The specific aims were to: 1) compare pain ratings and supplemental analgesic requirements at discharge from PACU (post anesthesia care unit; recovery room), 24 hours, and 48 hours and 12 weeks following 5, 10, and 20 mL boluses; 2) compare symptomatic adverse events including clinical dysphonia, Horner's syndrome and dyspnea, as well as unexpected hospitalization, evidence of local anesthetic toxicity, and perceived hand weakness at discharge from PACU following 5, 10, and 20 mL boluses; 3) compare impairment in diaphragmatic excursion at discharge from PACU following 5, 10, and 20 mL boluses; 4) compare patients' satisfaction with analgesia at 24 and 48 hours following 5, 10, and 20 mL boluses; 5) compare patient rating of functional outcome at baseline and at 12 weeks following 5, 10, and 20 mL boluses; and 6) compare the rates of general anesthesia required due to inadequate block following 5, 10, and 20 mL boluses.
After IRB approval from the William Beaumont Human Investigation Committee, subjects aged 18-80 years undergoing arthroscopic shoulder surgery were randomized into 3 groups to receive ISB with a 5, 10 or 20 mL initial bolus of ropivacaine 0.75% (http://clinicaltrials.gov
. identifier: NCT00672100). The subjects were eligible for enrollment if they were ASA risk class I-III. Exclusion criteria were opioid tolerance, defined as > 40 mg oxycodone equivalent daily over 2 weeks prior to study, significant preexisting pulmonary disease including diaphragmatic paralysis or history of phrenic nerve injury, hypersensitivity to opioids or ropivacaine, known or suspected history of alcohol or drug abuse or dependence within the previous 2 years, history of liver disease, or participation in another clinical study within 30 days of surgery. Written informed consent was obtained from all subjects. Subjects and observers were blinded as to group assignment.
Randomization was provided to the research pharmacist by a biostatistician who used a rotating block technique. The research pharmacist provided the specific patient allocation information directly to the unblinded anesthesiologist immediately prior to the procedure. Unblinded investigators then administered the anesthetic injection and established a continuous infusion through an interscalene catheter in the preoperative holding area. In the operating room the quality of the block was assessed by blinded investigators at the time of surgical manipulation. An inadequate block was defined as either intolerance to preoperative manipulation of the shoulder by the surgeon or failure to demonstrate hypesthesia to pinprick over the C5 and C6 dermatomes as assessed by the blinded anesthesiologist. Sedation with intravenous propofol was then established. Patients with failed blocks and those who were considered intolerant to the positioning (sitting with the head in a restraint device) were provided general anesthesia according to standard practice with propofol for induction, a laryngeal mask airway (LMA) and sevoflurane for anesthetic maintenance. Supplemental postoperative analgesia was provided per patient request in the PACU using intravenous fentanyl (in 25 mcg increments) and intravenous ketorolac (30 mg, one time dose), with oral hydrocodone/acetaminophen (5/500 mg orally every 4 hours as needed) as second-line therapy prior to discharge. A disposable infusion device (Pain Pump II, Stryker, Kalamazoo, MI, USA) was used for continuous infusion with the following settings: ropivacaine 0.2%; bolus: 3 mL; continuous infusion: 4 mL/h; lock-out: 20 minutes. A single dose of dexamethasone was allowed for postoperative nausea and vomiting (PONV) or PONV prophylaxis.
Ultrasound-guided placement (high frequency probe; 10-12 Hz) of an ISB and catheter was performed at the ipsilateral upper truck or C5 root, usually near a point midway between lines extending laterally from the cephalad border of the thyroid cartilage and from the cricoid cartilage, between the anterior and middle scalene muscles. Following penetration of the fascial sheath, observation of spread of 1 mL normal saline circumferentially surrounding the most cephalad nerve of the plexus confirmed correct placement in an out-of-plane view. The initial block was placed though the needle (18G Contiplex®, B. Braun Medical Inc., Bethlehem, PA, USA) prior to insertion of a non-stimulating 20 gauge nylon catheter. The interscalene catheters were advanced exactly 2 cm in all cases. The catheter used has a closed end with 3 orifices located 5, 10 and 15 mm from the tip. A standardized continuous infusion was started immediately after catheter placement.
After discharge home directly from the PACU, patients were contacted by telephone to collect outcome data at 24 hours, 48 hours, and 12 weeks postoperatively using a structured interview.
Categorical and Numeric Pain Rating Scales (NRS) were recorded at baseline (pre-operatively), at discharge from PACU, and at 24 and 48 hours. The primary efficacy outcome was the NRS pain score at discharge from PACU. Other pain assessments were secondary endpoints. A change in NRS of 1.8 was considered clinically significant [5
Diaphragmatic excursion at maximal effort for inspiration and exhalation was assessed by a blinded ultrasonographer bilaterally, both preoperatively and prior to discharge from PACU, using a low frequency probe (4 Hz) posterolaterally as described by Borgeat et al [6
]. A 50% reduction in ipsilateral diaphragmatic motion compared to baseline was considered clinically meaningful and represented the primary safety outcome measure. Because diaphragmatic excursion may decrease as a result of surgery, anesthesia, and opioid pain medications, the change in ipsilateral measurement was also compared to alterations in contralateral diaphragmatic motion.
Additional secondary outcome measures
At discharge from PACU, 24 and 48 hours patients were asked "Do you feel short of breath or are you having trouble catching your breath?" (yes/no)
At discharge from PACU, 24 and 48 hours patients were asked "Is your voice hoarse?" (yes/no)
Symptomatic horner's syndrome
At discharge from PACU, 24 and 48 hours patients were asked "Do you have blurred vision or a droopy eyelid?" If either of these effects were noted the patient was considered to have symptomatic Horner's Syndrome and a positive finding (yes/no) was recorded.
Perceived hand weakness
At discharge from PACU, 24 and 48 hours grip strength was assessed by asking the question, "Does your grip feel weak?" (yes/no)
A 24 and 48 hours the 5-point Likert categorical Helpfulness Scale was administered ("Is your interscalene infusion: extremely harmful; harmful; neutral: not harmful, but not helpful; helpful; extremely helpful?")
At baseline and again at 12 weeks subjects completed the Simple Shoulder Test. This test is a series of 12 (yes/no) questions. This has been shown to be a valid, reliable and consistent for subjects up to and including 60 years of age when similar injuries (rotator cuff dysfunction) are assessed [7
]. The use of this assessment collected by telephone interview [8
] has been validated and is comparable to more complicated scales when converted to a 100-point scale [9
Local anesthetic toxicity
At discharge from PACU, 24 and 48 hours the presence of any one of the following was considered a positive score: tinnitus, perioral numbness, feeling jittery (yes/no)
Unscheduled admission, total amount of local anesthetic used (read directly from the pump), type and amount of supplemental analgesics, nausea/vomiting, requirement for general anesthesia (defined as the use of a laryngeal mask airway and/or inhalational anesthesia, i.e. sevoflurane), early termination (catheter malfunction/dislodgement prior to 48 hours) were recorded.
Sample size for efficacy was determined by considering the equivalence of two means based on means and standard deviations from data previously collected as part of routine quality assurance monitoring and a minimum clinically significant difference for NRS pain at discharge from PACU of 1.8. Twelve subjects per group (N = 36) would yield 90% power at the 0.05 significance level. Power analysis for primary safety outcome (proportion of subjects with significant reductions in diaphragmatic excursion) using a 30% difference from expected outcome (5 mL vs. 20 mL) with 12 subjects in each group provided 90% power at the 0.01 significance level.
For each bolus group, most outcomes were measured repeatedly over time. Therefore, measurements obtained from a patient in each group over time were not independent. Continuous outcomes measured at only one time point were compared across the three bolus groups using either a one-way analysis of variance or a Kruskal-Wallis test depending on whether the response is normally or non-normally distributed respectively. Categorical outcomes were compared among the three bolus groups using either the Fisher's Exact or Chi-Square tests. Continuous outcomes measured at exactly two time-points were analyzed by first computing the paired differences (accounting for correlation in measurements between time points) within each bolus group and then analyzing the differences across the three bolus groups using a one-way analysis of variance or a Kruskal-Wallis test depending on whether the paired differences is normally or non-normally distributed respectively. Categorical outcomes were analyzed using the Cochran-Mantel-Haenszel statistics stratified by the bolus groups.
Continuous and categorical outcomes measured at more than two time-points were analyzed in the following manner: Normally and non-normally distributed outcomes measured were analyzed using generalized linear mixed models (GLMM), nonlinear mixed models (NLMM), general linear models (GLM), or nonlinear models (NLM) depending on whether the errors are correlated and/or the presence of random effects, and/or the presence of nonlinearity. To make the analysis more sensitive to individual variations, baseline outcome measurements were used as covariates in these analyses thereby altering all of these models to analyses of covariance (ANCOVA). All of the data were analyzed on an intent-to-treat principle using SAS JMP 8.0.
Additionally, all outcome measures were first analyzed using numerical and graphical techniques to determine their distributions. Based on this preliminary assessment, parametric, nonparametric, or exact statistical tests were used. Functional outcomes based on the Simple Shoulder Test were first scored according to the previously mentioned algorithm [9
]. Any subscales generated based on this algorithm were then be used in the analysis instead of the individual items.