Supplemental Digital Content
Table of contents
Supplement Table 1. Treatment effect within each assessment on primary outcome. – Page 2
Supplement Table 2. Treatments effect on the primary outcomes after replacing missing values – Page 3
Supplement Table 3. Opioid consumption – Page 4
Supplement Table 4. Treatment effect on the Ramsey score measured at 10-minute intervals during the first 60 minutes – Page 5
Supplement Table 5. Treatment effect on the time to emergence from anesthesia (minutes). – Page 6 Supplement Table 6. Monitor-recorded Nociception Level values. – Page 7
Supplement Table 7. Intraoperative MAC, BIS and AUC, TWA for hypotension. – Page 8 Supplemental Figure 1. Stopping boundaries. – Page 9
Supplement
Table 1. Treatment effect within each assessment on primary outcome.Outcome NOL
(N=34)^
routine opioid administration
(N=37)
Median difference [NOL minus Routine opioid administration]
(95%CI)
P value*§
Pain score in Recovery Period
Time point 1 0.0 [0.0, 5.0]
a0.0 [0.0, 4.0]
a0.0 (-1.0, 0.0) 0.490 Time point 2 1.0 [0.0, 5.5]
b5.0 [0.0, 7.0] -1.0 (-4.0, 0.0) 0.069 Time point 3 2.5 [0.0, 7.0]
b5.0 [2.0, 7.0] -1.0 (-3.0, 1.0) 0.218 Time point 4 5.0 [0.0, 6.0] 4.0 [2.0, 6.0] 0.0 (-2.0, 2.0) 0.930 Time point 5 4.5 [1.0, 7.0] 3.0 [2.0, 6.0]
c1.0 (-1.0, 3.0) 0.260 Time point 6 4.5 [2.0, 7.0]
c3.0 [1.0, 6.0] 1.0 (-1.0, 3.0) 0.188 Data reported as medians [Q1, Q3]
NOL: Nociception level
Group-by-time interaction P-value =0.054 from linear mixed effects model.
^ 1 patient is missing all Pain Score data so not included in this analysis
* Median difference (99.17 % CI) was estimated from the Hodges-Lehmann estimator of location shift
between groups and P values from Wilcoxon rank sum test.
§
Significant if P < 0.0083 using Bonferroni correction. (i.e., significance criterion = 0.05/6 = 0.0083)
a
3 missing data points,
b2 missing data points,
c1 missing data point
Supplement
Table 2. Treatments effect on the primary outcomes after replacing missing values
Outcome N
NOL
Mean (SE)
routine opioid administration
Mean (SE)
Difference in Means [
NOL minus Routine opioid administration
](95% CI) §*
Treatmen t effect P-value
Recovery Period (10-60 minutes) Primary Outcome:
Mean Pain Score
Main analysis^ (from Table 2)
a 34/37 4.12 (0.59) 4.04 (0.58) 0.08 (-1.43, 1.58) 0.895
Method 1: ignoring NOL
patient with all data missing £ b 34/37 4.15 (0.60) 4.02 (0.60) 0.13 (-1.41, 1.67) 0.825 Method 2: median score at
each time point in assigned group£
35/37 4.14 (0.60) 4.02 (0.59) 0.11 (-1.41, 1.64) 0.843
Method 3: possible best score£ 35/37 4.07 (0.61) 4.04 (0.60) 0.03 (-1.50, 1.57) 0.955 Method 4: possible worst
score £ 35/37 4.29 (0.62) 3.97 (0.62) 0.33 (-1.26, 1.91) 0.588
NOL: Nociception level
§ Difference in Means (99% CI) was estimated from a linear mixed model with an AR (1) correlation structure adjusting for preoperative opioid use. Pain score was measured at 10-minute intervals from awakening until 60 minutes had elapsed, for a total of 6 measurements. Treatment x time interaction p-values of the five listed methods are 0.054, 0.065, 0.060, 0.062, and 0.063, respectively.
* The confidence interval for the primary outcome is adjusted for the repeated testing in the group sequential design, so that the utilized critical z-statistic is 2.58 instead of 1.96. Correspondingly, the significance criterion for the primary outcome is P < 0.0099.
^ Main analysis: as in Table 2 -- no imputation of missing data, ignoring 1 patient with all missing data.
£ Methods 1-4: Replacing missing value with the mean of two adjacent scores; and if the missing score was at the beginning or the end of the first 60 minutes, using the adjacent measure as the value.
Method 1: ignoring 1 patient with all missing data; Method 2: assign median for the assigned group at each time point to the patient with all missing data; Method 3: assign best possible score at all time points to the patient with all missing data; Method 4: assign worst possible score at all time points to the patient with all missing data.
a In NOL group 1 patient missed all time points (intubated), 2 patients had 3 missing values, and 3 patients had 1 missing value; in Routine opioid administration group 4 patients had 1 missing time point.
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Supplement Table 3. Opioid consumption
Outcome NOL
(N=35)
routine opioid administration
(N=37)
Median difference*
[NOL minus Routine opioid administration]
(95%CI)
P value
Intraoperative
Fentanyl (mg) 0.50 [0.33, 0.78] 0.30 [0.20, 0.33] 0.2 (0.1, 0.4) < 0.001 Hydromorphone (mg) 0.60 [0.40, 0.60] 0.60 [0.40, 0.60] 0.0 (0.0, 0.0) 0.236 Fentanyl consumption rate
(mcg/hour) 124 [72, 169] 63 [43, 75] 66 (40, 91) < 0.001
Recovery Period (10-60 minutes) ^
Total morphine equivalents (mg) 3.3 [0.0, 7.7] 7.7 [0.0, 12.7] -2.0 (-6.7, 0.0) 0.070
Total boluses 1 [0, 2] 2 [0, 3] 0.54 (0.30, 0.97) § 0.039
Intraoperative + Recovery Period
Total morphine equivalents (mg) 56 [40, 84] 39 [28, 50] 20 (10, 31) < 0.001 Data reported as medians [Q1, Q3]
NOL: Nociception level
* Median difference was estimated from the Hodges-Lehmann estimator of location shift between groups and P values from Wilcoxon rank sum test. Significant if P < 0.05.
^ Combining anesthesiologist and nurse records
§ Incidence rate ratio [akin to ratio of means] (95% CI) and P values were estimated from negative binomial regression model adjusting for preoperative opioid use.
Supplement Table 4. Treatment effect on the Ramsey score measured at 10-minute intervals during the first 60 minutes
Outcome NOL
a(N=35)
routine opioid administration
b
(N=37)
Odds ratio [NOL / Routine
opioid administration]
(95% CI)
P value* NI delta
NI P-value
§Ramsay Sedation Scale
0.80 (0.35, 1.82) 0.594 1.2 0.169
1 0 (0) 1 (0.5)
2 92 (45) 85 (38)
3 106 (52) 132 (60)
4 5 (2.5) 3 (1.4)
Total 203 221
Data reported as N (%)
NOL: Nociception levelRamsay Sedation Scale: 1 = Patient is anxious and agitated or restless, or both 2 = Patient is co-operative, oriented, and tranquil 3 = Patient responds to commands only 4 = Patient exhibits brisk response to light glabellar tap or loud auditory stimulus 5 = Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus 6 = Patient exhibits no response
* Odds ratio and P value was estimated from proportional odds model adjusting for time and preop opioid use, and using bootstrap resampling with replacement (1000 samples) for estimating the confidence interval [the standard deviation method]
§ Noninferiority P-value obtained from a 1-tailed t-test using a test statistic defined as T¿=
^β1−δ SEβ1 , where ^β1 is the estimated treatment effect, SEβ
1 is the standard error of the treatment effect from primary analyses, and δ is the noninferiority delta (i.e., 1 point Ramsay score); Significant if P
< 0.025.
a
7 missing data points, including 1 whole patient missing;
b1 missing data point
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Supplement Table 5. Treatment effect on the time to emergence from anesthesia (minutes).
Outcome NOL
(N=35)
routine opioid administratio
n (N=37)
Hazard Ratio
^[NOL / Routine opioid administration
] (95%CI)
P value *
Time to Emergence from anesthesia (min) £
Median Emergence Time (min) (95%CI) 18 [16, 22] 20 [18, 22]
Cox proportional hazards regression ^ 1.01 (0.63, 1.63) 0.967
Log-rank test 0.996
Wilcoxon test 0.500
NOL: Nociception level
^ Hazard Ratio (95% CI) was estimated from Cox proportional hazards regression model adjusting for preoperative opioid use.
£ Time to Emergence from anesthesia was defined as the period from that last MAC fraction of ≥0.3 toward when the patient left the operating room.
* Significant if P < 0.05.
Supplement Table 6. Monitor recorded Nociception Level values
Outcome NOL
(N=35)
routine opioid administration
(N=37)
Median difference [NOL minus Routine opioid administration]
(95%CI)
P value*
TWA of NOL 13.4 [11.5, 15.8] 15.9 [12.2, 18.5] -1.9 (-3.8, 0.0) 0.052 Percent of recorded
measurements NOL >25 (%) 16 [12, 22] 21 [14, 27] -4.5 (-8.9, -0.6) 0.022 Minutes of NOL >25 37 [24, 53] 50 [39, 78] -13.7 (-24.8, -3.6) 0.009 Data reported as medians [Q1, Q3]
TWA = time-weighted average of NOL; NOL:
Nociception level
* Median difference was estimated from the Hodges-Lehmann estimator of location shift between groups and P values from Wilcoxon rank sum test. Significant if P < 0.05.
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Supplement Table 7. Intraoperative MAC, BIS and AUC, TWA for hypotension NOL
(N=35)
routine opioid administration
(N=37)
Difference in Means [NOL minus Routine opioid administration]
(95%CI)
P value^
Intraoperative
MAC§ 0.80 ± 0.13 0.83 ± 0.11 a -0.04 (-0.09, 0.02) 0.171
Median difference P value*
BIS 48 [44, 50] b 48 [41, 53]c 0.1 (-3.2, 3.7) 0.905
TWA MAP < 65 mmHg (mmHg) 0.14 [0.02, 0.26] 0.02 [0, 0.21] 0.0 (0.0, 0.1) 0.042 AUC MAP < 65 mmHg (mmHg x
min) 39 [8.0, 78] 7.0 [0.0, 51] 9.0 (0.0, 32) 0.059
TWA of MAP (mmHg) 83 [75, 87] 89 [81, 95] -5.4 (-10.3, 0.7) 0.072
Number of minutes MAP <65 mmHg 8.0 [2.0, 18] 2.0 [0.0, 10] 4.0 (0.0, 8.0) 0.022 Number of minutes MAP <60 mmHg 1.0 [0.0, 5.0 ] 0.0 [0.0, 2.0] 0.0 (0.0, 1.0) 0.311 Number of minutes MAP <55 mmHg 0.0 [0.0, 1.0] 0.0 [0.0, 1.0] 0.0 (0.0, 0.0) 0.731 Data reported as means ± SDs and medians [Q1, Q3]
NOL: Nociception level; MAC: minimum alveolar concentration; BIS: Bispectral index; AUC: area under MAP
< 65 mmHg; TWA = time-weighted average
* Median difference was estimated from the Hodges-Lehmann estimator of location shift between groups and P values from Wilcoxon rank sum test. Significant if P < 0.05.
§ Nitrous was ignored in MAC calculation as patients only use it in the first several minutes, and 104 Nitrous = 1 MAC.
a 1 missing data point, b 2 missing data points, c 3 missing data points.
Supplemental Figure 1. Stopping boundaries for efficacy (bottom blue)/ harm (top blue) and futility (pink) for the group sequential design. The observed z-statistic (difference in means / SE) effect size of 0.133 is within the futility region (0.667 to -0.667) for N=72 (second interim analysis).
We planned to conduct interim analyses for efficacy and futility at each 25% of the maximum planned sample size using a group sequential design with conservative gamma spending function parameters of -2 for efficacy and 0 (more aggressive) for futility. If the alternative hypothesis effect size (1.25 point difference in mean pain score) were true in the population sampled from, with the planned sample size we would cross an efficacy or futility boundary at each of the 4 looks with respective cumulative probabilities of 0.16, 0.50, 0.78 and 1.0. Z-statistic boundaries for efficacy (futility) were > 2.80 (≤ 0.156), > 2.58 (≤ 0.667), > 2.34 (≤ 1.42), and > 2.09 (≤ 2.09), respectively, for the 4 analyses.
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