Acta Anaesthesiol Scand 2014; 58: 168–176 Printed in Singapore. All rights reserved
© 2013 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd ACTA ANAESTHESIOLOGICA SCANDINAVICA
doi: 10.1111/aas.12233
Heart rate variability dynamics during controlled hypotension with nicardipine, remifentanil and dexmedetomidine S. Shin1, J. W. Lee1, S. H. Kim1, Y.-S. Jung2 and Y. J. Oh1
1 Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea and 2Department of Oral and Maxillofacial Surgery, Yonsei University College of Dentistry, Seoul, Korea
Background: This study was done to investigate how nicardipine, remifentanil and dexmedetomidine affect the balance of the autonomic nervous system in patients receiving controlled hypotension under general anaesthesia by evaluating heart rate variability indices. Methods: Sixty-two patients were randomly allocated to either the nicardipine-sevoflurane (Group N, n = 21), remifentanilsevoflurane (Group R, n = 21) or dexmedetomidine-sevoflurane (Group D, n = 20) group for controlled hypotension during orthognathic surgery. Electrocardiogram data acquisition was done after vital sign stabilization following anaesthesia induction (T1) and 30 min after controlled hypotension was induced (T2). Results: Total power and low frequency (LF) power was significantly decreased at T2 compared with T1 in all groups, while a decrease in high frequency (HF) power was only observed in Group N (P < 0.001). LF/HF ratios of Group R and D were significantly suppressed at T2 compared with T1 (P = 0.001 and
Introduction
C
ontrolled hypotension is an effective technique employed to reduce blood loss and improve the quality of the surgical field during various types of surgery. The ideal hypotensive agent should be easy to administer and titrate, have a short onset time and half-life, be rapidly eliminated without toxic metabolites, have negligible effects on vital organs and also a predictable and dose-dependent effect.1 Many different agents have been studied with regard to these factors, as well as operative outcomes such as intraoperative blood loss and the surgeon’s satisfaction.2–6 However, the changes in autonomic nervous system (ANS) activity during controlled hypotension induced with drugs that have distinct mechanisms of action at are not well known.
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P < 0.001, respectively), but was increased Group N (P = 0.009). The LF/HF ratio of Group N was significantly higher than Group R and D at T2 (P < 0.001 in both), with Group D showing a significantly lower LF/HF ratio compared with Group R (P < 0.001). Conclusions: Remifentanil and dexmedetomidine did not have sympathetic nervous system-stimulating effects during controlled hypotension, while remifentanil seemed to be superior in preserving the overall balance in autonomic nervous system activity. Nicardipine was found to stimulate the sympathetic nervous system, which may be problematic in patients vulnerable to disturbances in the autonomic nervous system. Accepted for publication 29 October 2013 © 2013 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
Different pharmacological agents each have their own pros and cons, and using a single agent for controlled hypotension may require high concentrations and result in exaggerated adverse effects. Therefore, a safe and effective combination of drugs that will prevent unwanted and possibly dangerous perturbations in the ANS during controlled hypotension is needed. Nicardipine and remifentanil have been favoured as adjuncts to volatile anaesthetics during controlled hypotension for a long time,1,7 and dexmedetomidine has recently received much attention regarding its ability as a hypotensive agent.5,8–10 ANS activity can be estimated by measuring heart rate (HR) variability (HRV), a method that analyses the fluctuations of R-R intervals of the electrocardiogram (ECG). HRV indices serve as quantitative markers of ANS activity, and the importance of
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evaluating the balance of sympathetic (SNS) and parasympathetic nervous system (PNS) activity during clinical general anaesthesia of various settings is well known.11 Virtually, all general anaesthetics and hypotensive agents interfere with sympathetic neural outflow and cardiovascular regulation, which may result in unintended changes in haemodynamic and electrocardiographic parameters. While the three aforementioned drugs should be expected to have different effects on ANS balance when used at doses effective enough to induce a hypotensive state during surgery, this aspect has not yet been widely investigated or directly compared between each drug in controlled settings. The existing HRV evidence indicates that nicardipine increases SNS and decreases PNS activity,12,13 while remifentanil increases PNS activity.14 Similar to remifentanil, dexmedetomidine has been reported to increase PNS activity relative to SNS activity, especially at higher doses.15,16 The primary outcome of this prospective, randomised study was to investigate the effects of nicardipine, remifentanil and dexmedetomidine on ANS balance and activity by measuring HRV in patients receiving controlled hypotension under general anaesthesia. A subanalysis of corrected QT intervals (QTc) was also conducted, as SNS stimulation is known to result in increased susceptibility to arrhythmogenesis and changes in QTc intervals.
Materials and methods The study protocol was approved by the Institutional Review Board and Hospital Research Ethics Committee of Severance Hospital (Severance Hospital Institutional Review Board, Yonsei University Health System, Seoul, Korea on 29 May 2012, protocol number 4–2012-0242). It was registered at http://clinicaltrials.gov (registration number NCT 01634594). Sixty-six adult patients of American Society of Anesthesiologists physical status I, scheduled for elective orthognathic surgery requiring controlled hypotension were recruited in this study. Informed consent was obtained from all patients. Exclusion criteria included patient refusal, known arrhythmias or hypertension, cardiac anomalies, history of cardiac surgery, pre-operative electrolyte imbalance and obesity (BMI > 30 kg/m2). Using a computer-generated table of random numbers, patients were randomly assigned to either the nicardipine-sevoflurane group (Group N), remifentanil-sevoflurane group (Group R) or the
dexmedetomidine-sevoflurane group (Group D). No patients received pre-medication. Monitoring was standardised with non-invasive blood pressure, ECG, pulse oximetry, axillary temperature and bispectral index (BIS) monitoring. For HRV analysis, patients were connected to a PowerLab 8/30 Data Acquisition System (ADInstruments, Sydney, NSW, Australia) for continuous recording of standard real-time automated three-lead ECG. Anaesthesia was induced with propofol 2 mg/kg and sevoflurane inhalation. When a steady state of endtidal sevoflurane concentration of 5.0 vol % was maintained for at least 5 min, nasotracheal intubation was facilitated with vecuronium 0.15 mg/kg. After induction of anaesthesia, radial artery cannulation was done for continuous monitoring of arterial blood pressure and blood gas analysis. Anaesthesia was maintained with end-tidal sevoflurane concentration 2.0 ± 1.0% and air 50% in oxygen, and patients were ventilated with a tidal volume of 8 ml/kg of ideal body weight at a respiratory rate of 10 breaths per min, to maintain end-tidal CO2 between 35 mmHg and 40 mmHg during the study period. When vital signs were stabilised after anaesthesia induction, ECG acquisition and vital sign recordings were done for 10 min (T1) with care taken not to give any external stimuli to the patient. Hypotensive agent administration was started at the beginning of surgery in order to maintain mean blood pressure (MBP) between 60 mmHg and 65 mmHg. In Group N, nicardipine was infused at 1.0–7.0 μg/kg/min. Patients of Group R received continuous infusion of remifentanil at 0.05–2.0 μg/ kg/min. In Group D, 1.0 μg/kg of dexmedetomidine was loaded for 10 min, followed by infusion at a rate of 0.2–1.0 μg/kg/h. None of the patients received other adjuvants other than the study drugs during controlled hypotension. ECG acquisition and vital sign recording were repeated once more when the MBP of the patients had been steadily maintained within the targeted range for 30 min (T2). Body temperature was maintained at approximately 36.5°C with a forced-air warmer throughout the study. The analysis of ECG recordings and intraoperative data was done by a separate anaesthesiologist that was blinded to group allocation.
HRV analysis HRV data was analysed with LabChart v7 software (ADInstruments) at 1024 Hz. Stable ECG recordings of 5 min without ectopic beats or artefacts were used for analysis at T1 and T2. Frequency domain HRV indices were obtained with power spectral density
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analysis using fast Fourier transformation.17 Two major power spectrum components were obtained. High frequency (HF, 0.15–0.4 Hz) power represents PNS activity while low frequency (LF, 0.04–0.15 Hz) power represents both SNS and PNS activity. The LF/HF ratio was calculated to evaluate the balance between SNS and PNS activity.
QTc interval analysis ECG data was analyzed with LabChart v7 software (ADInstruments). The QT interval was measured in lead II from the onset of the QRS complex to the end of the T wave. The values of QT intervals of six successive beats were averaged. Correction for HR was done using the Bazett formula.18
Statistical analysis A sample size was calculated based on preliminary results for the first 10 patients of each group. On the basis of a mean difference of 1.0 and SD of 1.0 in LF/HF ratio, we calculated that 20 patients could test the null hypothesis at 0.05 significance with a power of 0.8. Twenty-two patients were recruited in each group considering a 10% dropout rate. The χ2 test and one-way ANOVA with Bonferroni correction for multiple comparisons were used as appro-
priate for the comparison of categorical and numerical variables between groups. The paired t-test was used for comparison of variables within each group. HRV data was tested for normality using the Kolmogorov–Smirnov test. Non-normally distributed HRV data was analysed by the Kruskall– Wallis test with P-value adjusted with Bonferroni correction (P < 0.016) for multiple comparisons between groups, and the Wilcoxon signed-rank test for comparison within groups. All statistical analyses were performed with IBM SPSS Statistics 20.0 (IBM Corp., Armonk, NY, USA). A P-value of < 0.05 was considered as statistically significant. Data are described as mean ± SD, number of subjects or median (interquartile range).
Results The Consolidated Standards of Reporting Trials flow diagram of this study is shown in Fig. 1. Demographic data and intraoperative characteristics were not different between the three groups (Table 1). The patients were enrolled between 1 June 2012 and 12 February 2013. Of the 66 patients that were recruited for this study, three were eliminated due to abnormal intraoperative ECG readings that were inappropriate
Fig. 1. Consolidated Standards of Reporting Trials flow diagram of the study.
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Heart rate variability and hypotension Table 1 Patient characteristics and intraoperative data.
Age (years) Sex (M/F) Height (cm) Weight (kg) BMI (kg/m2) Intraoperative fluid (ml) Intraoperative transfusion (ml) Intraoperative urine output (ml) Estimated blood loss (ml) Operation time (min) Anaesthesia time (min)
Nicardipine group (n = 21)
Remifentanil group (n = 21)
Dexmedetomidine group (n = 20)
22.3 ± 2.3 13/8 168.7 ± 7.7 63.1 ± 9.1 22.1 ± 2.1 1995.2 ± 627.7 211.7 ± 197.7 287.6 ± 108.0 790.5 ± 281.8 246.0 ± 98.6 288.1 ± 101.0
23.9 ± 3.7 8/13 167.1 ± 7.7 61.2 ± 9.2 21.9 ± 2.4 1931.0 ± 743.4 161.2 ± 237.8 388.6 ± 223.9 695.2 ± 351.7 256.0 ± 81.2 299.2 ± 85.1
23.1 ± 3.1 13/7 170.2 ± 7.4 63.3 ± 12.9 21.7 ± 3.6 1717.5 ± 418.4 156.5 ± 201.3 348.8 ± 197.9 620.0 ± 122.9 209.0 ± 29.3 251.0 ± 31.2
P-value
0.327 0.654 0.207 0.140 0.125 0.134
Values are mean ± SD or numbers. BMI, body mass index; F, female; M, male.
Table 2 Changes in haemodynamics, bispectral index scores and end-tidal sevoflurane concentration. Heart rate (beats per min) Mean blood pressure (mmHg) Bispectral index score End-tidal sevoflurane concentration (%)
Group
T1
T2
Nicardipine Remifentanil Dexmedetomidine Nicardipine Remifentanil Dexmedetomidine Nicardipine Remifentanil Dexmedetomidine Nicardipine Remifentanil Dexmedetomidine
80.7 ± 10.7 80.1 ± 13.0 79.1 ± 13.0 79.6 ± 5.8 76.6 ± 5.5 77.5 ± 8.3 43.3 ± 5.8 44.1 ± 5.2 47.5 ± 7.6 1.8 ± 0.2 1.7 ± 0.2 1.8 ± 0.3
114.0 ± 9.5* 67.5 ± 7.6*† 69.2 ± 5.6*† 60.7 ± 3.1* 61.0 ± 3.0* 61.3 ± 3.0* 40.8 ± 10.4 41.9 ± 5.1 40.0 ± 8.2 2.3 ± 0.2* 2.2 ± 0.3* 2.4 ± 0.4*
Values are mean ± SD. *P < 0.05 compared with T1. †P < 0.05 compared with Group N.
for analysis with the software used in the present study and one patient was eliminated due to intraoperative hypokalaemia. The remaining 62 patients successfully completed the study without any complications, leaving 21 patients each in Group N and R, and 20 patients in Group D eligible for analysis.
junctional rhythms were not observed in any of the patients. MBPs of the three groups were significantly lower at T2 compared with T1 and were all within the targeted range of 60–65 mmHg. There were no differences in MBPs, BIS scores or end-tidal sevoflurane concentrations between the three groups (Table 2).
Changes in haemodynamic and bispectral index scores
Changes in HR variability
HR and MBPs were comparable among the three groups at T1. In Group N, HR was significantly increased at T2 compared with T1 (P < 0.001) and was also significantly faster than Group R and D at T2 (P < 0.001 in both). HRs of Groups R and D were significantly slower at T2 compared with T1 (P < 0.001 and P = 0.002, respectively). Arrhythmias such as atrioventricular (AV) block, bradycardia or
Total power and LF power was significantly decreased at T2 compared with T1 in all groups. However, significant decrease in HF power was only seen in Group N (P < 0.001), while those of Group R and D did not. Twenty (95%) patients of Group N showed decreased HF power at T2 compared with T1, compared with 14 (67%) and 10 (50%) patients in Group R and D, respectively. Combined with the changes in LF power, overall LF/HF
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Fig. 2. Changes in low frequency (LF), high frequency (HF) and LF/HF ratio of the three groups during controlled hypotension. P < 0.016 is considered significant.
ratios of Group R and D were significantly suppressed at T2 compared with T1 (P = 0.001 and P < 0.001, respectively), while the LF/HF ratio of Group N was significantly increased (P = 0.009). While 17 (81%) of the patients in Group N showed a trend of increasing LF/HF ratios, only five (24%) patients of Group R were found to do so. Moreover, all patients of Group D showed decreasing trends of LF/HF ratios at T2 compared with T1 (Fig. 2). The LF/HF ratio of Group N was significantly higher than those of Group R and D at T2 (P < 0.001 in
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both), with Group D showing a significantly lower LF/HF ratio compared with Group R (P < 0.001) (Table 3).
Changes in QTc intervals QTc intervals were comparable between the three groups at T1 (P = 1.000). All of the patients of Group N showed a trend of increased QTc intervals at T2, compared with 15 (71%) in Group R. However, the increases in QTc intervals of the study subjects of Group R were relatively subtle, and 17 (81%) patients
Heart rate variability and hypotension Table 3 Changes in heart rate variability indices. Total power (ms2) LF power (ms2) HF power (ms2) LF/HF ratio
Group
T1
T2
Nicardipine Remifentanil Dexmedetomidine Nicardipine Remifentanil Dexmedetomidine Nicardipine Remifentanil Dexmedetomidine Nicardipine Remifentanil Dexmedetomidine
1035.8 (654.8, 1397.1) 1019.3 (943.6, 1162.4) 975.9 (681.2, 1210.4) 120.8 (22.7, 219.6) 128.3 (52.9, 252.4) 142.4 (68.5, 238.8) 49.9 (11.1, 83.3) 84.3 (30.0, 154.6) 49.1 (17.5, 183.5) 2.1 (1.25, 3.3) 2.7 (0.9, 4.1) 2.2 (1.4, 3.5)
422.3 (230.1, 556.4)* 471.5 (307.0, 567.8)* 277.0 (208.1, 444.9)* 6.8 (2.8, 20.4)* 40.1 (15.5, 89.0)*† 21.2 (2.5, 63.4)* 1.8 (0.7, 6.6)* 45.4 (14.7, 81.5)† 49.2 (7.2, 94.8)† 3.3 (2.6, 4.4)* 1.4 (0.8, 1.9)*† 0.6 (0.4, 0.7)*†‡
Values are median (IQR). *P < 0.05 compared with T1. †P < 0.05 compared with Group N. ‡P < 0.05 compared with Group R. HF, high frequency; LF, low frequency; IQR, interquartile range.
Fig. 3. Changes in QTc intervals of the three groups during controlled hypotension. P < 0.05 is considered significant.
of Group D showed decreased QTc intervals at T2. Consequently, an overall significant prolongation in QTc was observed in Group N at T2 compared with T1 (466.0 ± 64.3 sec vs. 388.0 ± 26.8 ms, P < 0.001), while there was no overall change in QTc intervals in Group R at T2 compared with T1 (393.6 ± 27.1 ms vs. 392.1 ± 23.0 ms, P = 0.713). On the other hand, QTc intervals were significantly shortened at T2 compared with T1 in Group D (374.8 ± 31.0 ms vs. 391.2 ± 34.4 ms, P < 0.001) (Fig. 3). Group N showed significantly longer QTc intervals compared with Group R and Group D at T2 (P < 0.001 in both), while no difference was seen between Group R and D (P = 0.535).
Discussion Controlled hypotension during general anaesthesia is usually achieved by combining different hypoten-
sive agents to the main inhalation anaesthetic. The application of controlled hypotension is not limited to operations that may result in large volumes of blood loss and consequent transfusion,19 but is also used for procedures that require a bloodless operative field.1 While many agents have been routinely used for controlled hypotension, the changes in ANS activity that may be caused by drugs with different mechanisms of action were not widely studied. The results of the present study show that the combination of nicardipine and sevoflurane causes tachycardia, activates the SNS and significantly prolongs the QTc interval during controlled hypotension. While both remifentanil and dexmedetomidine were found to suppress compensatory tachycardia and SNS stimulation in response to hypotension, remifentanil seemed to preserve the balance in ANS activity more effectively compared with dexmedetomidine. Moreover, remifentanil and
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dexmedetomidine does not seem to have QTc prolonging effects when used with sevoflurane as hypotensive agents. Nicardipine has been preferred over other vasodilators in that it produces limited reflex tachycardia and rebound hypertension.20 However, Group N of the present study showed a significant increase in HR, with mean HR values exceeding 100 bpm at T2, which may be problematic in patients with cardiovascular diseases or decreased cardiac output. Considering the comparative levels of sevoflurane in all three groups, the tachycardia observed with nicardipine does not seem to be due to insufficient anaesthesia. Kimura et al.12 found nicardipine to cause tachycardia and decrease HF power after infusion for 30 min during controlled hypotension. Similarly, Koh et al.13 reported an increase in LF/HF ratio and plasma catecholamine levels during nicardipine infusion and attributed this to SNS activation and suppression of vagal cardiac neural outflow. The results of the present study support these previous reports, as seen by the relatively elevated LF/HF ratio of Group N at T2. An interesting finding was that the absolute value of LF power of Group N was not increased at T2 but that the decrease in HF power was much greater that it resulted in a significant increase in LF/HF ratio. Compared with the previous study by Koh et al.,13 in which a concomitant increase in SNS indicator was observed with a decrease in PNS indicator with nicardipine infusion, the present study differs in that both SNS and PNS indicators were decreased. Rather, it was the almost complete vagal withdrawal seen with nicardipine that lead to the relative increase in LF/HF power. This difference may have been due to the longer duration of infusion in the present study compared with the previous study (at least 30 min vs. 10 min), or a difference in infusion doses. Moreover, this may imply that it is the relative balance of the SNS and PNS that causes reflex tachycardia rather than the increase in SNS activity per se. Further studies are needed to explore this aspect. Remifentanil causes hypotension and bradycardia by blockade of the SNS, and the minimal effects of remifentanil on the QTc interval also seems to be related to its ability to suppress tachycardia and SNS activation in response to hypotension. Although suppression in LF power and a consequent decrease in LF/HF ratio were observed with remifentanil, the degree of SNS suppression was relatively smaller than with dexmedetomidine. The response observed with dexmedetomine was in stark contrast to nicardipine, and indeed
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the ability of dexmedetomidine to modify the cardiac autonomic state by suppressing cardiac noradrenaline release and activating vagal acetylcholine release has been reported.21 Dexmedetomidine produces a predictable and stable haemodynamic response with continuous infusion and is known to cause a significant reduction in circulating catecholamines leading to a decrease in blood pressure and HR.22,23 The HRV indices of Group D show that the capability of dexmedetomidine to suppress compensatory stimulation of the SNS is valid during controlled hypotension. The relative suppression of LF to HF power was more profound with dexmedetomidine compared with remifentanil, resulting in a markedly lower LF/HF ratio. This may imply an over-suppressive effect of dexemedetomidine on SNS activity, rather than maintaining its balance during controlled hypotension. Although rare, refractory cardiogenic shock24 and bradycardia progressing to pulseless electrical activity during sedation with dexmedetomidine25 have been reported. Considering the strong ability of dexmedetomidine to suppress compensatory SNS activation even during controlled hypotension, safe use in patients with AV block or heart failure cannot be guaranteed. Moreover, the indications of controlled hypotension are not limited to young and healthy patients that were enrolled in this study, but are also applied to surgical procedures such as hip replacement surgery or shoulder arthroscopy. The patient population that undergoes such operations is elderly in general, and it is well known that aging has a significant impact on the cardiovascular system and the ANS. The ability of the ANS to adapt to environmental changes such as baroreceptor reflex function are markedly diminished with advancing age,26 which may render elderly patients more susceptible to changes in ANS balance. In this sense, remifentanil may be a safer choice in older patients with underlying cardiovascular diseases with regard to its ability to maintain the balance of the ANS even when used at high doses for controlled hypotension. However, the changes in autonomic function in the elderly is not well understood, and further clinical studies are needed to determine the response of the ANS and cardiovascular system in older patients during controlled hypotension induced with agents of different action mechanisms. We found in our subanalysis of QTc intervals that remifentanil seems to be relatively safe compared with the two other drugs when used for controlled hypotension with sevoflurane. QT interval prolongation is closely related to ANS activity, and it is well
Heart rate variability and hypotension
known that SNS stimulation leads to QTc prolongation, which is why the effects of anaesthetics on QTc intervals are studied the most during anaesthesia induction and tracheal intubation.27–30 The ability of remifentanil to attenuate QTc prolongation during procedures that activate the SNS such as laryngoscopy and tracheal intubation has been confirmed in previous studies.27,31 The QTc prolongation that was seen with nicardipine may also be related to sympathetic overstimulation. Berger et al.32 suggested that changes in autonomic tone associated with vasodilation causes QT prolongation and found these effects to persist despite correction for HR. Interestingly, nicardipine is considered as a ‘very improbable’ medication with regard to QT interval prolongation based on a survey of expert opinion,33 and Schwartz et al. reported that QTc remained unchanged when nicardipine was administered to lower the MBP by 17% from baseline in healthy individuals.34 However, the results of our study found otherwise, as the mean QTc values of Group N were significantly prolonged when compared with T1 as well as the other two groups. While none of the patients of Group R or D showed prolonged QTc intervals over 440 ms during hypotensive anaesthesia, 14 (66.7%) patients of Group N presented with QTc intervals greater than 440 ms at T2. This QTc-prolonging effect of nicardipine may act as a trigger of potentially lethal dysrhythmia such as torsades de pointes in susceptible patients with sss (LQTS), when used in doses high enough to induce controlled hypotension. Another notable finding is the QTc shortening that was observed with dexmedetomidine during controlled hypotension. In a recent study by Tsutsui et al.,21 α2-adrenoreceptor agonistic action was found to have an inhibitory effect on ventricular tachyarrhythmias and attenuate QT prolongation in a rabbit model of acquired LQTS. Although extremely rare, short QT intervals may also be a risk for cardiovascular events.35 Further studies are needed to investigate the clinical significance of the effects that nicardipine and dexmedetomidine have on QTc intervals at different clinical concentrations. This study has several limitations. First, this study was conducted in young, healthy patients without underlying cardiovascular diseases or diabetes. Although perturbations in ANS balance can be expected to be problematic in elderly patients with comorbidities, the results of the present study cannot be extrapolated to this patient population. Future studies conducted in patients that are more vulnerable to changes in ANS balance should
provide more insight into this matter. Second, we only recorded ECG data for 30 min after inducing controlled hypotension. Considering that some operations may require an extended period of hypotension, repeated measurements further into the operation may have provided more insight into the effects of each agent over time. Third, the effect of sevoflurane cannot be completely excluded. With regard to HRV, several studies found sevoflurane to decrease cardiac vagal activity,36–38 while others did not.39,40 The clinical significance of using sevoflurane per se on ANS balance is unclear, and the inconsistent results implicate that the entire anaesthetic milieu should be taken into consideration, rather than a single factor. In conclusion, while both remifentanil and dexmedetomidine were not found to have SNSstimulating effects during controlled hypotension, remifentanil seems to be relatively more competent in preserving the overall balance in ANS activity than dexmedetomidine. Nicardipine was found to stimulate the SNS as well as cause QTc prolongation, which may be problematic in patients vulnerable to disturbances in the ANS.
Acknowledgements This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science and Technology (MEST) (NRF-2010–0022999). Conflicts of interest: The authors have no conflict of interest. Funding: Ministry of Education, Science and Technology (MEST) (NRF-2010–0022999).
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S. Shin et al. 8. Durmus M, But AK, Dogan Z, Yucel A, Miman MC, Ersoy MO. Effect of dexmedetomidine on bleeding during tympanoplasty or septorhinoplasty. Eur J Anaesthesiol 2007; 24: 447–53. 9. Richa F, Yazigi A. Effect of dexmedetomidine on blood pressure and bleeding in maxillo-facial surgery. Eur J Anaesthesiol 2007; 24: 985–6. 10. Richa F, Yazigi A. Comparison between dexmedetomidine and remifentanil for intraoperative controlled hypotension. J Oral Maxillofac Surg 2009; 67: 2549–50. 11. Neukirchen M, Kienbaum P. Sympathetic nervous system: evaluation and importance for clinical general anesthesia. Anesthesiology 2008; 109: 1113–31. 12. Kimura T, Ito M, Komatsu T, Nishiwaki K, Shimada Y. Heart rate and blood pressure power spectral analysis during calcium channel blocker induced hypotension. Can J Anaesth 1999; 46: 1110–6. 13. Koh J, Hidaka I, Miyata M. Effects of nicardipine and diltiazem on fractal features of short-term heart rate variability – application of coarse graining spectral analysis. J Anesth 2002; 16: 108–13. 14. Tirel O, Chanavaz C, Bansard JY, Carre F, Ecoffey C, Senhadji L, Wodey E. Effect of remifentanil with and without atropine on heart rate variability and RR interval in children. Anaesthesia 2005; 60: 982–9. 15. Hogue CW Jr., Talke P, Stein PK, Richardson C, Domitrovich PP, Sessler DI. Autonomic nervous system responses during sedative infusions of dexmedetomidine. Anesthesiology 2002; 97: 592–8. 16. Tarvainen MP, Georgiadis S, Laitio T, Lipponen JA, Karjalainen PA, Kaskinoro K, Scheinin H. Heart rate variability dynamics during low-dose propofol and dexmedetomidine anesthesia. Ann Biomed Eng 2012; 40: 1802–13. 17. Malik M, Bigger JT, Camm AJ, Kleiger RE, Malliani A, Moss AJ, Schwartz PJ. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Task force of the European society of cardiology and the North American society of pacing and electrophysiology. Eur Heart J 1996; 17: 354–81. 18. Luo S, Michler K, Johnston P, Macfarlane PW. A comparison of commonly used QT correction formulae: the effect of heart rate on the QTc of normal ECGs. J Electrocardiol 2004; 37 (Suppl): 81–90. 19. Choi WS, Samman N. Risks and benefits of deliberate hypotension in anaesthesia: a systematic review. Int J Oral Maxillofac Surg 2008; 37: 687–703. 20. Tobias JD. Nicardipine: applications in anesthesia practice. J Clin Anesth 1995; 7: 525–33. 21. Tsutsui K, Hayami N, Kunishima T, Sugiura A, Mikamo T, Kanamori K, Yamagishi N, Yamagishi S, Watanabe H, Ajiki K, Murakawa Y. Dexmedetomidine and clonidine inhibit ventricular tachyarrhythmias in a rabbit model of acquired long QT syndrome. Circ J 2012; 76: 2343–7. 22. Carollo DS, Nossaman BD, Ramadhyani U. Dexmedetomidine: a review of clinical applications. Curr Opin Anaesthesiol 2008; 21: 457–61. 23. Arcangeli A, D’Alo C, Gaspari R. Dexmedetomidine use in general anaesthesia. Curr Drug Targets 2009; 10: 687–95. 24. Sichrovsky TC, Mittal S, Steinberg JS. Dexmedetomidine sedation leading to refractory cardiogenic shock. Anesth Analg 2008; 106: 1784–6. 25. Gerlach AT, Murphy CV. Dexmedetomidine-associated bradycardia progressing to pulseless electrical activity: case report and review of the literature. Pharmacotherapy 2009; 29: 1492.
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26. Hotta H, Uchida S. Aging of the autonomic nervous system and possible improvements in autonomic activity using somatic afferent stimulation. Geriatr Gerontol Int 2010; 10 (Suppl. 1): S127–36. 27. Kweon TD, Nam SB, Chang CH, Kim MS, Lee JS, Shin CS, June DB, Han DW. The effect of bolus administration of remifentanil on QTc interval during induction of sevoflurane anaesthesia. Anaesthesia 2008; 63: 347–51. 28. Chang DJ, Kweon TD, Nam SB, Lee JS, Shin CS, Park CH, Han DW. Effects of fentanyl pretreatment on the QTc interval during propofol induction. Anaesthesia 2008; 63: 1056– 60. 29. Erdil F, Demirbilek S, Begec Z, Ozturk E, But A, Ozcan Ersoy M. The effect of esmolol on the QTc interval during induction of anaesthesia in patients with coronary artery disease. Anaesthesia 2009; 64: 246–50. 30. Kim DH, Kweon TD, Nam SB, Han DW, Cho WY, Lee JS. Effects of target concentration infusion of propofol and tracheal intubation on QTc interval. Anaesthesia 2008; 63: 1061–4. 31. Cafiero T, Di Minno RM, Di Iorio C. QT interval and QT dispersion during the induction of anesthesia and tracheal intubation: a comparison of remifentanil and fentanyl. Minerva Anestesiol 2011; 77: 160–5. 32. Berger E, Patel K, Anwar S, Davies W, Sheridan DJ. Investigation of the effects of physiological and vasodilationinduced autonomic activation on the QTc Interval in healthy male subjects. Br J Clin Pharmacol 2005; 60: 17–23. 33. Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA 2003; 289: 2120–7. 34. Schwartz AB, Moskowitz RM, Klausner SC. The electrophysiologic effects of nicardipine hydrochloride in man. Can J Cardiol 1987; 3: 14–7. 35. Bjerregaard P, Nallapaneni H, Gussak I. Short QT interval in clinical practice. J Electrocardiol 2010; 43: 390–5. 36. Nakatsuka I, Ochiai R, Takeda J. Changes in heart rate variability in sevoflurane and nitrous oxide anesthesia: effects of respiration and depth of anesthesia. J Clin Anesth 2002; 14: 196–200. 37. Paisansathan C, Lee M, Hoffman WE, Wheeler P. Sevoflurane anesthesia decreases cardiac vagal activity and heart rate variability. Clin Auton Res 2007; 17: 370–4. 38. Picker O, Scheeren TW, Arndt JO. Inhalation anaesthetics increase heart rate by decreasing cardiac vagal activity in dogs. Br J Anaesth 2001; 87: 748–54. 39. Sato J, Saito S, Takahashi T, Saruki N, Tozawa R, Goto F. Sevoflurane and nitrous oxide anaesthesia suppresses heart rate variabilities during deliberate hypotension. Eur J Anaesthesiol 2001; 18: 805–10. 40. Kanaya N, Hirata N, Kurosawa S, Nakayama M, Namiki A. Differential effects of propofol and sevoflurane on heart rate variability. Anesthesiology 2003; 98: 34–40.
Address: Young Jun Oh Department of Anesthesiology and Pain Medicine Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul, 120-752 Korea e-mail: [email protected]
© 2013 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd ACTA ANAESTHESIOLOGICA SCANDINAVICA
doi: 10.1111/aas.12233
Heart rate variability dynamics during controlled hypotension with nicardipine, remifentanil and dexmedetomidine S. Shin1, J. W. Lee1, S. H. Kim1, Y.-S. Jung2 and Y. J. Oh1
1 Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea and 2Department of Oral and Maxillofacial Surgery, Yonsei University College of Dentistry, Seoul, Korea
Background: This study was done to investigate how nicardipine, remifentanil and dexmedetomidine affect the balance of the autonomic nervous system in patients receiving controlled hypotension under general anaesthesia by evaluating heart rate variability indices. Methods: Sixty-two patients were randomly allocated to either the nicardipine-sevoflurane (Group N, n = 21), remifentanilsevoflurane (Group R, n = 21) or dexmedetomidine-sevoflurane (Group D, n = 20) group for controlled hypotension during orthognathic surgery. Electrocardiogram data acquisition was done after vital sign stabilization following anaesthesia induction (T1) and 30 min after controlled hypotension was induced (T2). Results: Total power and low frequency (LF) power was significantly decreased at T2 compared with T1 in all groups, while a decrease in high frequency (HF) power was only observed in Group N (P < 0.001). LF/HF ratios of Group R and D were significantly suppressed at T2 compared with T1 (P = 0.001 and
Introduction
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ontrolled hypotension is an effective technique employed to reduce blood loss and improve the quality of the surgical field during various types of surgery. The ideal hypotensive agent should be easy to administer and titrate, have a short onset time and half-life, be rapidly eliminated without toxic metabolites, have negligible effects on vital organs and also a predictable and dose-dependent effect.1 Many different agents have been studied with regard to these factors, as well as operative outcomes such as intraoperative blood loss and the surgeon’s satisfaction.2–6 However, the changes in autonomic nervous system (ANS) activity during controlled hypotension induced with drugs that have distinct mechanisms of action at are not well known.
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P < 0.001, respectively), but was increased Group N (P = 0.009). The LF/HF ratio of Group N was significantly higher than Group R and D at T2 (P < 0.001 in both), with Group D showing a significantly lower LF/HF ratio compared with Group R (P < 0.001). Conclusions: Remifentanil and dexmedetomidine did not have sympathetic nervous system-stimulating effects during controlled hypotension, while remifentanil seemed to be superior in preserving the overall balance in autonomic nervous system activity. Nicardipine was found to stimulate the sympathetic nervous system, which may be problematic in patients vulnerable to disturbances in the autonomic nervous system. Accepted for publication 29 October 2013 © 2013 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
Different pharmacological agents each have their own pros and cons, and using a single agent for controlled hypotension may require high concentrations and result in exaggerated adverse effects. Therefore, a safe and effective combination of drugs that will prevent unwanted and possibly dangerous perturbations in the ANS during controlled hypotension is needed. Nicardipine and remifentanil have been favoured as adjuncts to volatile anaesthetics during controlled hypotension for a long time,1,7 and dexmedetomidine has recently received much attention regarding its ability as a hypotensive agent.5,8–10 ANS activity can be estimated by measuring heart rate (HR) variability (HRV), a method that analyses the fluctuations of R-R intervals of the electrocardiogram (ECG). HRV indices serve as quantitative markers of ANS activity, and the importance of
Heart rate variability and hypotension
evaluating the balance of sympathetic (SNS) and parasympathetic nervous system (PNS) activity during clinical general anaesthesia of various settings is well known.11 Virtually, all general anaesthetics and hypotensive agents interfere with sympathetic neural outflow and cardiovascular regulation, which may result in unintended changes in haemodynamic and electrocardiographic parameters. While the three aforementioned drugs should be expected to have different effects on ANS balance when used at doses effective enough to induce a hypotensive state during surgery, this aspect has not yet been widely investigated or directly compared between each drug in controlled settings. The existing HRV evidence indicates that nicardipine increases SNS and decreases PNS activity,12,13 while remifentanil increases PNS activity.14 Similar to remifentanil, dexmedetomidine has been reported to increase PNS activity relative to SNS activity, especially at higher doses.15,16 The primary outcome of this prospective, randomised study was to investigate the effects of nicardipine, remifentanil and dexmedetomidine on ANS balance and activity by measuring HRV in patients receiving controlled hypotension under general anaesthesia. A subanalysis of corrected QT intervals (QTc) was also conducted, as SNS stimulation is known to result in increased susceptibility to arrhythmogenesis and changes in QTc intervals.
Materials and methods The study protocol was approved by the Institutional Review Board and Hospital Research Ethics Committee of Severance Hospital (Severance Hospital Institutional Review Board, Yonsei University Health System, Seoul, Korea on 29 May 2012, protocol number 4–2012-0242). It was registered at http://clinicaltrials.gov (registration number NCT 01634594). Sixty-six adult patients of American Society of Anesthesiologists physical status I, scheduled for elective orthognathic surgery requiring controlled hypotension were recruited in this study. Informed consent was obtained from all patients. Exclusion criteria included patient refusal, known arrhythmias or hypertension, cardiac anomalies, history of cardiac surgery, pre-operative electrolyte imbalance and obesity (BMI > 30 kg/m2). Using a computer-generated table of random numbers, patients were randomly assigned to either the nicardipine-sevoflurane group (Group N), remifentanil-sevoflurane group (Group R) or the
dexmedetomidine-sevoflurane group (Group D). No patients received pre-medication. Monitoring was standardised with non-invasive blood pressure, ECG, pulse oximetry, axillary temperature and bispectral index (BIS) monitoring. For HRV analysis, patients were connected to a PowerLab 8/30 Data Acquisition System (ADInstruments, Sydney, NSW, Australia) for continuous recording of standard real-time automated three-lead ECG. Anaesthesia was induced with propofol 2 mg/kg and sevoflurane inhalation. When a steady state of endtidal sevoflurane concentration of 5.0 vol % was maintained for at least 5 min, nasotracheal intubation was facilitated with vecuronium 0.15 mg/kg. After induction of anaesthesia, radial artery cannulation was done for continuous monitoring of arterial blood pressure and blood gas analysis. Anaesthesia was maintained with end-tidal sevoflurane concentration 2.0 ± 1.0% and air 50% in oxygen, and patients were ventilated with a tidal volume of 8 ml/kg of ideal body weight at a respiratory rate of 10 breaths per min, to maintain end-tidal CO2 between 35 mmHg and 40 mmHg during the study period. When vital signs were stabilised after anaesthesia induction, ECG acquisition and vital sign recordings were done for 10 min (T1) with care taken not to give any external stimuli to the patient. Hypotensive agent administration was started at the beginning of surgery in order to maintain mean blood pressure (MBP) between 60 mmHg and 65 mmHg. In Group N, nicardipine was infused at 1.0–7.0 μg/kg/min. Patients of Group R received continuous infusion of remifentanil at 0.05–2.0 μg/ kg/min. In Group D, 1.0 μg/kg of dexmedetomidine was loaded for 10 min, followed by infusion at a rate of 0.2–1.0 μg/kg/h. None of the patients received other adjuvants other than the study drugs during controlled hypotension. ECG acquisition and vital sign recording were repeated once more when the MBP of the patients had been steadily maintained within the targeted range for 30 min (T2). Body temperature was maintained at approximately 36.5°C with a forced-air warmer throughout the study. The analysis of ECG recordings and intraoperative data was done by a separate anaesthesiologist that was blinded to group allocation.
HRV analysis HRV data was analysed with LabChart v7 software (ADInstruments) at 1024 Hz. Stable ECG recordings of 5 min without ectopic beats or artefacts were used for analysis at T1 and T2. Frequency domain HRV indices were obtained with power spectral density
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analysis using fast Fourier transformation.17 Two major power spectrum components were obtained. High frequency (HF, 0.15–0.4 Hz) power represents PNS activity while low frequency (LF, 0.04–0.15 Hz) power represents both SNS and PNS activity. The LF/HF ratio was calculated to evaluate the balance between SNS and PNS activity.
QTc interval analysis ECG data was analyzed with LabChart v7 software (ADInstruments). The QT interval was measured in lead II from the onset of the QRS complex to the end of the T wave. The values of QT intervals of six successive beats were averaged. Correction for HR was done using the Bazett formula.18
Statistical analysis A sample size was calculated based on preliminary results for the first 10 patients of each group. On the basis of a mean difference of 1.0 and SD of 1.0 in LF/HF ratio, we calculated that 20 patients could test the null hypothesis at 0.05 significance with a power of 0.8. Twenty-two patients were recruited in each group considering a 10% dropout rate. The χ2 test and one-way ANOVA with Bonferroni correction for multiple comparisons were used as appro-
priate for the comparison of categorical and numerical variables between groups. The paired t-test was used for comparison of variables within each group. HRV data was tested for normality using the Kolmogorov–Smirnov test. Non-normally distributed HRV data was analysed by the Kruskall– Wallis test with P-value adjusted with Bonferroni correction (P < 0.016) for multiple comparisons between groups, and the Wilcoxon signed-rank test for comparison within groups. All statistical analyses were performed with IBM SPSS Statistics 20.0 (IBM Corp., Armonk, NY, USA). A P-value of < 0.05 was considered as statistically significant. Data are described as mean ± SD, number of subjects or median (interquartile range).
Results The Consolidated Standards of Reporting Trials flow diagram of this study is shown in Fig. 1. Demographic data and intraoperative characteristics were not different between the three groups (Table 1). The patients were enrolled between 1 June 2012 and 12 February 2013. Of the 66 patients that were recruited for this study, three were eliminated due to abnormal intraoperative ECG readings that were inappropriate
Fig. 1. Consolidated Standards of Reporting Trials flow diagram of the study.
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Heart rate variability and hypotension Table 1 Patient characteristics and intraoperative data.
Age (years) Sex (M/F) Height (cm) Weight (kg) BMI (kg/m2) Intraoperative fluid (ml) Intraoperative transfusion (ml) Intraoperative urine output (ml) Estimated blood loss (ml) Operation time (min) Anaesthesia time (min)
Nicardipine group (n = 21)
Remifentanil group (n = 21)
Dexmedetomidine group (n = 20)
22.3 ± 2.3 13/8 168.7 ± 7.7 63.1 ± 9.1 22.1 ± 2.1 1995.2 ± 627.7 211.7 ± 197.7 287.6 ± 108.0 790.5 ± 281.8 246.0 ± 98.6 288.1 ± 101.0
23.9 ± 3.7 8/13 167.1 ± 7.7 61.2 ± 9.2 21.9 ± 2.4 1931.0 ± 743.4 161.2 ± 237.8 388.6 ± 223.9 695.2 ± 351.7 256.0 ± 81.2 299.2 ± 85.1
23.1 ± 3.1 13/7 170.2 ± 7.4 63.3 ± 12.9 21.7 ± 3.6 1717.5 ± 418.4 156.5 ± 201.3 348.8 ± 197.9 620.0 ± 122.9 209.0 ± 29.3 251.0 ± 31.2
P-value
0.327 0.654 0.207 0.140 0.125 0.134
Values are mean ± SD or numbers. BMI, body mass index; F, female; M, male.
Table 2 Changes in haemodynamics, bispectral index scores and end-tidal sevoflurane concentration. Heart rate (beats per min) Mean blood pressure (mmHg) Bispectral index score End-tidal sevoflurane concentration (%)
Group
T1
T2
Nicardipine Remifentanil Dexmedetomidine Nicardipine Remifentanil Dexmedetomidine Nicardipine Remifentanil Dexmedetomidine Nicardipine Remifentanil Dexmedetomidine
80.7 ± 10.7 80.1 ± 13.0 79.1 ± 13.0 79.6 ± 5.8 76.6 ± 5.5 77.5 ± 8.3 43.3 ± 5.8 44.1 ± 5.2 47.5 ± 7.6 1.8 ± 0.2 1.7 ± 0.2 1.8 ± 0.3
114.0 ± 9.5* 67.5 ± 7.6*† 69.2 ± 5.6*† 60.7 ± 3.1* 61.0 ± 3.0* 61.3 ± 3.0* 40.8 ± 10.4 41.9 ± 5.1 40.0 ± 8.2 2.3 ± 0.2* 2.2 ± 0.3* 2.4 ± 0.4*
Values are mean ± SD. *P < 0.05 compared with T1. †P < 0.05 compared with Group N.
for analysis with the software used in the present study and one patient was eliminated due to intraoperative hypokalaemia. The remaining 62 patients successfully completed the study without any complications, leaving 21 patients each in Group N and R, and 20 patients in Group D eligible for analysis.
junctional rhythms were not observed in any of the patients. MBPs of the three groups were significantly lower at T2 compared with T1 and were all within the targeted range of 60–65 mmHg. There were no differences in MBPs, BIS scores or end-tidal sevoflurane concentrations between the three groups (Table 2).
Changes in haemodynamic and bispectral index scores
Changes in HR variability
HR and MBPs were comparable among the three groups at T1. In Group N, HR was significantly increased at T2 compared with T1 (P < 0.001) and was also significantly faster than Group R and D at T2 (P < 0.001 in both). HRs of Groups R and D were significantly slower at T2 compared with T1 (P < 0.001 and P = 0.002, respectively). Arrhythmias such as atrioventricular (AV) block, bradycardia or
Total power and LF power was significantly decreased at T2 compared with T1 in all groups. However, significant decrease in HF power was only seen in Group N (P < 0.001), while those of Group R and D did not. Twenty (95%) patients of Group N showed decreased HF power at T2 compared with T1, compared with 14 (67%) and 10 (50%) patients in Group R and D, respectively. Combined with the changes in LF power, overall LF/HF
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Fig. 2. Changes in low frequency (LF), high frequency (HF) and LF/HF ratio of the three groups during controlled hypotension. P < 0.016 is considered significant.
ratios of Group R and D were significantly suppressed at T2 compared with T1 (P = 0.001 and P < 0.001, respectively), while the LF/HF ratio of Group N was significantly increased (P = 0.009). While 17 (81%) of the patients in Group N showed a trend of increasing LF/HF ratios, only five (24%) patients of Group R were found to do so. Moreover, all patients of Group D showed decreasing trends of LF/HF ratios at T2 compared with T1 (Fig. 2). The LF/HF ratio of Group N was significantly higher than those of Group R and D at T2 (P < 0.001 in
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both), with Group D showing a significantly lower LF/HF ratio compared with Group R (P < 0.001) (Table 3).
Changes in QTc intervals QTc intervals were comparable between the three groups at T1 (P = 1.000). All of the patients of Group N showed a trend of increased QTc intervals at T2, compared with 15 (71%) in Group R. However, the increases in QTc intervals of the study subjects of Group R were relatively subtle, and 17 (81%) patients
Heart rate variability and hypotension Table 3 Changes in heart rate variability indices. Total power (ms2) LF power (ms2) HF power (ms2) LF/HF ratio
Group
T1
T2
Nicardipine Remifentanil Dexmedetomidine Nicardipine Remifentanil Dexmedetomidine Nicardipine Remifentanil Dexmedetomidine Nicardipine Remifentanil Dexmedetomidine
1035.8 (654.8, 1397.1) 1019.3 (943.6, 1162.4) 975.9 (681.2, 1210.4) 120.8 (22.7, 219.6) 128.3 (52.9, 252.4) 142.4 (68.5, 238.8) 49.9 (11.1, 83.3) 84.3 (30.0, 154.6) 49.1 (17.5, 183.5) 2.1 (1.25, 3.3) 2.7 (0.9, 4.1) 2.2 (1.4, 3.5)
422.3 (230.1, 556.4)* 471.5 (307.0, 567.8)* 277.0 (208.1, 444.9)* 6.8 (2.8, 20.4)* 40.1 (15.5, 89.0)*† 21.2 (2.5, 63.4)* 1.8 (0.7, 6.6)* 45.4 (14.7, 81.5)† 49.2 (7.2, 94.8)† 3.3 (2.6, 4.4)* 1.4 (0.8, 1.9)*† 0.6 (0.4, 0.7)*†‡
Values are median (IQR). *P < 0.05 compared with T1. †P < 0.05 compared with Group N. ‡P < 0.05 compared with Group R. HF, high frequency; LF, low frequency; IQR, interquartile range.
Fig. 3. Changes in QTc intervals of the three groups during controlled hypotension. P < 0.05 is considered significant.
of Group D showed decreased QTc intervals at T2. Consequently, an overall significant prolongation in QTc was observed in Group N at T2 compared with T1 (466.0 ± 64.3 sec vs. 388.0 ± 26.8 ms, P < 0.001), while there was no overall change in QTc intervals in Group R at T2 compared with T1 (393.6 ± 27.1 ms vs. 392.1 ± 23.0 ms, P = 0.713). On the other hand, QTc intervals were significantly shortened at T2 compared with T1 in Group D (374.8 ± 31.0 ms vs. 391.2 ± 34.4 ms, P < 0.001) (Fig. 3). Group N showed significantly longer QTc intervals compared with Group R and Group D at T2 (P < 0.001 in both), while no difference was seen between Group R and D (P = 0.535).
Discussion Controlled hypotension during general anaesthesia is usually achieved by combining different hypoten-
sive agents to the main inhalation anaesthetic. The application of controlled hypotension is not limited to operations that may result in large volumes of blood loss and consequent transfusion,19 but is also used for procedures that require a bloodless operative field.1 While many agents have been routinely used for controlled hypotension, the changes in ANS activity that may be caused by drugs with different mechanisms of action were not widely studied. The results of the present study show that the combination of nicardipine and sevoflurane causes tachycardia, activates the SNS and significantly prolongs the QTc interval during controlled hypotension. While both remifentanil and dexmedetomidine were found to suppress compensatory tachycardia and SNS stimulation in response to hypotension, remifentanil seemed to preserve the balance in ANS activity more effectively compared with dexmedetomidine. Moreover, remifentanil and
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dexmedetomidine does not seem to have QTc prolonging effects when used with sevoflurane as hypotensive agents. Nicardipine has been preferred over other vasodilators in that it produces limited reflex tachycardia and rebound hypertension.20 However, Group N of the present study showed a significant increase in HR, with mean HR values exceeding 100 bpm at T2, which may be problematic in patients with cardiovascular diseases or decreased cardiac output. Considering the comparative levels of sevoflurane in all three groups, the tachycardia observed with nicardipine does not seem to be due to insufficient anaesthesia. Kimura et al.12 found nicardipine to cause tachycardia and decrease HF power after infusion for 30 min during controlled hypotension. Similarly, Koh et al.13 reported an increase in LF/HF ratio and plasma catecholamine levels during nicardipine infusion and attributed this to SNS activation and suppression of vagal cardiac neural outflow. The results of the present study support these previous reports, as seen by the relatively elevated LF/HF ratio of Group N at T2. An interesting finding was that the absolute value of LF power of Group N was not increased at T2 but that the decrease in HF power was much greater that it resulted in a significant increase in LF/HF ratio. Compared with the previous study by Koh et al.,13 in which a concomitant increase in SNS indicator was observed with a decrease in PNS indicator with nicardipine infusion, the present study differs in that both SNS and PNS indicators were decreased. Rather, it was the almost complete vagal withdrawal seen with nicardipine that lead to the relative increase in LF/HF power. This difference may have been due to the longer duration of infusion in the present study compared with the previous study (at least 30 min vs. 10 min), or a difference in infusion doses. Moreover, this may imply that it is the relative balance of the SNS and PNS that causes reflex tachycardia rather than the increase in SNS activity per se. Further studies are needed to explore this aspect. Remifentanil causes hypotension and bradycardia by blockade of the SNS, and the minimal effects of remifentanil on the QTc interval also seems to be related to its ability to suppress tachycardia and SNS activation in response to hypotension. Although suppression in LF power and a consequent decrease in LF/HF ratio were observed with remifentanil, the degree of SNS suppression was relatively smaller than with dexmedetomidine. The response observed with dexmedetomine was in stark contrast to nicardipine, and indeed
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the ability of dexmedetomidine to modify the cardiac autonomic state by suppressing cardiac noradrenaline release and activating vagal acetylcholine release has been reported.21 Dexmedetomidine produces a predictable and stable haemodynamic response with continuous infusion and is known to cause a significant reduction in circulating catecholamines leading to a decrease in blood pressure and HR.22,23 The HRV indices of Group D show that the capability of dexmedetomidine to suppress compensatory stimulation of the SNS is valid during controlled hypotension. The relative suppression of LF to HF power was more profound with dexmedetomidine compared with remifentanil, resulting in a markedly lower LF/HF ratio. This may imply an over-suppressive effect of dexemedetomidine on SNS activity, rather than maintaining its balance during controlled hypotension. Although rare, refractory cardiogenic shock24 and bradycardia progressing to pulseless electrical activity during sedation with dexmedetomidine25 have been reported. Considering the strong ability of dexmedetomidine to suppress compensatory SNS activation even during controlled hypotension, safe use in patients with AV block or heart failure cannot be guaranteed. Moreover, the indications of controlled hypotension are not limited to young and healthy patients that were enrolled in this study, but are also applied to surgical procedures such as hip replacement surgery or shoulder arthroscopy. The patient population that undergoes such operations is elderly in general, and it is well known that aging has a significant impact on the cardiovascular system and the ANS. The ability of the ANS to adapt to environmental changes such as baroreceptor reflex function are markedly diminished with advancing age,26 which may render elderly patients more susceptible to changes in ANS balance. In this sense, remifentanil may be a safer choice in older patients with underlying cardiovascular diseases with regard to its ability to maintain the balance of the ANS even when used at high doses for controlled hypotension. However, the changes in autonomic function in the elderly is not well understood, and further clinical studies are needed to determine the response of the ANS and cardiovascular system in older patients during controlled hypotension induced with agents of different action mechanisms. We found in our subanalysis of QTc intervals that remifentanil seems to be relatively safe compared with the two other drugs when used for controlled hypotension with sevoflurane. QT interval prolongation is closely related to ANS activity, and it is well
Heart rate variability and hypotension
known that SNS stimulation leads to QTc prolongation, which is why the effects of anaesthetics on QTc intervals are studied the most during anaesthesia induction and tracheal intubation.27–30 The ability of remifentanil to attenuate QTc prolongation during procedures that activate the SNS such as laryngoscopy and tracheal intubation has been confirmed in previous studies.27,31 The QTc prolongation that was seen with nicardipine may also be related to sympathetic overstimulation. Berger et al.32 suggested that changes in autonomic tone associated with vasodilation causes QT prolongation and found these effects to persist despite correction for HR. Interestingly, nicardipine is considered as a ‘very improbable’ medication with regard to QT interval prolongation based on a survey of expert opinion,33 and Schwartz et al. reported that QTc remained unchanged when nicardipine was administered to lower the MBP by 17% from baseline in healthy individuals.34 However, the results of our study found otherwise, as the mean QTc values of Group N were significantly prolonged when compared with T1 as well as the other two groups. While none of the patients of Group R or D showed prolonged QTc intervals over 440 ms during hypotensive anaesthesia, 14 (66.7%) patients of Group N presented with QTc intervals greater than 440 ms at T2. This QTc-prolonging effect of nicardipine may act as a trigger of potentially lethal dysrhythmia such as torsades de pointes in susceptible patients with sss (LQTS), when used in doses high enough to induce controlled hypotension. Another notable finding is the QTc shortening that was observed with dexmedetomidine during controlled hypotension. In a recent study by Tsutsui et al.,21 α2-adrenoreceptor agonistic action was found to have an inhibitory effect on ventricular tachyarrhythmias and attenuate QT prolongation in a rabbit model of acquired LQTS. Although extremely rare, short QT intervals may also be a risk for cardiovascular events.35 Further studies are needed to investigate the clinical significance of the effects that nicardipine and dexmedetomidine have on QTc intervals at different clinical concentrations. This study has several limitations. First, this study was conducted in young, healthy patients without underlying cardiovascular diseases or diabetes. Although perturbations in ANS balance can be expected to be problematic in elderly patients with comorbidities, the results of the present study cannot be extrapolated to this patient population. Future studies conducted in patients that are more vulnerable to changes in ANS balance should
provide more insight into this matter. Second, we only recorded ECG data for 30 min after inducing controlled hypotension. Considering that some operations may require an extended period of hypotension, repeated measurements further into the operation may have provided more insight into the effects of each agent over time. Third, the effect of sevoflurane cannot be completely excluded. With regard to HRV, several studies found sevoflurane to decrease cardiac vagal activity,36–38 while others did not.39,40 The clinical significance of using sevoflurane per se on ANS balance is unclear, and the inconsistent results implicate that the entire anaesthetic milieu should be taken into consideration, rather than a single factor. In conclusion, while both remifentanil and dexmedetomidine were not found to have SNSstimulating effects during controlled hypotension, remifentanil seems to be relatively more competent in preserving the overall balance in ANS activity than dexmedetomidine. Nicardipine was found to stimulate the SNS as well as cause QTc prolongation, which may be problematic in patients vulnerable to disturbances in the ANS.
Acknowledgements This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science and Technology (MEST) (NRF-2010–0022999). Conflicts of interest: The authors have no conflict of interest. Funding: Ministry of Education, Science and Technology (MEST) (NRF-2010–0022999).
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Address: Young Jun Oh Department of Anesthesiology and Pain Medicine Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul, 120-752 Korea e-mail: [email protected]
