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*Tufts-New England Medical Center;
Tufts University School of Medicine;
Brigham and Women’s Hospital and Harvard Medical School;
Caritas St. Elizabeth’s Medical Center, Boston, Massachusetts
Address correspondence and reprint requests to Daniel Carr, MD, Tufts-New England Medical Center, 750 Washington St., Boston, MA 02111. Address e-mail to daniel.carr{at}tufts.edu
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Abstract |
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IMPLICATIONS: Preoperative interscalene block with levobupivacaine provides safe and effective analgesia for same-day elective shoulder surgery, but the benefit of this one-time intervention does not persist.
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Introduction |
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Methods |
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Exclusion criteria included a history of allergy to amide local anesthetics, opioids, nonsteroidal antiinflammatory drugs (NSAIDs), or other medications administered during surgery, current or previous stomach ulcers, severe renal, hepatic, respiratory, or cardiac disease, neurological (e.g., seizure), neuromuscular or psychiatric disorder, blood clotting disorder or blood dyscrasia, drug or alcohol abuse within the previous 6 mo, pregnancy or lactation, weight over 100 kg, participation in a clinical trial with an investigational drug within the previous month, or any severe chronic or terminal disease that could interfere with the absorption, metabolism, elimination, or desired effect of the study drug.
A random number table was used to allocate patients to receive an interscalene block before (PRE) or after (POST) surgery. This allocation was printed on a sheet of paper inside a sealed opaque envelope that was numbered with each patient’s place in the accrual sequence for each institution. After each patient’s written informed consent, the envelope corresponding to that patient’s enrollment number was opened by a research nurse, who informed the investigator before surgery whether to administer 0.5% levobupivacaine via interscalene block immediately before the operation or immediately upon arrival in the postanesthesia care unit (PACU) after the surgical procedure. Syringes containing levobupivacaine were prepared in and dispensed by the inpatient pharmacy of each institution. A total of 30 mL of levobupivacaine was administered in divided doses of 3–5 mL. Interscalene block was performed using either the paresthesia or the nerve stimulator technique. The effect of the block was assessed immediately after it was performed in an interval of no more than several minutes. Efficacy and adverse effects were assessed at predetermined time points during the perioperative and postoperative study periods. At hospital discharge, each patient was given a diary card to record clinical outcomes through postoperative Day 7.
Preoperative sedation was achieved with incremental bolus doses of 0.5 mg of midazolam IV up to 5 mg. After the induction with propofol, a nondepolarizing muscle relaxant (pancuronium or vecuronium) was used for tracheal intubation, the time of which was termed Time 0. General anesthesia was maintained during surgery with a mixture of oxygen/70% nitrous oxide and isoflurane. Perioperative monitoring included electrocardiogram (heart rate), oximetry (arterial oxygen saturation), and automated oscillometric arm cuff on the unoperated side (systolic and diastolic blood pressure). Fentanyl, in doses ranging from 50–100 µg, was administered IV to a maximum of 5 µg/kg when intraoperative arterial blood pressure increased more than 15% of the baseline value and was not normalized despite increasing the isoflurane concentration as large as 1%. Baseline values represented an average of three measurements taken before the induction of anesthesia. The duration of surgery and specific operative procedure were recorded.
Time to first analgesic request was measured from intubation (time 0). Pain intensity was assessed using a 0 to 10 cm visual analog scale (VAS). This scale consisted of a 10-cm line of which the left end (0) represented "no pain" and the right end (10 cm) represented the "worst imaginable pain." Assessments of pain intensity were made with the patient’s arm at rest and with attempts at elbow flexion.
After ensuring that the patient was able to accurately communicate information about her pain, pain intensity was monitored at the time of awakening from anesthesia, every 30 min for the first 2 h, every hour through 6 h, and then every 2 h through 12 h after surgery and then entered in the outpatient diary once daily through postoperative Day 7. Pain intensity was also assessed at the time of the first spontaneous request for postoperative analgesia. Global assessments of pain relief were documented by both the patient and the attending anesthesiologist at the end of the first 12-h period after intubation using a 4-point scale: 0 = poor, 1 = fair, 2 = good, and 3 = excellent.
Measurements of the functionality of the operated arm were based on the ability of the patient to move the operated arm scored as 1 = none or 2 = present and the degree of flexion of the elbow with and without resistance. Assessments of movement were made at the time of awakening, every 15 min for the first 2 h, and then every 2 h through 12 h after surgery and were documented in a patient diary once daily through postoperative Day 7 after discharge. Elbow flexion was measured with a goniometer at the time of awakening, every 15 min for the first 2 h, and then every 2 h through 12 h after surgery.
Quality of life was assessed using the acute SF-36 Health Survey (11). Patients completed the questionnaire on postoperative Days 1 and 7. The questionnaire included nine domains, namely: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, mental health, and reported health transitions. The scale range for each domain was 0 to 100.
Heart rate, systolic, and diastolic arterial blood pressures were recorded for all patients immediately before the injection of levobupivacaine, 15 min postinjection, every 5 min during surgery, and every 30 min thereafter until discharge from the recovery room. Spontaneous reports of adverse events were recorded by the study staff during the acute postoperative period until discharge and reported by the patient for 7 days after discharge. All adverse events were graded prospectively by the study staff who used a 4-point scale (none, mild, moderate, or severe) to quantitate the clinical impressions of the investigators or the symptom severity of the patients. All adverse events were followed until resolution or until the event was determined to be stable at an acceptable level of intensity. The investigators assessed the causal relationship of each adverse event to the study drug as definite, probable, possible, unlikely, or none. All serious adverse events were reported to the IRB.
On Day 7, at the follow-up visit, patients were interviewed concerning any medications taken since hospital discharge and any symptoms possibly associated with the study drug and interscalene block.
Cumulative consumption of analgesics was calculated for opioids and NSAIDs separately over three time intervals: (a) from 1 h before surgery until awakening, (b) from emergence from the operative general anesthetic until midnight on the day of surgery, and (c) from postoperative Day 1 through Day 7. Because patients were prescribed or otherwise ingested a variety of analgesics, we combined these medications into analgesic equivalents for purposes of comparison. The total number of analgesic equivalents for a patient i was calculated using the formula below:
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where j is the type of medication, either NSAID or opioid; nj,t is the last NSAID or opioid medication used within either the 12-h or 7-day window; Ti, j, k is the total dosage of either NSAID or opioid medication k for subject i used within the 12- or 7-day window; and Ek is equianalgesic dosage for medication k. Equianalgesic coefficients (Table 1) were taken as the pooled consensus values from standard texts (12–15). Doses of individual medications were aggregated and compared by first dividing the dose of each by the corresponding equianalgesic coefficient.
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The maximum VAS score between the time of intubation and midnight on the day of surgery was identified for each patient. Mean VAS scores were calculated over postoperative Days 1 through 7. Maximum and mean VAS scores were analyzed using a two-way analysis of variance fitting treatment group (PRE versus POST), site, and their interaction. Consumption of analgesics was compared between groups using the Mann-Whitney U-test.
The percentage of patients discharged from the hospital after surgery in each group was expressed as a survival curve, and comparison between groups was performed using a log-rank test.
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Results |
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The safety population, defined as all randomized patients who received study drug, included 100 patients. Similarly, the intent-to-treat population, defined as all randomized patients who received study drug and for whom there was at least one postintubation assessment of efficacy, included 100 patients. The measurable population included 74 patients. All patients received 30 mL of levobupivacaine 0.5% in incremental doses over 5 min. Twelve patients in each group had a failed or incomplete blockade, i.e., insufficient to block nociception in the judgment of the attending anesthesiologist. Three patients in the preoperative blockade group and one in the postoperative blockade group received a prohibited medication during or after surgery (additional local anesthetic by the surgeon or morphine by the attending anesthesiologist) and also were excluded. Thus, 35 patients (70%) in the PRE group and 39 (75%) in the POST group were measurable. The PRE and POST groups did not differ in demographic and baseline variables (Table 2) or in the duration of surgery (data not shown).
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The global assessment of pain control at 12 h by both patient and physician was excellent for most patients in both treatment groups. The odds ratios for a patient providing a rating of excellent did not differ significantly between groups (0.548 and 0.762).
Patterns of NSAID use were similar between the two treatment groups and did not differ significantly during surgery, on the day of surgery, or during the first 7 postoperative days. However, opioid use during surgery was significantly less in the preoperative group (1.19 equivalents) than in the postoperative treatment group (3.01; P < 0.001). In the 7 days after surgery, opioid use in the PRE and POST groups did not differ significantly.
The mean time to hospital discharge was 20 h for the preoperative and 17 h for the postoperative treatment group. This difference was not significant. The actuarial survival curves of patients discharged home versus time elapsed after surgery did not differ between groups.
At the time of emergence and shortly after surgery, the mean pain score for the preoperative treatment group was 0.33, and that for the postoperative treatment group was 4.08. From 1.5 to 6 h after surgery, i.e., after placement of the interscalene blockade in the POST group, scores in both groups were under 1.0. Mean pain scores for pre- and postoperative treatment groups were, respectively, 2.7 and 3.09 on Day 1, 1.74 and 2.68 for Days 2–4, and on Days 5–7 did not exceed 1.73. A similar pattern was seen for pain scores with arm movement.
The percentage of patients with arm movement without resistance on awakening was considerably larger in the postoperative (87.2%) than in the preoperative group (34.3%). By 1.5 h, the percentages were similar (45.7% versus 41.0%). Later on the day of surgery, the percentages of patients with arm movement were larger in the preoperative treatment group than in the postoperative group. A similar pattern was seen for arm movement with resistance. On postoperative Day 1 and subsequent days, most patients in both treatment groups had arm movement, both with and without resistance. The mean degree of elbow flexion was similar between the two groups.
For the physical functioning subscale, the means on Day 1 were 50.1 in the preoperative and 44.6 in the postoperative group, indicating substantial limitations in the ability to perform physical tasks in both groups. By Day 7, scores improved to 58.2 in the preoperative and 54.7 in the postoperative group.
For the role-physical subscale, on Day 1, the means were 29.3 in the preoperative and 20.9 in the postoperative group. For the bodily pain subscale, the mean scores were 44.1 and 42.3, respectively. These results indicate considerable difficulty with daily activities and persistent physical pain of moderate severity.
For the reported health transition scale, which measures the patient’s perception of general health over the past week, mean scores were 57.1 in the preoperative and 54.1 in the postoperative group on Day 1. Mean scores decreased substantially in both groups on Day 7.
For the general health, vitality, social functioning, role-emotional, and mental health subscales, mean scores were generally in the low-normal to normal ranges, with only slight and insignificant differences between the treatment groups.
No patient was excluded from the safety analyses. No deaths occurred in the course of this study, and no patient was withdrawn from the study because of adverse events. However, nearly all (98%) patients experienced at least one adverse event during the study. The most frequently occurring adverse events were mild or moderate nausea and vomiting, mild or moderate hypertension and hypotension, mild or moderate headache, mild or moderate paraesthesia, and mild hypoxia. Rates of occurrences were similar between the two groups, except for hypotension and headache, which occurred more frequently in the postoperative treatment group, and nausea and vomiting, which occurred more frequently in the preoperative treatment group.
Adverse events considered by the investigator to be treatment-related were experienced by 17 patients (35%) in the preoperative treatment group and 19 (37%) in the postoperative treatment group. Adverse events in two or more patients were hypotension (four patients), urinary retention (two patients), and miosis (two patients). The most frequently reported adverse events in this category were paresthesia and hypotension, which occurred more frequently in the preoperative treatment group. There were serious adverse events in 10 patients, but none was considered to be related to the study drug.
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Discussion |
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Levobupivacaine, the levo isomer of racemic bupivacaine, is a long-acting, local anesthetic that has been widely used in obstetrics and surgery. Although bupivacaine has the advantages of a sustained duration of action, which reduces the requirement for repeated administrations, and a beneficial ratio of sensory to motor blockade, it is significantly more cardiotoxic than other local anesthetics (6,16,17). Levobupivacaine has comparable anesthetic potency to bupivacaine but has less cardiotoxic potential, both in animal experiments (18–20) and in humans (21). Accordingly, we felt comfortable administering 30 mL of levobupivacaine 0.5% in divided doses.
Not surprisingly, levobupivacaine was well tolerated by patients in both treatment groups. No patient died or was withdrawn from the study because of an adverse event, and although 98% of patients experienced an adverse event, most of these were mild or moderate in severity and were assessed by the investigator as not related to the study drug. Drug-related adverse events were experienced by 17 (35%) patients in the preoperative group and 19 (37%) in the postoperative treatment group. Most of these were mild in severity, and the most common adverse events assessed by the investigator as being related to the study drug were paraesthesia and hypotension. Serious adverse events occurred in 10 patients, but none was considered to be related to the study drug. Thus, the safety profile of 0.5% levobupivacaine in patients undergoing shoulder surgery is favorable, whether it is administered before or after surgery. We attribute the relatively frequent incidence of failed or incomplete blocks as a consequence of the brief time (<10 minutes) to secure adequate surgical anesthesia. This brief interval reflected the need for the hospital pharmacist to initiate preparation of the study drug only on being told the outcome of patient randomization soon before the scheduled start time of these elective procedures. If a longer observation interval could have elapsed between placing the blockade and beginning the operation, the success rate would likely have been higher.
Although the positive results of our study were restricted to findings during the first postoperative day, we were encouraged to see that preoperative blockade had a clear advantage over postoperative blockade during that interval. To the patient and his or her family, any interval of effective pain control is a desirable outcome, even if it is not persistent (22). One may speculate that if the discharge process in the PACU had been individualized to maximally exploit the decreased pain, reduced perioperative opioid requirement, and increased function evident in the PRE group, then perhaps their time to discharge might have been less than in the POST group. However, PACU care was provided according to usual hospital protocols.
Our failure to demonstrate benefits in the PRE group during the first postsurgical week is consistent with negative findings of another randomized, controlled trial (23). In that study, 35 mL of lidocaine 1% was used for pre- or postoperative interscalene block in patients undergoing elective shoulder surgery (23). Perhaps because of the shorter duration of action of lidocaine than levobupivacaine, that study found no differences in pain scores in the 24 hours after operation.
A consensus view has emerged in the decade or so since anesthesiologists began to investigate the efficacy of preemptive analgesia by means of randomized, controlled trials. This current view indicates that the emergence of postoperative pain and inflammation after a brief interval of perioperative suppression may still produce hyperalgesia and impair quality of life (2–4,24,25). The present findings suggest that a long-duration pain management strategy that begins before surgery and that targets several analgesic pathways simultaneously (26) may be required to extend optimal pain control into the realm of outpatient surgery. Further studies will be required to evaluate whether such multimodal therapy (4) with systemic NSAIDs and regional local anesthesia may extend the early benefits that we found in our preoperative block group.
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Acknowledgments |
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Footnotes |
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References |
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