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Prone position results in enhanced pressor response to ephedrine compared with supine position during general anesthesia
Journal of Clinical Anesthesia (2016) 31, 94–100
Original Contribution
Prone position results in enhanced pressor response to ephedrine compared with supine position during general anesthesia☆ Jiangyan Xia MD (Lecturer)a,b , Jing Yuan MD (Lecturer) a,b , Xinjian Lu MD (Lecturer)a,b , Ning Yin PhD (Professor)a,b,⁎ a
Department of Anesthesiology, Zhongda Hospital, Southeast University, 210009 Nanjing, Jiangsu, China Medical School of Southeast University, 210009, Nanjing, Jiangsu, China
b
Received 9 July 2015; revised 23 November 2015; accepted 18 January 2016
Keywords: Ephedrine; General anesthesia; Intraoperative hypotension; Prone position; Supine position; Vasopressor
Abstract Study Objective: To elucidate and compare the pressor response to ephedrine in the prone or supine position during general anesthesia (GA). Design: Prospective cohort study. Setting: Department of General Surgery or Spine Surgery, Zhongda Hospital, Southeast University, Nanjing, China. Patients: Fifty-six patients who were scheduled to undergo elective surgery in the supine or prone position (n = 28 each) and using a generic GA protocol. Interventions: During surgery, the patients received intravenous (IV) ephedrine when their systolic blood pressure (SBP) decreased to 90 to 110 mm Hg. Measurements: Hemodynamic changes were measured at 1-minute intervals for 10 minutes and were compared with baseline. Main Results: Forty-nine patients (23 in the prone position and 26 in the supine position) completed the study. There were no significant differences between the groups with regard to demographic characteristics, hemodynamic parameters, end-tidal concentration of sevoflurane, and dose of propofol and remifentanil (all PN .05). After the bolus injection of ephedrine, a significant increase in SBP was observed in both groups compared to baseline, but the duration and magnitude of the increase in SBP were longer and greater in the prone position than in the supine position. The magnitude of increase of the mean blood pressure was significantly greater in the prone position compared to the supine position at 2 to 7 minutes after ephedrine injection. Ephedrine could cause significant increase in diastolic blood pressure 2 minutes after IV injection, which could last until at least 9 minutes in the prone position group compared to only for 5 minutes in the supine position group (all Pb .05). Conclusion: Compared to the supine position, the prone position could augment the pressor response to IV ephedrine during GA. Further studies are recommended to identify its association with other confounding factors such as surgery type or duration, patient history of cardiovascular disease, or patient hydration status. © 2016 Elsevier Inc. All rights reserved.
☆
Conflict of interest: The authors declare that they have no conflict of interest. ⁎ Corresponding author at: PhD, 87 Dingjiaqiao Road, Nanjing, Jiangsu, China, 210009. Tel.: +86 13813806217; fax: + 86 021 64085875. E-mail addresses: [email protected], [email protected] (N. Yin).
http://dx.doi.org/10.1016/j.jclinane.2016.01.023 0952-8180/© 2016 Elsevier Inc. All rights reserved.
Prone response to ephedrine compare with supine
95
1. Introduction
2.2. Inclusion and exclusion criteria
Hypotension is a frequent and common phenomenon during general anesthesia (GA) [1,2]. Intraoperative hypotension (IOH) has been reported to be independently associated with adverse perioperative outcomes and longterm mortality [3-6]. Immediate correction of IOH is of great importance for anesthetized patients because IOH might play a role in the development of postoperative ischemic stroke [3,6,7]. Fluctuation in intraoperative blood pressure (BP) is associated with 30-day mortality in patients undergoing aortocoronary bypass surgery [8]. Maintaining BP at a normal level, decreasing the fluctuation in intraoperative BP, and shortening the duration of IOH should decrease the incidence of complications related to inadequate major organ perfusion. The prone position is used to facilitate surgical procedures to the spine and other neurosurgical procedures. However, the position is associated with a decrease in patient's stroke volume and cardiac index (CI) [9,10]. The decreased cardiac output and other factors including compression of patient's abdomen and thorax can pose a high risk of hypotension in this position. Among all the techniques adopted to correct IOH, vasopressors possess unique characteristics. Ephedrine is 1 of the most frequently used vasoconstrictors for treating IOH related to GA and epidural anesthesia [11,12]. Although some studies suggest that the prone position is accompanied with a higher sympathetic tone than the supine position in conscious subjects [13-15], and although some other studies support different opinions [16,17], there is still no study that compared the role of ephedrine on reversing IOH during GA in these 2 different surgical positions. Hence, a prospective clinical study was designed to elucidate the pressor response to ephedrine in these 2 different body positions during GA.
Patients who were between 20 and 64 years of age with an American Society of Anesthesiologists physical status classification of I or II were included in the study. Patients with a history of hypertension, cardiovascular disorders, sinus bradycardia, diabetes mellitus, body mass index N 30 kg/m2, or any motor or sensory neurodegenerative disease were excluded. No patient took any medications that might influence body's cardiovascular functions 24 hours preoperatively. Patients did not consume any solid food for 8 hours and liquids for at least 2 hours before entering the operating room.
2. Materials and methods 2.1. Patients, study design, and ethical considerations Patients (n = 56) who were hospitalized at the departments of general surgery or spine surgery of the Zhongda Hospital, Southeast University (Nanjing, China), and scheduled to undergo elective surgery under GA in the supine or prone position were enrolled in this prospective cohort study. Consecutive patients were enrolled until there were 28 patients in each group. The study protocol was reviewed and approved by the institutional review board of the Southeast University Zhongda Hospital (Nanjing, China). The study was registered at the Chinese Clinical Trial Center (ChiCTR; registration no. ChiCTR-RNRC-13003094; registered on March 7, 2013; principal investigator: Jiangyan Xia). The study was conducted between March and July 2013. Written informed consent was obtained preoperatively from each patient.
2.3. Surgical procedure, patient groups, and GA Surgeries in the supine position mainly included gastrectomy and enterectomy, whereas the procedures in the prone positions were mainly lumbar disc excision and vertebral fusion. Patients were assigned to 1 of the 2 groups according to the type of surgery they had to undergo: supine position (n = 28) or prone position (n = 28). A central venous catheter was inserted into the right internal jugular vein after GA induction and used for fluid supplementation and bolus injection of ephedrine. Lactated Ringer's solution was infused continuously at a rate of 10 mL/kg per hour during the study. The following parameters were monitored and recorded: noninvasive BP monitor, electrocardiogram, pulse oximetry, end-tidal carbon dioxide, body temperature, and urine output. Lead II of the electrocardiogram was continuously monitored throughout the study. Central venous pressure was not measured as part of the study protocol. The protocol for induction and maintenance of GA was identical between the 2 groups. GA was induced with fentanyl (4-5 μg/kg), followed by propofol (2-2.5 mg/kg intravenous [IV]), and endotracheal intubation was facilitated with cisatracurium (0.2 mg/kg IV). Depth of anesthesia (DOA) was maintained with end-tidal concentration of sevoflurane (1%-2.5%) plus propofol (4-6 mg/kg per hour), remifentanyl (5-10 μg/kg per hour), and cisatracurium 0.15 mg/kg per hour. Ventilation was controlled mechanically: tidal volume was set at 8 mL/kg and end-tidal carbon dioxide was kept at 30 to 40 mm Hg by adjusting the frequency of ventilation. Patients in the treatment group were placed in the prone position after endotracheal intubation.
2.4. Administration of ephedrine and measurement of hemodynamic changes A single-dose bolus injection of ephedrine 0.1 mg/kg was administered to patients through the central venous catheter when their systolic BP (SBP) decreased to 90 to 110 mm Hg. Hemodynamic parameters were measured at 1-minute intervals for 10 minutes after the bolus injection of ephedrine. All BP measurements were performed using an automated BP apparatus during the operation. In all patients, no vasoconstrictors or vasodilators were used before the
96 measurement, and the concentration of the general anesthetics was not changed for at least 20 minutes before measuring the hemodynamic measurements. No significant blood loss occurred during surgery before ephedrine injection. Hemodynamic parameters measured in the study included SBP, diastolic BP (DBP), mean arterial pressure (MAP), and heart rate (HR). Baseline values (immediately before ephedrine administration) and postephedrine values were measured and compared.
2.5. Withdrawal criteria If the SBP was higher than 160 mm Hg after the IV injection of 0.1 mg/kg ephedrine, a bolus of 25 to 50 μg nitroglycerin or 20 to 40 mg esmolol was given as a rescue treatment to recover the BP to normal levels, and such patients were withdrawn from the study. Patients who required vasoconstrictors or increasing the rate of fluid infusion after anesthesia induction to reverse IOH were also withdrawn from the study.
2.6. Statistical analysis Results are presented as mean ± SD. MAP was calculated as DBP plus 1/3 × (SBP − DBP). GraphPad Prism 5.0 was used for statistical analysis. Intergroup statistical comparisons were performed using 2-way measure analysis of variance, followed by an unpaired t test with the Bonferroni correction. BP and HR values over time after ephedrine injection were analyzed using repeated measure (1 way) analysis of variance, followed by a paired t test with Bonferroni correction for paired data in each group. Pb .05 was considered as the lowest level of statistical significance.
3. Results 3.1. Characteristics of the patients Of the 56 recruited patients, 2 in the supine position and 5 in the prone position were excluded because they required vasoconstrictors or increased the rate of fluid infusion after GA induction to reverse IOH. Therefore, 26 and 23 patients in the supine and prone groups, respectively, completed the study and were included for analysis.
3.2. Demographic and baseline characteristics The 2 groups were comparable with respect to age, sex, body weight, and height (PN .05; Table 1). Baseline (immediately before ephedrine injection) hemodynamic parameters of SBP, DBP, MAP, and HR were comparable between the 2 groups (PN .05; Table 1). There were no significant differences between the 2 groups with regard to end-tidal concentration of sevoflurane and dosage of
J. Xia et al. propofol and remifentanil used to maintain the DOA (PN .05; Table 2).
3.3. Safety assessments In the present study, ephedrine was used in a dose less than the clinically recommended one to observe the pressor reaction in 2 different body positions [1]. No patient had an exaggerated pressor response to 0.1 mg/kg IV ephedrine. No patients died during the study.
3.4. Hemodynamic changes Increases of absolute change and percentage change in SBP, DBP, MAP, and HR were compared between the 2 groups. After the bolus injection of ephedrine, absolute and relative changes in SBP, DBP, MAP, and HR were compared between the 2 groups. Significant increases in SBP were observed in both groups compared to pre-ephedrine values. However, the duration and magnitude of the increase in SBP were greater in the prone position than in the supine position, especially the increase in magnitude (Fig. 1A). Similar responses were also observed in DBP and MAP. For MAP, the magnitude of the increase was significantly greater in the prone position compared to the supine position 2 to 7 minutes after ephedrine injection (Fig. 1C). For DBP, ephedrine could cause significant increases 2 minutes after IV injection, and the increase lasted until at least 9 minutes compared to pre-ephedrine values in the prone position. However, DBP was significantly increased for only 5 minutes in the prone position (Fig. 1B). The absolute and relative changes of SBP, DBP, and MAP increases were significantly greater in the prone position compared to the supine position (Figs. 2 and 3). In the prone position group, the highest increase in the absolute value of SBP was 23.4 ± 1.8 mm Hg, whereas it was 10.0 ± 1.4 mm Hg in the supine position (Fig. 2A). The highest increase in the relative changes of SBP, DBP, and MAP in the 2 groups were 23.1% vs 9.9%, 20.9% vs 16.9%, and 22.7% vs 13.8%, respectively (Fig. 3A-C). Although ephedrine would cause a greater Table 1
Demographic characteristics of the 2 groups
Demographic characteristics
Group Supine position (n = 26)
Prone position (n = 23)
Sex (male/female) Age (y) Weight (kg) Height (cm) SBP (mm Hg) DBP (mm Hg) MAP (mm Hg) HR (beats/minute)
9/17 46.08 ± 10.73 63.65 ± 11.42 164.35 ± 8.21 101.5 ± 7.9 61.3 ± 8.5 73.9 ± 8.3 66.3 ± 9.9
9/14 47.78 ± 7.90 65.57 ± 7.40 166.26 ± 6.99 102.1 ± 7.0 64.3 ± 6.5 76.9 ± 6.1 65.2 ± 6.8
Values are presented as mean ± SD or number.
Prone response to ephedrine compare with supine Table 2
Concentration of general anesthetics of the 2 groups
General anesthetics
Sevoflurane (vol%) Propofol (mg/kg/h) Remifentanyl (μg/kg/h)
Group Supine position (n = 26)
Prone position (n = 23)
1.76 ± 0.25 4.15 ± 0.60 8.73 ± 0.87
1.76 ± 0.21 4.15 ± 0.44 8.65 ± 0.88
Values are presented as mean ± SD.
increase in HR in the prone position compared to the supine position, the baseline value of HR was slightly lower in the prone position, and there was no significant difference in HR between the 2 groups after IV ephedrine (Fig. 1D).
4. Discussion Use of GA is often accompanied by IOH, which is associated with high perioperative mortality and morbidity rates. Therefore, reversal of IOH by vasopressors in patients under GA is critical for anesthetists. It has been reported that body positions during surgery could influence the pressor response to vasopressors during GA. The prone position
97 during GA could increase the incidence of IOH compared to the supine position. Anesthetists usually consider reducing the depth of GA or administering intravenous fluids or vasopressors to manage IOH [11,18]. Longer durations of IOH often lead to higher occurrence of perioperative complications [19]. Although vasoconstrictors often possess the advantage of rapid onset and reliability, indiscriminate use of vasoconstrictors may lead to adverse outcomes such as tachycardia, hypertension, and other adverse effects. Among all the frequently used vasopressors, ephedrine is a conventional agent used to manage and prevent hypotension [20]. Ephedrine acts on α-adrenergic and β-adrenergic receptors and displaces norepinephrine from adrenergic terminals [20,21]. The release of catecholamines and subsequent activation of adrenergic receptors are thought to be the primary mechanism involved in the cardiovascular response to ephedrine. Investigations have revealed that systemic and pulmonary pressor responses to ephedrine are mediated by direct α-adrenergic receptor stimulation, whereas β-receptors modulate the responses [22]. The response has been reported not to be reduced even after the depletion of catecholamines with reserpine [22]. A preclinical study suggested that the pressor and positive chronotropic response to ephedrine are directly mediated by the activation of α-adrenergic and β-adrenergic receptors [23].
Fig. 1 Absolute values of SBP (A), DBP (B), MAP (C), and HR (D) after IV administration of 0.1 mg/kg of ephedrine in patients in the prone or supine position during GA. Values are presented as mean ± SD; aPb .05 vs baseline; ⁎Pb .05 vs the supine position.
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Fig. 2 Changes in SBP (A), DBP (B), MAP (C), and HR (D) after IV administration of 0.1 mg/kg of ephedrine in patients in the prone or supine position during GA. Values are presented as mean ± SD; ⁎Pb .05 vs the supine position.
Previous investigations of response to IV ephedrine under different clinical conditions have demonstrated that the pressor effect of ephedrine is greater in anesthetized compared to awake patients. Propofol, enflurane, and clonidine premedication would enhance the pressor response to ephedrine [24-26]. The response was reported to be related to the sympathetic tone and was more intense at lower basal levels of sympathetic activity [27]. This study showed that the prone position was associated with a more significant augmentation of the pressor response to IV ephedrine during GA compared to the supine position. The magnitude and duration of the pressor effect to IV ephedrine were much greater in the prone position than in the supine position during GA. Moving a patient to the prone position will cause a decrease in CI and an increase in the systemic vascular resistance [28,29]. The decrease in CI could be attributed to the compression of the thorax, obstruction of the inferior vena cava, and compression of the abdomen [28,29]. The decrease in CI and vasodilating effect of GA may increase the risk of IOH. Previous studies have suggested that the prone position might have a significant effect on the parasympathetic activity, partially attributed to the volume receptor of the right atrium [17]. The compression of the trigeminal or facial nerve might also increase the vagal nerve tone in the prone position [30]. GA could weaken or blunt the body's
baroreceptor reflex and impair the body's compensatory reactions [31-33]. Among the 49 subjects in this study, approximately 50% (23/49) had an instantaneous and transient BP decrease after the bolus injection of ephedrine, which might be the effect of instantaneous activation of the β-adrenergic receptors by ephedrine. Previous studies also suggested that the increased response to ephedrine might be related to different DOA and different anesthetics [25,34]. In this present study, the 2 study groups were submitted to the exact same GA and fluid administration protocols. There were no significant differences in the doses and concentrations of anesthetics used for induction and maintenance of GA between the 2 groups. Pre-ephedrine hemodynamic parameters were almost identical between the 2 groups. Hypotension and hypertension can both result in cardiovascular and cerebral vascular complications and increase postoperative mortality and morbidity. Reducing intraoperative BP variations should contribute to a better postoperative prognosis. This study has a number of limitations. A noninvasive BP monitor was used to measure hemodynamic parameters, which is, in itself, a key limitation. The objective of this study was only to elucidate and compare the pressor response to ephedrine in 2 surgical positions. However, it did not attempt to compare the various surgery types, nor the type of preparation (eg, for bowel surgery). Surgery involving traction
Prone response to ephedrine compare with supine
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Fig. 3 Percentage changes in SBP (A), DBP (B), MAP (C), and HR (D) after IV administration of 0.1 mg/kg of ephedrine in patients in the prone or supine position during GA. Values are presented as mean ± SD; ⁎Pb .05 vs the supine position.
on abdominal viscera could cause decrease in BP, and a spinal surgery could have less impact on BP. Hence, it is obvious that the surgery type probably played an important role in the intraoperative fluctuations in BP. Even the other confounding factors associated with the surgery such as surgery duration and other medications could have some potential role in such fluctuations. Moreover, this study involved only a small sample size. Further studies should be performed to expose the involved mechanisms and elucidate the underlying doseresponse curve to the commonly used vasoconstrictors during different perioperative statuses. Such research would help to adopt more appropriate dosages of vasopressors and keep the intraoperative hemodynamic values more stable. Furthermore, these findings would decrease and avoid hypotension and hemodynamic variations and related cardiovascular and cerebral vascular complications. We have shown that, in patients without cardiovascular diseases, compared to the supine position, the prone position could augment the pressor response to IV ephedrine during GA. Hypotension in the prone position patients could be more easily reversed by IV ephedrine than in the supine position during GA. However, further studies with large sample size are required to validate this information. Because the study involved only the comparison of surgery positions, further studies are recommended to identify its association
with other confounding factors such as surgery type, surgery duration, or patient cardiovascular or neurologic disease.
Authors' contributions NY and JYX conceived and plan the program. JY recorded patients' information. XJL analyzed the data. JYX contributed to the writing of the manuscript. All authors read and approved the final manuscript.
Competing interests The authors declare that they have no competing interests.
Acknowledgments This project was supported by the National Natural Science Foundation of China (grant no. H1502/81201449). We are grateful to all the participating patients of this study. We thank the staff members of this trial, our colleagues, and
100 all the study staff for their enormous efforts in collecting and ensuring the accuracy and completeness of all the data.
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J. Xia et al. [16] Tetzlaff JE, O'Hara JF Jr, Yoon HJ, Schubert A. Heart rate variability and the prone position under general versus spinal anesthesia. J Clin Anesth 1998;10:656-9. [17] Miyata S, Noda A, Fujii Y, Maekawa A, Okuda M, Nakazaki C, et al. The effects of the prone position on the physiological function in healthy students. Open Gen Intern Med J 2012;5:9-12. [18] Bhattarai B, Bhat SY, Upadya M. Comparison of bolus phenylephrine, ephedrine and mephentermine for maintenance of arterial pressure during spinal anesthesia in cesarean section. JNMA J Nepal Med Assoc 2010;49:23-8. [19] Charlson ME, MacKenzie CR, Gold JP, Ales KL, Topkins M, Fairclough GP Jr, et al. The preoperative and intraoperative hemodynamic predictors of postoperative myocardial infarction or ischemia in patients undergoing noncardiac surgery. Ann Surg 1989; 210:637-48. [20] Zaimis E. Vasopressor drugs and catecholamines. Anesthesiology 1968;29:732-62. [21] Kobayashi S, Endou M, Sakuraya F, Matsuda N, Zhang XH, Azuma M, et al. The sympathomimetic actions of l-ephedrine and dpseudoephedrine: direct receptor activation or norepinephrine release? Anesth Analg 2003;97:1239-45. [22] Liles JT, Dabisch PA, Hude KE, Pradhan L, Varner KJ, Porter JR, et al. Pressor responses to ephedrine are mediated by a direct mechanism in the rat. J Pharmacol Exp Ther 2006;316:95-105. [23] Liles JT, Baber SR, Deng W, Porter JR, Corll C, Murthy SN, et al. Pressor responses to ephedrine are not impaired in dopamine betahydroxylase knockout mice. Br J Pharmacol 2007;150:29-36. [24] Nishikawa T, Kimura T, Taguchi N, Dohi S. Oral clonidine preanesthetic medication augments the pressor responses to intravenous ephedrine in awake or anesthetized patients. Anesthesiology 1991;74:705-10. [25] Kanaya N, Satoh H, Seki S, Nakayama M, Namiki A. Propofol anesthesia enhances the pressor response to intravenous ephedrine. Anesth Analg 2002;94:1207-11 [table of contents]. [26] Goyagi T, Tanaka M, Nishikawa T. Oral clonidine premedication enhances the pressor response to ephedrine during spinal anesthesia. Anesth Analg 1998;87:1336-9. [27] Philipp T, Distler A, Cordes U. Sympathetic nervous system and bloodpressure control in essential hypertension. Lancet 1978;2:959-63. [28] Toyota S, Amaki Y. Hemodynamic evaluation of the prone position by transesophageal echocardiography. J Clin Anesth 1998;10:32-5. [29] Edgcombe H, Carter K, Yarrow S. Anaesthesia in the prone position. Br J Anaesth 2008;100:165-83. [30] Schaller B. Trigeminocardiac reflex. A clinical phenomenon or a new physiological entity? J Neurol 2004;251:658-65. [31] Seagard JL, Elegbe EO, Hopp FA, Bosnjak ZJ, von Colditz JH, Kalbfleisch JH, et al. Effects of isoflurane on the baroreceptor reflex. Anesthesiology 1983;59:511-20. [32] Bedran-de-Castro MT, Farah VM, Krieger EM. Influence of general anesthetics on baroreflex control of circulation. Braz J Med Biol Res 1990;23:1185-93. [33] Tanaka M, Nishikawa T. The concentration-dependent effects of general anesthesia on spontaneous baroreflex indices and their correlations with pharmacological gains. Anesth Analg 2005;100: 1325-32 [table of contents]. [34] Hayakawa-Fujii Y, Iida H, Dohi S. Propofol anesthesia enhances pressor response to ephedrine in patients given clonidine. Anesth Analg 1999;89:37-41.
Original Contribution
Prone position results in enhanced pressor response to ephedrine compared with supine position during general anesthesia☆ Jiangyan Xia MD (Lecturer)a,b , Jing Yuan MD (Lecturer) a,b , Xinjian Lu MD (Lecturer)a,b , Ning Yin PhD (Professor)a,b,⁎ a
Department of Anesthesiology, Zhongda Hospital, Southeast University, 210009 Nanjing, Jiangsu, China Medical School of Southeast University, 210009, Nanjing, Jiangsu, China
b
Received 9 July 2015; revised 23 November 2015; accepted 18 January 2016
Keywords: Ephedrine; General anesthesia; Intraoperative hypotension; Prone position; Supine position; Vasopressor
Abstract Study Objective: To elucidate and compare the pressor response to ephedrine in the prone or supine position during general anesthesia (GA). Design: Prospective cohort study. Setting: Department of General Surgery or Spine Surgery, Zhongda Hospital, Southeast University, Nanjing, China. Patients: Fifty-six patients who were scheduled to undergo elective surgery in the supine or prone position (n = 28 each) and using a generic GA protocol. Interventions: During surgery, the patients received intravenous (IV) ephedrine when their systolic blood pressure (SBP) decreased to 90 to 110 mm Hg. Measurements: Hemodynamic changes were measured at 1-minute intervals for 10 minutes and were compared with baseline. Main Results: Forty-nine patients (23 in the prone position and 26 in the supine position) completed the study. There were no significant differences between the groups with regard to demographic characteristics, hemodynamic parameters, end-tidal concentration of sevoflurane, and dose of propofol and remifentanil (all PN .05). After the bolus injection of ephedrine, a significant increase in SBP was observed in both groups compared to baseline, but the duration and magnitude of the increase in SBP were longer and greater in the prone position than in the supine position. The magnitude of increase of the mean blood pressure was significantly greater in the prone position compared to the supine position at 2 to 7 minutes after ephedrine injection. Ephedrine could cause significant increase in diastolic blood pressure 2 minutes after IV injection, which could last until at least 9 minutes in the prone position group compared to only for 5 minutes in the supine position group (all Pb .05). Conclusion: Compared to the supine position, the prone position could augment the pressor response to IV ephedrine during GA. Further studies are recommended to identify its association with other confounding factors such as surgery type or duration, patient history of cardiovascular disease, or patient hydration status. © 2016 Elsevier Inc. All rights reserved.
☆
Conflict of interest: The authors declare that they have no conflict of interest. ⁎ Corresponding author at: PhD, 87 Dingjiaqiao Road, Nanjing, Jiangsu, China, 210009. Tel.: +86 13813806217; fax: + 86 021 64085875. E-mail addresses: [email protected], [email protected] (N. Yin).
http://dx.doi.org/10.1016/j.jclinane.2016.01.023 0952-8180/© 2016 Elsevier Inc. All rights reserved.
Prone response to ephedrine compare with supine
95
1. Introduction
2.2. Inclusion and exclusion criteria
Hypotension is a frequent and common phenomenon during general anesthesia (GA) [1,2]. Intraoperative hypotension (IOH) has been reported to be independently associated with adverse perioperative outcomes and longterm mortality [3-6]. Immediate correction of IOH is of great importance for anesthetized patients because IOH might play a role in the development of postoperative ischemic stroke [3,6,7]. Fluctuation in intraoperative blood pressure (BP) is associated with 30-day mortality in patients undergoing aortocoronary bypass surgery [8]. Maintaining BP at a normal level, decreasing the fluctuation in intraoperative BP, and shortening the duration of IOH should decrease the incidence of complications related to inadequate major organ perfusion. The prone position is used to facilitate surgical procedures to the spine and other neurosurgical procedures. However, the position is associated with a decrease in patient's stroke volume and cardiac index (CI) [9,10]. The decreased cardiac output and other factors including compression of patient's abdomen and thorax can pose a high risk of hypotension in this position. Among all the techniques adopted to correct IOH, vasopressors possess unique characteristics. Ephedrine is 1 of the most frequently used vasoconstrictors for treating IOH related to GA and epidural anesthesia [11,12]. Although some studies suggest that the prone position is accompanied with a higher sympathetic tone than the supine position in conscious subjects [13-15], and although some other studies support different opinions [16,17], there is still no study that compared the role of ephedrine on reversing IOH during GA in these 2 different surgical positions. Hence, a prospective clinical study was designed to elucidate the pressor response to ephedrine in these 2 different body positions during GA.
Patients who were between 20 and 64 years of age with an American Society of Anesthesiologists physical status classification of I or II were included in the study. Patients with a history of hypertension, cardiovascular disorders, sinus bradycardia, diabetes mellitus, body mass index N 30 kg/m2, or any motor or sensory neurodegenerative disease were excluded. No patient took any medications that might influence body's cardiovascular functions 24 hours preoperatively. Patients did not consume any solid food for 8 hours and liquids for at least 2 hours before entering the operating room.
2. Materials and methods 2.1. Patients, study design, and ethical considerations Patients (n = 56) who were hospitalized at the departments of general surgery or spine surgery of the Zhongda Hospital, Southeast University (Nanjing, China), and scheduled to undergo elective surgery under GA in the supine or prone position were enrolled in this prospective cohort study. Consecutive patients were enrolled until there were 28 patients in each group. The study protocol was reviewed and approved by the institutional review board of the Southeast University Zhongda Hospital (Nanjing, China). The study was registered at the Chinese Clinical Trial Center (ChiCTR; registration no. ChiCTR-RNRC-13003094; registered on March 7, 2013; principal investigator: Jiangyan Xia). The study was conducted between March and July 2013. Written informed consent was obtained preoperatively from each patient.
2.3. Surgical procedure, patient groups, and GA Surgeries in the supine position mainly included gastrectomy and enterectomy, whereas the procedures in the prone positions were mainly lumbar disc excision and vertebral fusion. Patients were assigned to 1 of the 2 groups according to the type of surgery they had to undergo: supine position (n = 28) or prone position (n = 28). A central venous catheter was inserted into the right internal jugular vein after GA induction and used for fluid supplementation and bolus injection of ephedrine. Lactated Ringer's solution was infused continuously at a rate of 10 mL/kg per hour during the study. The following parameters were monitored and recorded: noninvasive BP monitor, electrocardiogram, pulse oximetry, end-tidal carbon dioxide, body temperature, and urine output. Lead II of the electrocardiogram was continuously monitored throughout the study. Central venous pressure was not measured as part of the study protocol. The protocol for induction and maintenance of GA was identical between the 2 groups. GA was induced with fentanyl (4-5 μg/kg), followed by propofol (2-2.5 mg/kg intravenous [IV]), and endotracheal intubation was facilitated with cisatracurium (0.2 mg/kg IV). Depth of anesthesia (DOA) was maintained with end-tidal concentration of sevoflurane (1%-2.5%) plus propofol (4-6 mg/kg per hour), remifentanyl (5-10 μg/kg per hour), and cisatracurium 0.15 mg/kg per hour. Ventilation was controlled mechanically: tidal volume was set at 8 mL/kg and end-tidal carbon dioxide was kept at 30 to 40 mm Hg by adjusting the frequency of ventilation. Patients in the treatment group were placed in the prone position after endotracheal intubation.
2.4. Administration of ephedrine and measurement of hemodynamic changes A single-dose bolus injection of ephedrine 0.1 mg/kg was administered to patients through the central venous catheter when their systolic BP (SBP) decreased to 90 to 110 mm Hg. Hemodynamic parameters were measured at 1-minute intervals for 10 minutes after the bolus injection of ephedrine. All BP measurements were performed using an automated BP apparatus during the operation. In all patients, no vasoconstrictors or vasodilators were used before the
96 measurement, and the concentration of the general anesthetics was not changed for at least 20 minutes before measuring the hemodynamic measurements. No significant blood loss occurred during surgery before ephedrine injection. Hemodynamic parameters measured in the study included SBP, diastolic BP (DBP), mean arterial pressure (MAP), and heart rate (HR). Baseline values (immediately before ephedrine administration) and postephedrine values were measured and compared.
2.5. Withdrawal criteria If the SBP was higher than 160 mm Hg after the IV injection of 0.1 mg/kg ephedrine, a bolus of 25 to 50 μg nitroglycerin or 20 to 40 mg esmolol was given as a rescue treatment to recover the BP to normal levels, and such patients were withdrawn from the study. Patients who required vasoconstrictors or increasing the rate of fluid infusion after anesthesia induction to reverse IOH were also withdrawn from the study.
2.6. Statistical analysis Results are presented as mean ± SD. MAP was calculated as DBP plus 1/3 × (SBP − DBP). GraphPad Prism 5.0 was used for statistical analysis. Intergroup statistical comparisons were performed using 2-way measure analysis of variance, followed by an unpaired t test with the Bonferroni correction. BP and HR values over time after ephedrine injection were analyzed using repeated measure (1 way) analysis of variance, followed by a paired t test with Bonferroni correction for paired data in each group. Pb .05 was considered as the lowest level of statistical significance.
3. Results 3.1. Characteristics of the patients Of the 56 recruited patients, 2 in the supine position and 5 in the prone position were excluded because they required vasoconstrictors or increased the rate of fluid infusion after GA induction to reverse IOH. Therefore, 26 and 23 patients in the supine and prone groups, respectively, completed the study and were included for analysis.
3.2. Demographic and baseline characteristics The 2 groups were comparable with respect to age, sex, body weight, and height (PN .05; Table 1). Baseline (immediately before ephedrine injection) hemodynamic parameters of SBP, DBP, MAP, and HR were comparable between the 2 groups (PN .05; Table 1). There were no significant differences between the 2 groups with regard to end-tidal concentration of sevoflurane and dosage of
J. Xia et al. propofol and remifentanil used to maintain the DOA (PN .05; Table 2).
3.3. Safety assessments In the present study, ephedrine was used in a dose less than the clinically recommended one to observe the pressor reaction in 2 different body positions [1]. No patient had an exaggerated pressor response to 0.1 mg/kg IV ephedrine. No patients died during the study.
3.4. Hemodynamic changes Increases of absolute change and percentage change in SBP, DBP, MAP, and HR were compared between the 2 groups. After the bolus injection of ephedrine, absolute and relative changes in SBP, DBP, MAP, and HR were compared between the 2 groups. Significant increases in SBP were observed in both groups compared to pre-ephedrine values. However, the duration and magnitude of the increase in SBP were greater in the prone position than in the supine position, especially the increase in magnitude (Fig. 1A). Similar responses were also observed in DBP and MAP. For MAP, the magnitude of the increase was significantly greater in the prone position compared to the supine position 2 to 7 minutes after ephedrine injection (Fig. 1C). For DBP, ephedrine could cause significant increases 2 minutes after IV injection, and the increase lasted until at least 9 minutes compared to pre-ephedrine values in the prone position. However, DBP was significantly increased for only 5 minutes in the prone position (Fig. 1B). The absolute and relative changes of SBP, DBP, and MAP increases were significantly greater in the prone position compared to the supine position (Figs. 2 and 3). In the prone position group, the highest increase in the absolute value of SBP was 23.4 ± 1.8 mm Hg, whereas it was 10.0 ± 1.4 mm Hg in the supine position (Fig. 2A). The highest increase in the relative changes of SBP, DBP, and MAP in the 2 groups were 23.1% vs 9.9%, 20.9% vs 16.9%, and 22.7% vs 13.8%, respectively (Fig. 3A-C). Although ephedrine would cause a greater Table 1
Demographic characteristics of the 2 groups
Demographic characteristics
Group Supine position (n = 26)
Prone position (n = 23)
Sex (male/female) Age (y) Weight (kg) Height (cm) SBP (mm Hg) DBP (mm Hg) MAP (mm Hg) HR (beats/minute)
9/17 46.08 ± 10.73 63.65 ± 11.42 164.35 ± 8.21 101.5 ± 7.9 61.3 ± 8.5 73.9 ± 8.3 66.3 ± 9.9
9/14 47.78 ± 7.90 65.57 ± 7.40 166.26 ± 6.99 102.1 ± 7.0 64.3 ± 6.5 76.9 ± 6.1 65.2 ± 6.8
Values are presented as mean ± SD or number.
Prone response to ephedrine compare with supine Table 2
Concentration of general anesthetics of the 2 groups
General anesthetics
Sevoflurane (vol%) Propofol (mg/kg/h) Remifentanyl (μg/kg/h)
Group Supine position (n = 26)
Prone position (n = 23)
1.76 ± 0.25 4.15 ± 0.60 8.73 ± 0.87
1.76 ± 0.21 4.15 ± 0.44 8.65 ± 0.88
Values are presented as mean ± SD.
increase in HR in the prone position compared to the supine position, the baseline value of HR was slightly lower in the prone position, and there was no significant difference in HR between the 2 groups after IV ephedrine (Fig. 1D).
4. Discussion Use of GA is often accompanied by IOH, which is associated with high perioperative mortality and morbidity rates. Therefore, reversal of IOH by vasopressors in patients under GA is critical for anesthetists. It has been reported that body positions during surgery could influence the pressor response to vasopressors during GA. The prone position
97 during GA could increase the incidence of IOH compared to the supine position. Anesthetists usually consider reducing the depth of GA or administering intravenous fluids or vasopressors to manage IOH [11,18]. Longer durations of IOH often lead to higher occurrence of perioperative complications [19]. Although vasoconstrictors often possess the advantage of rapid onset and reliability, indiscriminate use of vasoconstrictors may lead to adverse outcomes such as tachycardia, hypertension, and other adverse effects. Among all the frequently used vasopressors, ephedrine is a conventional agent used to manage and prevent hypotension [20]. Ephedrine acts on α-adrenergic and β-adrenergic receptors and displaces norepinephrine from adrenergic terminals [20,21]. The release of catecholamines and subsequent activation of adrenergic receptors are thought to be the primary mechanism involved in the cardiovascular response to ephedrine. Investigations have revealed that systemic and pulmonary pressor responses to ephedrine are mediated by direct α-adrenergic receptor stimulation, whereas β-receptors modulate the responses [22]. The response has been reported not to be reduced even after the depletion of catecholamines with reserpine [22]. A preclinical study suggested that the pressor and positive chronotropic response to ephedrine are directly mediated by the activation of α-adrenergic and β-adrenergic receptors [23].
Fig. 1 Absolute values of SBP (A), DBP (B), MAP (C), and HR (D) after IV administration of 0.1 mg/kg of ephedrine in patients in the prone or supine position during GA. Values are presented as mean ± SD; aPb .05 vs baseline; ⁎Pb .05 vs the supine position.
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Fig. 2 Changes in SBP (A), DBP (B), MAP (C), and HR (D) after IV administration of 0.1 mg/kg of ephedrine in patients in the prone or supine position during GA. Values are presented as mean ± SD; ⁎Pb .05 vs the supine position.
Previous investigations of response to IV ephedrine under different clinical conditions have demonstrated that the pressor effect of ephedrine is greater in anesthetized compared to awake patients. Propofol, enflurane, and clonidine premedication would enhance the pressor response to ephedrine [24-26]. The response was reported to be related to the sympathetic tone and was more intense at lower basal levels of sympathetic activity [27]. This study showed that the prone position was associated with a more significant augmentation of the pressor response to IV ephedrine during GA compared to the supine position. The magnitude and duration of the pressor effect to IV ephedrine were much greater in the prone position than in the supine position during GA. Moving a patient to the prone position will cause a decrease in CI and an increase in the systemic vascular resistance [28,29]. The decrease in CI could be attributed to the compression of the thorax, obstruction of the inferior vena cava, and compression of the abdomen [28,29]. The decrease in CI and vasodilating effect of GA may increase the risk of IOH. Previous studies have suggested that the prone position might have a significant effect on the parasympathetic activity, partially attributed to the volume receptor of the right atrium [17]. The compression of the trigeminal or facial nerve might also increase the vagal nerve tone in the prone position [30]. GA could weaken or blunt the body's
baroreceptor reflex and impair the body's compensatory reactions [31-33]. Among the 49 subjects in this study, approximately 50% (23/49) had an instantaneous and transient BP decrease after the bolus injection of ephedrine, which might be the effect of instantaneous activation of the β-adrenergic receptors by ephedrine. Previous studies also suggested that the increased response to ephedrine might be related to different DOA and different anesthetics [25,34]. In this present study, the 2 study groups were submitted to the exact same GA and fluid administration protocols. There were no significant differences in the doses and concentrations of anesthetics used for induction and maintenance of GA between the 2 groups. Pre-ephedrine hemodynamic parameters were almost identical between the 2 groups. Hypotension and hypertension can both result in cardiovascular and cerebral vascular complications and increase postoperative mortality and morbidity. Reducing intraoperative BP variations should contribute to a better postoperative prognosis. This study has a number of limitations. A noninvasive BP monitor was used to measure hemodynamic parameters, which is, in itself, a key limitation. The objective of this study was only to elucidate and compare the pressor response to ephedrine in 2 surgical positions. However, it did not attempt to compare the various surgery types, nor the type of preparation (eg, for bowel surgery). Surgery involving traction
Prone response to ephedrine compare with supine
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Fig. 3 Percentage changes in SBP (A), DBP (B), MAP (C), and HR (D) after IV administration of 0.1 mg/kg of ephedrine in patients in the prone or supine position during GA. Values are presented as mean ± SD; ⁎Pb .05 vs the supine position.
on abdominal viscera could cause decrease in BP, and a spinal surgery could have less impact on BP. Hence, it is obvious that the surgery type probably played an important role in the intraoperative fluctuations in BP. Even the other confounding factors associated with the surgery such as surgery duration and other medications could have some potential role in such fluctuations. Moreover, this study involved only a small sample size. Further studies should be performed to expose the involved mechanisms and elucidate the underlying doseresponse curve to the commonly used vasoconstrictors during different perioperative statuses. Such research would help to adopt more appropriate dosages of vasopressors and keep the intraoperative hemodynamic values more stable. Furthermore, these findings would decrease and avoid hypotension and hemodynamic variations and related cardiovascular and cerebral vascular complications. We have shown that, in patients without cardiovascular diseases, compared to the supine position, the prone position could augment the pressor response to IV ephedrine during GA. Hypotension in the prone position patients could be more easily reversed by IV ephedrine than in the supine position during GA. However, further studies with large sample size are required to validate this information. Because the study involved only the comparison of surgery positions, further studies are recommended to identify its association
with other confounding factors such as surgery type, surgery duration, or patient cardiovascular or neurologic disease.
Authors' contributions NY and JYX conceived and plan the program. JY recorded patients' information. XJL analyzed the data. JYX contributed to the writing of the manuscript. All authors read and approved the final manuscript.
Competing interests The authors declare that they have no competing interests.
Acknowledgments This project was supported by the National Natural Science Foundation of China (grant no. H1502/81201449). We are grateful to all the participating patients of this study. We thank the staff members of this trial, our colleagues, and
100 all the study staff for their enormous efforts in collecting and ensuring the accuracy and completeness of all the data.
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