Original Contributions

Frequency of Hypotension and Bradycardia During General Anesthesia, Epidural Anesthesia, or Integrated Epidural-General Anesthesia for Total Hip Replacement
Battista Borghi, MD,* Andrea Casati, MD, Sergio Iuorio, MD, Danilo Celleno, MD, Michele Michael, MD, Pierluigi Serafini, MD, Antonio Pusceddu, MD,** Guido Fanelli, MD, on Behalf of the Study Group on Orthopedic Anesthesia of the Italian Society of Anesthesia, Analgesia, and Intensive Care (SIAARTI)
IRCSS Istituti Ortopedici, Rizzoli, Bologna, Italy; Vita-Salute University of Milano, Department of Anesthesiology, IRCCS H San Raffaele, Milano, Italy; University of Ancona, Department of Anesthesiology, Istituto Emergenze Mediche Chirurgiche, Ancona, Italy; Ospedale Fatebenefratelli, Isola Tiberina, Roma, Italy; Casa di Cura S. Maria Castellanza, Varese, Italy; Ospedale SantAgostino, Modena, Italy; Ospedale di Desio, Desio, Italy

*Staff Anesthesiologist, Department of Anesthesiology, IRCCS Istituti Ortopedici Rizzoli, Bologna, Italy Staff Anesthesiologist, Vita-Salute University of Milano, Department of Anesthesiology, IRCCS H San Raffaele, Milano, Italy Chief Anesthesiology, University of Ancona, Department of Anesthesiology, Istituto Emergenze Mediche Chirurgiche, Ancona, Italy Chief Anesthesiology, Ospedale Fatebenefratelli, Isola Tiberina, Roma, Italy Staff Anesthesiologist, Casa di Cura S. Maria Castellanza, Varese, Italy Staff Anesthesiologist, Ospedale SantAgostino, Modena, Italy **Staff Anesthesiologist, Ospedale di Desio, Desio, Italy Co-authors are listed in the Appendix. Address correspondence to Dr. A. Casati at the Department of Anesthesiology, IRCCS H San Raffaele, via Olgettina 60, 20132 Milan, Italy. E-mail: casati.andrea@hsr.it Received for publication January 24, 2001; revised manuscript accepted for publication October 23, 2001.

Study Objective: To evaluate the frequency of hypotension and bradycardia during integrated epidural-general anesthesia as compared with general anesthesia or epidural anesthesia alone. Design: Prospective, randomized, open, multicenter study Setting: Inpatient anesthesia at 7 University or Hospital Departments of anesthesia. Patients: 210 ASA physical status I, II, and III patients undergoing elective total hip replacement. Interventions: Using a balanced randomization method, each hospital enrolled 30 consecutive patients who received integrated epidural-general anesthesia, epidural anesthesia, or general anesthesia. Measurements and Main Results: Occurrence of clinically relevant hypotension (systolic arterial blood pressure (BP) decrease 30% from baseline), or bradycardia (heart rate (HR) 45 bpm) requiring pharmacologic treatment were recorded, as well as routine cardiovascular parameters. Clinically relevant hypotension during induction of nerve block was reported in 13 patients receiving epidural block (18%) and 16 patients receiving epidural-general anesthesia (22%) (p 0.67). Subsequently, 22 of the remaining 54 patients in the epidural-general anesthesia group (41%) developed hypotension after the
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Journal of Clinical Anesthesia 14:102106, 2002 2002 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010

Epidural-general anesthesia for major orthopedic surgery: Borghi et al.

induction of general anesthesia, as compared with 16 patients of the general anesthesia group (23%) (p 0.049). No differences in HR or in frequency of bradycardia were observed in the three groups. Conclusions: The induction of general anesthesia in patients with an epidural block up to T10 increased the odds of developing clinically relevant hypotension as compared with those patients who received no epidural block, and was associated with a twofold increase of the odds of hypotension as compared with the use of epidural anesthesia alone. 2002 by Elsevier Science Inc. Keywords: Bradycardia, epidural anesthesia, general anesthesia, total hip replacement.

Introduction
The combination of epidural anesthesia with light general anesthesia is widely used by most anesthesiologists who provide anesthesia for major orthopedic surgery. This approach has been demonstrated to provide clinically relevant advantages, such as reduced perioperative blood losses and improved pain control.1,2 Indeed, some authors have also reported positive effects on perioperative morbidity with the combination.3,4 Although in a previous epidemiologic study we observed an incidence of cardiovascular side effects during integrated epidural-general anesthesia similar to that reported with only epidural blockade,5 to date, no properly designed, randomized study has evaluated the cardiovascular effects of this integrated approach as compared with the use of epidural or general anesthesia alone. We therefore conducted this prospective, randomized, open study to compare the frequency of hypotension and bradycardia in a homogeneous population of orthopedic patients receiving epidural-general anesthesia, general anesthesia, or epidural anesthesia for total hip replacement.

Materials and Methods

Seven hospitals of the collaborative Study Group on Orthopedic Anesthesia of the Italian Society of Anesthesia, Analgesia and Intensive Care participated in the study. Ethical Committee approval was obtained in each hospital before the study, and all studied patients gave their written informed consent before being randomized to the anesthesia treatment. Each of the seven participating hospitals enrolled 30 consecutive patients undergoing elective hip arthroplasty. Patients with contraindication to epidural catheter placement, obesity, or with arterial hypertension not controlled with oral medications, and severe pulmonary, renal, hepatic, cerebrovascular, or psychiatric diseases were excluded from the study. In all cases, the antihypertensive medications were continued until the day of surgery. After patient arrival in the operating theater, an 18gauge intravenous (IV) cannula was placed in the forearm, and all patients were premedicated with 0.04 mg kg1 IV diazepam. In no case was a prophylactic IV volume expansion given to any study patient, although all patients had a 5-mL kg1 min1 continuous IV infusion with lactated

Ringers solution after placement of the IV cannula. Using a balanced, computer-generated, randomization sequence patients were allocated to receive epidural anesthesia (Group EA), general anesthesia (Group GA), or the integrated epidural-general anesthesia (Group EGA). Standard monitoring was used throughout the study, including non invasive, automatic arterial blood pressure (BP) measurement every 5 minutes, continuous electrocardiography (Lead II), heart rate (HR) monitoring, and pulse oximetry. All subjects remained in the horizontal supine position throughout the study. The epidural catheter was always inserted at the L3-L4 or L4-L5 interspace using the midline approach and lossof-resistance technique. After a 60-mg test dose of lidocaine 2% excluded intrathecal placement of the catheter, 10 mL of ropivacaine 7.5 mg ml1 was injected incrementally to obtain a sensory level (loss of pinprick sensation) up to T10, and a modified Bromage score 2. Two 5-mL top-up boluses were available to the anesthesiologists if the first bolus did not provide an adequate sensory level (maximum volume of 20 mL). If an adequate sensory block was not achieved within 30 minutes from the first anesthetic injection, the epidural catheter position was considered inadequate, and the patient was excluded from the study. General anesthesia was induced with IV fentanyl (1 g kg1) and propofol (2 mg kg1), followed by vecuronium bromide (0.1 mg kg1) to facilitate tracheal intubation. Afterwards, general anesthesia was maintained using a 60% nitrous oxide in oxygen mixture and isoflurane. The end-tidal concentration of isoflurane was continuously monitored with an infrared gas analyzer, and maintained in a range of 0.7%1.5% in the GA group, or in a range of 0.3% 0.7% in the EGA group, according to HR and BP values, as well as other clinical signs of anesthesia depth. In all patients, mechanical ventilation was adjusted to maintain the end-tidal CO2 partial pressure (PETCO2) ranging between 32 and 38 mmHg. During surgery, the rate of IV crystalloid infusion was increased to 8 mL kg1 h1, and an additional 3 mL was infused for every 1 mL of blood loss. In all patients, uncoagulated blood was collected from the surgical wound into a reservoir using an aspirator and collection bag connected to the inferior edge of the surgical wound. If there was a decrease in hemoglobin of more than 2 g dL1, a kit was attached to the reservoir to concentrate, wash, and infuse red cells (Compact-A Dideco, Mirandola, Modena, Italy). The autologous washed red cells recovered during surgery were immediately returned to the patient.6 Hemodynamic variables were recorded every 5 minutes for the first 30 minutes, and then every 15 minutes until completion of surgery. Clinically relevant hypotension was defined as a decrease in systolic arterial blood pressure (SBP) of 30% or more from baseline values and was treated with 5 mg etilephrine IV. Clinically relevant bradycardia was defined as HR decrease below 45 beats per minute (bpm) and was treated with 0.5 mg atropine IV. To calculate the required study size, we took into account the frequency of hypotension reported during
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Table 1. Anthropometric Variables of the Study Patients, Including Duration of Surgery, Perioperative Blood Loss, and Frequency of Homologous Blood Transfusion Group GA (n 70) Age (yrs) Weight (kg) Height (kg) Gender (male/female) ASA physical status (I/II/III) Cardiovascular disease Hypertension Ischemic heart disease Duration of surgery (min) Intraoperative blood losses (mL) Postoperative blood losses (mL) Homologous blood transfusion 64 10 70 11 163 9 23/47 11/45/14 28 (40%) 5 (13%) 112 41 479 107 545 110 16 (22%) Group EA (n 70) 66 10 70 11 165 9 32/38 11/47/12 25 (35%) 9 (12%) 106 29 547 99 502 129 9 (13%) Group EGA (n 70) 64 11 71 10 163 8 25/45 9/48/13 21 (30%) 7 (10%) 102 47 465 102 593 106 13 (18%)

Group GA general anesthesia only, Group EA epidural anesthesia only, Group EGA integrated epidural-general anesthesia.

epidural anesthesia alone7 to detect a 25% difference in the frequency of clinically relevant hypotension accepting a two-tailed error of 5% and a error of 10% the size of study population was 70 patients per group.8 Statistical analysis was performed using the program Systat 7.0 (SPSS Inc, Chicago, IL). After the presence of a center-effect was excluded, normal distribution of data were verified with the Kolmogorov-Smirnov test. Continuous variables were analyzed using analysis of variance with the Tukeys test for posthoc comparisons. Two-way analysis of variance for repeated measures was used to analyze changes over time, with Fishers and Scheffe s tests used for multiple comparisons. The contingency table analysis with the chi-square test and the appropriate corrections was used for dichotomous variables. Fishers exact test with Bonferronis correction was used for posthoc comparisons. A value of p 0.05 was considered as significant. Continuous variables are presented as means SD. Dichotomous data are presented as numbers with percentages in parentheses.

sia in Group EGA increased the odds of hypotension by 4.0 times (95% confidence intervals: 2.8 5.8) (p 0.0,005). The cumulative frequency of hypotension throughout the procedure was higher in Group EGA (38 patients; 54%) than in Group EA (25 patients; 35%) (odds ratio: 2.1; 95% confidence intervals: 1.53.0) (p 0.04). No differences in the frequency of clinically relevant bradycardia were reported among the three groups.

Discussion
Most anesthesiologists combine epidural blockade with light general anesthesia when providing anesthesia for major surgery.1 4 This integrated approach has been demonstrated to improve the recovery and rehabilitation after surgery mainly due to the use of postoperative epidural analgesia, which results in a shorter hospital stay as compared with other analgesia techniques.9 11 However, there is great concern about the risk of emphasizing the cardiovascular side effects of epidural blockade with the cardiovascular depression induced by general anesthetics. This study is the first clinical report to compare the frequency of hypotension and bradycardia in patients receiving combination general-epidural anesthesia as compared with patients receiving epidural anesthesia or general anesthesia alone. The present results showed that the induction of general anesthesia in patients with an epidural block increased nearly four times the odds of hypotension as compared with those patients without an epidural block, and was associated with a twofold increase in the odds of hypotension as compared with the use of epidural anesthesia alone. On the contrary, no effects on HR or frequency of bradycardia were observed. Evaluating the frequency and risk factors for hypotension and bradycardia during epidural blockade, Curatolo et al.7 reported a 15% frequency of hypotension in patients receiving only epidural anesthesia. The frequency of hypotension that we observed in the present investigation is higher than that reported by Curatolo et al. A possible explanation for this difference may be related to the

Results
No differences in demography, history of hypertension, duration of surgery, amount of perioperative blood loss, or frequency of homologous blood transfusion were observed (Table 1). Adequate epidural block (sensory block at T10 with modified Bromage score 2) was achieved after 23 7 minutes in Group EA and 21 8 minutes in Group EGA, respectively (p 0.10). Figure 1 shows the changes in noninvasive arterial BP and HR observed in the three groups throughout the study. Clinically relevant hypotension requiring etilephrine administration was observed in 13 patients from Group EA (18%) and 16 patients from Group EGA (22%) during the induction of the epidural blockade (p 0.67). Subsequently, 22 of the remaining 54 patients in Group EGA (41%) became hypotensive after the induction of general anesthesia as compared with 16 patients in Group GA (23%) (p 0.049). The induction of general anesthe104 J. Clin. Anesth., vol. 14, March 2002

Epidural-general anesthesia for major orthopedic surgery: Borghi et al.

Figure 1. Changes in systolic (SAP) and diastolic (DAP) arterial blood pressure, and heart rate (HR) in patients undergoing total hip arthroplasty under either general (Group GA, n 70), epidural (Group EA, n 70), or integrated epidural-general anesthesia (Group EGA, n 70). *p 0.05 general anesthesia group vs. epidural and integrated epidural-general anesthesia groups. #p 0.05, integrated epidural-general anesthesia group vs. general anesthesia and epidural anesthesia groups.

differences in study populations, because in the present study we included much older patients. However, it must be also considered that the blood loss associated with total hip arthroplasty could have increased the cumulative incidence of hypotension as compared with Curatolo et al.s7 findings. Kasaba et al.12 evaluated the cardiovascular effects of propofol anesthesia in patients with lumbar or thoracic epidural anesthesia, and reported that mean arterial blood pressure (MAP) was more significantly reduced in those patients with an epidural blockade, although the HR decreased only in those patients with a thoracic block, because of the effecs of sympathetic block of cardioaccelerator centers. An explanation of the increased frequency of hypotension observed when general anesthesia is combined with epidural blockade could be related to the depression of baroreflex activity produced by inhalational drugs, which is even more marked in elderly patients.13

Furthermore, reducing the end-tidal concentration of isoflurane in those patients receiving integrated epiduralgeneral anesthesia did not compensate for the combined depressant effect of epidural and general anesthesia on cardiovascular function, probably because of the increased potency of inhalational drugs induced by the epidural block itself.14 Cardiovascular depression induced by both propofol15 and isoflurane16 reasonably emphasized the effects produced by the sympathetic blockade related to epidural anesthesia,17 also resulting in a significant reduction in SBP from the 25th to the 60th minute after induction of general anesthesia. In the present study, we did not give routine crystalloid expansion before block placement. However, it has been shown that the use of prophylactic IV administration of fluids does not prevent the frequency of hypotension during epidural-general anesthesia,5 and the efficacy of
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this approach also remains controversial when concurrent general anesthesia is not used.18 20 Although the clinical relevance of the observed increase in the frequency of hypotension remains to be clarified, the present results suggest that the hemodynamic effects induced by general anesthesia are probably additive to those of epidural block; and physicians must be aware of this effect when choosing the appropriate anesthesia technique for individual patients. In conclusion, the results of this prospective, randomized, open study demonstrate that inducing general anesthesia in patients with an epidural block already in place increases the chance of hypotension as compared with patients receiving general anesthesia or epidural anesthesia alone. Further studies are required to better understand the clinical relevance of this effect, especially in those patients with poor cardiovascular homeostasis.

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Appendix
Physicians participating in the study and the SIAARTI Study Group on Orthopedic Anesthesia include: E. Pignotti, PhD (Biostatistician, IRCCS Istituti Ortopedici Rizzoli, Bologna, Italy); Stefano Bugamelli, MD, Umberto Righi, MD, Paini Matteo Bonfatti, MD, Alessandro Ricci, MD, Maria Lia Nepoti, MD, Fabio Facchini, MD, Francesca Stagni, MD (Department of Anesthesiology, IRCCS Istituti Ortopedici Rizzoli, Bologna, Italy); Alessandro Luzi, MD, Lioudmila Sinkovets, MD, Guiseppina Mercuri, MD (Department of Anesthesiology, Istituto Emergenze Medico Chirurgiche, Ancona, Italy); Andrea Albertin, MD (Department of Anesthesiology, IRCCS H. San Raffaele, Milano, Italy); Paolo Costantino (Department of Anesthesiology, Ospedale Fatebenefratelli, Isola Tiberina, Rome, Italy); Marco Morandini, MD, Andrea Solmi, MD, Massimo Caldi, MD (Department of Anesthesiology, Casa di cura S. Maria Castellanza, Varese, Italy); Francesco Ponzetta, MD, Monica Menegon Angela Donato, MD, Marco Rambaldi, MD, principal investigator (Department of Anesthesiology, Ospedale S. Agostino, Modena, Italy); Maria Grazia Rusconi, MD, Enrico Storti, MD, Guiliano Arosio, MD (Department of Anesthesiology, Ospedale di Desio, Desio, Italy).
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Acknowledgments
The study was supported from grants from IRCCS Istituti Ortopedici Rizzoli and the Italian Society of Anesthesia Analgesia and Intensive Care (SIAARTI). 17.

References
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