time were independent risk factors associated with bradycardia during spinal anesthesia combined with dexmedetomidine infusion. The estimated threshold of the baseline HR predicting bradycardia was < 73 bpm. An estimated tourniquet time of 72.5 minutes was a threshold for bradycardia.
Although an intravenous infusion of dexmedetomidine can induce satisfactory sedation during spinal anesthesia, hemodynamic instability, such as bradycardia, hypotension, and transient hypertension, may occur.[9] In this study, the incidence of bradycardia was 25.3% in patients who underwent spinal anesthesia combined with sedation with dexmedetomidine. Bradycardia is defined as an HR of < 60 bpm, and bradycardia requiring intervention during anesthesia is generally considered to be an HR of < 50 bpm. It has been reported that bradycardia has a 13% incidence rate owing to sympathetic nerve blockade after spinal anesthesia. [7] Dexmedetomidine reduces blood pressure, HR, and plasma catecholamine levels in a dose-dependent manner.[10] The incidence of bradycardia after spinal anesthesia combined with intravenous dexmedetomidine administration has been reported to be 20–30%.[11, 12] The risk factors for bradycardia in spinal anesthesia hare underlying HR of < 60 bpm, male sex, age < 37 years, current treatment with beta-blockers, and sensory blocker level of ≥ T5.[7, 13]
Tourniquets are commonly used in orthopedic surgery to reduce blood loss during upper or lower extremity surgeries. Hemodynamic changes associated with tourniquet inflation are described as hyperdynamic. Tourniquet inflation leads to an increase in the HR, SBP, and DBP that persist until tourniquet deflation.[14] A recent study reported that dexmedetomidine attenuates hyperdynamic response in patients undergoing lower extremity surgery using a tourniquet.[15] Therefore, the increased risk of bradycardia development with the increase in tourniquet time shown in this study can be thought of as an effect of dexmedetomidine.
Dexmedetomidine-induced hemodynamic instability is manifested as a symptom of hypotension and bradycardia, which is known to manifest itself in a dose-dependent manner.[10] Since dexmedetomidine was administered according to a prescribed loading and maintenance dose, a higher total infused dose of dexmedetomidine in patients with bradycardia could have been associated with a longer surgery and anesthesia duration.
Dexmedetomidine-induced bradycardia is associated with a high loading dose. A recent study has reported that the incidence of bradycardia was significantly higher when the loading dose was 1.0 mcg/kg than when it was 0.8 mcg/kg.[16] Ko et al. reported that the effective loading dose of dexmedetomidine for adequate sedation is 0.86 µg/kg; however, a dose higher than 0.5 µg/kg is associated with hemodynamic instability.[17] In our study, an average loading dose of 0.7 mcg/kg was administered with a 25.3% incidence of bradycardia. In patients with initial bradycardia or surgery, which is expected to have a longer tourniquet duration, the anesthesiologist can prevent bradycardia by lowering the loading dose of dexmedetomidine. In addition, anticholinergic premedication can effectively prevent bradycardia.[18] If patients cannot tolerate bradycardia, alternative drugs such as midazolam can be effective.
Our study has some limitations. First, owing to the inherent limitations of the retrospective study design, bradycardia events were indirectly measured. Since vital signs are recorded on the anesthesia record every 5 min, the HR at the time of the bradycardia event may not be recorded. Therefore, we defined bradycardia as when at least one episode of vasopressor or anticholinergic agent administration at the judgment of the anesthesiologist in charge occurred. Second, the involvement of several anesthesiologists may have resulted in inconsistencies in the management of bradycardia. However, our institution’s protocol for bradycardia management has been appropriately applied. Finally, medications or autonomic function in patients might be associated with the development of bradycardia. We could not collect data on the medications and autonomic function of the patients. Despite these limitations, our study is the first to validate the risk factors for bradycardia in spinal anesthesia combined with intravenous dexmedetomidine administration.
In conclusion, the occurrence of bradycardia should be carefully monitored in patients undergoing spinal anesthesia with sedation using dexmedetomidine. A long tourniquet time and low baseline HR could be predictive factors for bradycardia.
Ethics approval and consent to participate: This study was approved by Seoul Paik Hospital, Inje University Institutional Review Board (2019-07-005-003). The requirement for informed consent was waived by Seoul Paik Hospital, Inje University Institutional Review Board since we used de-identified administrative claims data. All methods were performed in accordance with the relevant guidelines and regulations.
Consent for publication: Not applicable.
Availability of data and materials: The datasets generated and analyzed during the current study are not publicly available due to privacy and ethical concerns, but available from the corresponding author on reasonable request.
Competing interests: All authors have no competing interests.
Funding: This research was supported by the Chung-Ang University Research Grants in 2020.
Authors' contributions: EJ Ahn designed this study. EJ Ahn collected data. EJ Ahn and HJ Kim analyzed the data. EJ Ahn and HJ Kim wrote and revised the manuscript.
Acknowledgments: Not applicable.
Authors' information
EunJin Ahn: Assistant Professor, Department of Anesthesiology & Pain Medicine, Chung-Ang University Hospital, College of Medicine, Seoul, Korea.
Tel: +82-2-6299-2571, E-mail: [email protected]
Hyo-Jin Kim: Clinical associate professor, Department of Anesthesiology & Pain Medicine, Chung-Ang University Hospital, College of Medicine, Seoul, Korea.
Tel: +82-2-6299-2571, E-mail: [email protected]
This study was approved by Seoul Paik Hospital, Inje University Institutional Review Board (2019-07-005-003). The requirement for informed consent was waived since we used de-identified administrative claims data. All methods were performed in accordance with the relevant guidelines and regulations.