Abstract
Background
Pulmonary complications related to residual neuromuscular blockade lead to morbidity and mortality. Using an interrupted time series design we tested if proportions of re-intubation for respiratory failure or new non-invasive ventilation were changed after a system-wide transition of the standard reversal agent from neostigmine to sugammadex.
Methods
Adult patients undergoing a procedure with general anesthesia that included pharmacologic reversal of neuromuscular blockade and admission≥1 night were eligible. Groups were determined by date of surgery: August 15th, 2015 to May 10th, 2016 (pre-sugammadex) and August 15th, 2016 to May 11th, 2017 (post-sugammadex). The period from May 11th, 2016 to August 14th, 2016 marked the institutional transition (wash-out / wash-in) from neostigmine to sugammadex. The primary outcome was defined as a composite of re-intubation for respiratory failure or new non-invasive ventilation. Event proportions were parsed into ten-day intervals in each cohort and trend lines were fitted. Segmented logistic regression models appropriate for an interrupted time series design and adjusting for potential confounders were utilized to evaluate the immediate effect of the implementation of sugammadex and on the difference between pre-intervention and post-intervention slopes of the outcomes. Models containing all parameters (full) and only significant parameters (parsimonious) were fitted and are reported.
Results
Of 13,031 screened patients, 7,316 patients were included. The composite respiratory outcome occurred in 6.1% of the pre-sugammadex group and 4.2% of the post-sugammadex group. Adjusted OR and 95% confidence intervals (CI) for the composite respiratory outcome were 0.795 (95% CI, 0.523–1.208) for the immediate effect of intervention and 0.986 (95% CI, 0.959–1.013) for the difference between pre-intervention and post-intervention slopes in the full model, and 0.667 (95% CI, 0.536–0.830) for the immediate effect of the intervention in the parsimonious model.
Conclusion
The system-wide transition of the standard pharmacologic reversal agent from neostigmine to sugammadex was associated with a reduction in the odds of the composite respiratory outcome. This observation is supported by non-significant within-group time trends and a significant reduction in intercept/level from pre- to post-sugammadex in a parsimonious logistic regression model adjusting for covariates.
Introduction
Postoperative pulmonary complications (PPCs) are associated with increased perioperative mortality.1 Residual neuromuscular blockade (NMB) from pharmacologic muscle relaxation results in decreased functional residual capacity, laryngeal and pharyngeal dysfunction. This is clinically associated with hypoventilation, airway collapse, and impaired airway protection which all contribute to PPCs.2–5 Optimal reversal pharmacologic muscle relaxation is therefore critical to avoid PPCs.6,7
For many years, cholinesterase inhibition has been the only reversal mechanism for non-depolarizing muscle relaxants with neostigmine being the preferred agent. Neostigmine reverses the effects of non-depolarizing muscle relaxants by increasing the concentration of acetylcholine at the synaptic cleft and displacing the non-depolarizing muscle relaxants from nicotinic acetylcholine-receptors.8 Significant muscarinic side effects such as bradycardia, double vision, and postoperative nausea and vomiting are common. Vagolytic drugs such as glycopyrrolate or atropine are used to counteract the muscarinic side effects but have their own spectrum of side effects including tachycardia and xerostomia.9–11 Further, the peak effect of neostigmine occurs approximately 10 minutes after injection with a duration of action of about 20–30 minutes.8 These pharmacodynamic properties can lead to residual paralysis in the postoperative period.
Sugammadex has been recently introduced into clinical practice in the United States. It irreversibly binds to and encapsulates the muscle relaxants rocuronium and vecuronium.12 Given its mechanism of action, muscarinic side effects are rare.9,11,13 Current literature consistently reports that sugammadex has a plasma elimination half-life of 2.2 hours and reverses the effects of rocuronium in less than 2.2 minutes independent of the depth of NMB.8,14–17 Complete reversal, defined as a train of four ratio>0.9, occurs at least 2.5-times faster than any neostigmine initiated reversal.18,19 Consequently, sugammadex led to a significant reduction in signs of postoperative residual paralysis compared to neostigmine (relative risk of 0.40 [95% CI, 0.28–0.57]).11 Despite the faster reversal of NMB and fewer signs of residual paralysis with sugammadex compared to neostigmine, a decrease in the incidence of severe PPC, defined as newly initiated non-invasive ventilation (NIV) or re-intubation for respiratory failure has not yet been demonstrated.11,20,21
In 2016, our tertiary academic medical center changed the standard NMB reversal agent from neostigmine to sugammadex. Using an interrupted time series study design, we examined the effects of such a system-wide change on the incidence of severe PPCs after procedures requiring general anesthesia. We hypothesized that the transition from neostigmine to sugammadex would be associated with an immediate and persistent reduction in the odds of composite adverse outcome (re-intubation for respiratory failure or initiation of new NIV).
Methods
Study Design
The Colorado Multiple Institutional Review Board approved this study and waived the requirement for informed consent. The manuscript was written according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.22 An interrupted time series (ITS) design was chosen and groups were determined according to the date of surgery: August 15th, 2015 to May 10th, 2016 (pre-sugammadex) and August 15th, 2016 to May 11th, 2017 (post-sugammadex). The period from May 11th, 2016 to August 14th, 2016 marked the institutional transition (wash-out / wash-in) from neostigmine to sugammadex.
Sample
Adult patients undergoing a procedure with general anesthesia at the University of Colorado Anschutz Medical Center that included administration of neostigmine or sugammadex and hospital admission≥1 night were eligible. Exclusion criteria included: patients not receiving any reversal agent or receiving both reversal agents; patients not receiving rocuronium or vecuronium; patients with missing American Society of Anesthesiologists (ASA) status, ASA status 5 (patients not expected to survive the procedure), or ASA 6 (declared brain-dead organ donors); and patients with more than one procedure requiring neostigmine or sugammadex during the time period (Figure 1).
Figure 1: Study flow diagram.
ASA: American Society of Anesthesiology physical status: 1, normal healthy patient; 2, patient with mild systemic disease; 3, patient with severe systemic disease; 4 patient with severe systemic disease that is a constant threat to life; 5, moribund patient who is not expected to survive without the operation; 6, cadaveric organ donor.
Data Extraction and Outcomes
The following data were collected immediately before surgery: Age, weight, gender, race, ethnicity, ASA physical status, and formal diagnosis of obstructive sleep apnea (OSA) or sleep apnea documented in the standardized anesthesia preoperative assessment. Intraoperative data included amounts of opioids administered normalized as oral morphine equivalents, surgical subspecialty, epidural anesthesia, duration of surgery, final train of four counts or sustained tetanus, and administration of rocuronium, vecuronium, neostigmine, and sugammadex as well as the dose of neostigmine and sugammadex.
The primary outcome was a composite of either re-intubation for respiratory failure or the need for new NIV. Secondary outcomes included postoperative intensive care unit (ICU) admission, postoperative hypoxic events, and in-hospital mortality. ICU admission was defined as postoperative admission to the ICU at any time during hospitalization. Hypoxia was defined as any duration of verified SpO2<90% in the medical record following transfer out of the post-anesthesia care unit (PACU) during hospitalization.
To screen patients who were likely to have been re-intubated after the procedure, the electronic medical record (EMR) was first searched for patients who had an order for mechanical ventilation placed after leaving the operating room or an intubation order placed following an order to extubate. Individual chart review of all patients identified in this fashion was performed to confirm that patients had in fact been extubated in the operating room and re-intubation had occurred for respiratory failure post-operatively. NIV was identified as recorded by nursing staff or respiratory therapists in the PACU, floor, or ICU EMR flow sheets. In our hospital NIV is administered using the following modes: Continuous Positive Airway Pressure, Bi-level Positive Airway Pressure, Average Volume-Assured Pressure Support, or Pressure Control Ventilation. Only patients not identified on a standardized pre-operative pulmonary comorbidity questionnaire as using NIV pre-operatively (e.g., for OSA) were classified with the outcome new NIV.
Statistical Analysis
Statistical Analyses were conducted using SAS software version 9.4 software (SAS Institute, Cary, North Carolina). Event proportions were parsed into 27 ten-day intervals in each cohort and trend lines were fitted using graphical software for visual comparison. Kolmogorov-Smirnov tests were conducted within groups for all continuous variables, and median values and interquartile ranges were reported for distributions that departed appreciably from normality. Variables were compared pre- and post-sugammadex with Chi-Square and Mann-Whitney U tests as appropriate.
Proportions of each primary and secondary outcomes were plotted over time, together with lines fit to the observed data and predicted lines from logistic regressions incorporating significant group, time, and the group by time interaction effects (but no potential confounders) to visually inform the modeling process. Segmented logistic regression models appropriate for an ITS design were then utilized to evaluate the impact of the implementation of sugammadex.23,24 All models included the same set of 11 pre-specified individual-level demographic and clinical variables to control for potential confounding: age, gender, ASA physical status, weight, duration of surgery, intraoperative oral morphine equivalents, race, ethnicity, OSA, surgical subspecialty, and epidural anesthesia. “Success” of the intervention was defined as a reduction in the mean (proportion) of the composite respiratory outcome, in a model with no evidence of non-zero slope in either period.
The following parameters were estimated from the segmented logistic regression corresponding to the ITS design (these parameter estimates can be exponentiated to provide estimates of the corresponding odds ratios (OR)):
β0: logit of outcome at time 0 for the pre-intervention period (intercept).
β1: pre-intervention slope of outcome, i.e. the time effect before sugammadex introduction.
β2: log-OR of outcome at the beginning of the intervention period compared to end of the pre-intervention period, i.e. the immediate effect of sugammadex.
β3: difference between pre-intervention and post-intervention slopes, i.e. change in slope of outcome over time after introducing sugammadex.
Two regression models are presented: a “full” and a “parsimonious” model. Per Mascha et al., we fit a full model that included all of the β estimates above, regardless of their statistical significance.25 Our a-priori statistical analysis plan included a parsimonious model for which all parameters were initially estimated, and then non-significant β values were sequentially removed.24 An alpha level of 0.05 for two-sided tests was utilized to identify increases or decreases in outcomes post-sugammadex transition.
Prior to the study, a simple power analysis evaluating power for comparing unadjusted proportions pre and post introduction of sugammadex was conducted instead of a power analysis that captured the more complex interrupted time series design. The baseline incidence of the primary composite outcome was estimated at 5.5%.26 Based on previously reported reduction in the risk for signs of postoperative residual paralysis, we conservatively estimated the incidence of the primary respiratory outcome after the introduction of sugammadex at 3.85%.11 Following preliminary data extraction for the two time periods, we estimated that a sample size of 7,000 patients would yield 90% power with a two-sided alpha of 0.05 (G*Power 3.1.9.2).27
Results
Of 13,031 screened patients undergoing surgery during the specified time intervals, 7,316 patients were included with 3,420 patients in the pre-sugammadex group and 3,896 patients in the post-sugammadex group. Baseline characteristics and perioperative variables are summarized in Table 1. Sugammadex (p<0.001) and rocuronium use (p=0.003), sugammadex dosing (p<0.001), and ASA physical status (p=0.013) was higher in the post-sugammadex group. Intraoperative oral morphine equivalents (p<0.001), supplementary epidural anesthesia (p=0.001), neostigmine (p<0.001) and vecuronium use (p<0.001), and neostigmine dosing (p<0.001) were higher in the pre-sugammadex group. Distributions for race (p<0.001) and surgical subspecialty (p<0.001) were statistically different between the pre- and post-sugammadex groups. There were no other significant differences in baseline characteristics and perioperative variables.
Table 1.
Patient and demographic characteristics.
| Characteristic | Pre-sugammadex group (N=3,420) | Post-sugammadex group (N=3,896) | p-value |
|---|---|---|---|
| Demographic characteristics | |||
| Age – years | 0.119 | ||
| Median (q1, q3) | 56 (43, 67) | 57 (43, 68) | |
| Weight – kg | 0.159 | ||
| Median (q1, q3) | 77.8 (65.8, 93.3) | 78.5 (65.8, 94.8) | |
| Women – no. (%) | 1,905 (55.7) | 2,197 (56.4) | 0.555 |
| Race – no. (%) | <0.001 | ||
| White or Caucasian | 2,373 (69.4) | 2,446 (62.8) | |
| Black or AA | 239 (7.0) | 284 (7.3) | |
| Asian | 55 (1.6) | 84 (2.2) | |
| AI, AN, NH, OPI | 21 (0.6) | 35 (0.9) | |
| Other or more than one | 352 (10.3) | 363 (9.3) | |
| Not provided | 380 (11.1) | 684 (17.6) | |
| Hispanic ethnicity– no. (%) | 446 (13.0) | 481 (12.3) | 0.379 |
| ASA physical status | 0.013 | ||
| Median (q1, q3) | 3 (2, 3) | 3 (2, 3) | |
| OSA – no. (%) | 733 (21.4) | 844 (22.7) | 0.204 |
| Perioperative characteristics | |||
| Intraoperative OME (mg) | <0.001 | ||
| Median (q1, q3) | 76.0 (55.0, 105.0) | 75.0 (52.6, 103.0) | |
| Duration of surgery – minutes | 0.899 | ||
| Median (q1, q3) | 199 (146, 274) | 199 (145, 279) | |
| Surgical subspecialty – no. (%) | <0.001 | ||
| General Surgery | 999 (29.2) | 1,001 (25.7) | |
| Neurosurgery | 449 (13.1) | 511 (13.1) | |
| Orthopedic Surgery | 510 (14.9) | 634 (16.3) | |
| Cardiothoracic Surgery | 331 (9.7) | 325 (8.3) | |
| Urology | 294 (8.6) | 329 (8.4) | |
| IR/GI/Cardiology/others | 179 (5.2) | 298 (7.6) | |
| ENT/ophthalmology/OMF/Plastic/Dental | 186 (5.4) | 234 (6.0) | |
| Vascular/Transplant surgery | 177 (5.2) | 231 (5.9) | |
| Obstetrics/Gynecology | 295 (8.6) | 333 (8.5) | |
| Epidural – no. (%) | 433 (12.7) | 400 (10.3) | 0.001 |
| Rocuronium – no. (%) | 3,393 (99.2) | 3,885 (99.7) | 0.003 |
| Vecuronium – no. (%) | 145 (4.2) | 83 (2.1) | <0.001 |
| Sugammadex – no. (%) | 1 (0) | 3,873 (99.4) | <0.001 |
| Sugammadex – dosing (mg) | <0.001 | ||
| Median (q1, q3) | - | 100 (75, 160) | |
| Neostigmine – no. (%) | 3,419 (100.0) | 23 (0.6) | <0.001 |
| Neostigmine – dosing (mg) | <0.001 | ||
| Median (q1, q3) | 3.0 (2.0, 3.5) | 3.0 (2.0, 4.0) | |
| Final TOF count/ST – no. (%) | 0.225 | ||
| 0/4 | 19 (0.6) | 56 (1.4) | |
| 1/4 | 48 (1.4) | 105 (2.7) | |
| 2/4 | 51 (1.5) | 95 (2.4) | |
| 3/4 | 50 (1.5) | 75 (1.9) | |
| 4/4 | 850 (24.9) | 1,194 (30.6) | |
| Sustained tetanus | 2,133 (62.4) | 2,241 (57.5) | |
| No peripheral nerve stimulation recorded | 269 (7.9) | 130 (3.3) |
The Kolmogorov-Smirnov test was significant (p<0.001) within groups of all continuous variables; Mann-Whitney U tests was used. q1: first quartile, q3: third quartile, AA: African American, AI: American Indian, AN: Alaska Native, NH: Native Hawaiian. OPI: other Pacific Islander, ASA: American Society of Anesthesiology physical status (ranks from 1–6, a status of 1 presents a healthy person, 4 presents a person with severe systemic disease which is a constant threat to life), OSA: obstructive sleep apnea (formal diagnosis or sleep apnea documented in standardized anesthesia preoperative assessment), OME: oral morphine equivalents, GI: gastroenterology, IR: Interventional Radiology, ENT: Ear, Nose and Throat Surgery, OMF: Oral and Maxillofacial Surgery, TOF: train of four count. ST: sustained tetanus. The p-value for the TOF count/ST signifies Chi-square test results for 4/4 or ST versus 1/4, 2/4, 3/4, or not recorded.
Calculation of unadjusted proportions indicated that the primary outcome of re-intubation for new respiratory failure or NIV occurred in 6.1% of the pre-sugammadex group and 4.2% of the post-sugammadex group (Table 2, left panel). This difference was driven by more NIV in the pre-sugammadex (5.9%) compared to post-sugammadex groups (3.9%).
Table 2.
Primary and secondary outcomes by group: Unadjusted Rates and Model-Based Estimates from Full (F) and Parsimonious (P) Models
| Outcome | Unadjusted Rates | Model | Estimates from Model Adjusted for 11 Patient Characteristics | ||||
|---|---|---|---|---|---|---|---|
| Pre-sugammadex Group | Post-sugammadex Group | Parameters | Odds Ratio Exp (β) | 95% Confidence Limits | p-value | ||
| Re-intubation for RF or new NIV – no. (%) | 209 (6.1) | 164 (4.2) | F | β0 | <0.001 | ≤0.001 | <0.001 |
| β1 | 1.001 | 0.982–1.019 | 0.939 | ||||
| β2 | 0.795 | 0.523–1.208 | 0.893 | ||||
| β3 | 0.986 | 0.959–1.013 | 0.312 | ||||
| P | β0 | <0.001 | ≤0.001 | <0.001 | |||
| β2 | 0.667 | 0.536–0.830 | <0.001 | ||||
| ICU admission – no. (%) | 1,071 (31.3) | 1,163 (29.9) | F | β0 | 0.003 | 0.002–0.005 | <0.001 |
| β1 | 1.002 | 0.991–1.014 | 0.683 | ||||
| β2 | 0.894 | 0.702–1.139 | 0.365 | ||||
| β3 | 0.998 | 0.982–1.014 | 0.067 | ||||
| P | β0 | 0.003 | 0.002–0.006 | <0.001 | |||
| β2 | 0.925 | 0.818–1.047 | 0.220 | ||||
| SpO2<90% – no. (%) | 2,014 (58.9) | 2,176 (55.9) | F | β0 | 0.032 | 0.021–0.048 | <0.001 |
| β1 | 1.011 | 1.001–1.020 | 0.032 | ||||
| β2 | 0.717 | 0.584–0.880 | 0.002 | ||||
| β3 | 0.995 | 0.982–1.009 | 0.501 | ||||
| P | β0 | 0.033 | 0.022–0.049 | <0.001 | |||
| β1 | 1.008 | 1.002–1.015 | 0.015 | ||||
| β2 | 0.718 | 0.585–0.882 | 0.002 | ||||
| In-hospital mortality – no. (%) | 28 (0.82) | 18 (0.46) | F | β0 | <0.001 | ≤0.001 | <0.001 |
| β1 | 1.018 | 0.969–1.071 | 0.478 | ||||
| β2 | 0.759 | 0.245–2.350 | 0.633 | ||||
| β3 | 0.946 | 0.875–1.023 | 0.162 | ||||
| P | β0 | <0.001 | ≤0.001 | <0.001 | |||
| β2 | 0.568 | 0.307–1.050 | 0.071 | ||||
F: full model including all parameter estimates (β0, β1, β2, β3); P: parsimonious model including only significant parameter estimates; β0: logit of outcome at time 0 for pre-intervention (intercept); β1: pre-intervention slope is change in odds of outcome (i.e. odds ratio) per 10-day interval; β2: change in odds of outcome at the start of post-intervention compared to end of pre-intervention (change in intercept, immediate effect); β3: difference between periods in slopes of outcome over time (post-intervention – pre-intervention). RF: respiratory failure, new NIV: initiation of non-invasive ventilation in patients without a history of non-invasive ventilation at home, ICU: Intensive Care Unit, SpO2: Peripheral blood oxygen saturation by pulse oximetry.
Figure 2 illustrates the observed proportions of the composite respiratory outcome and the secondary outcome hypoxic events prior to and after the institutional transition from neostigmine to sugammadex. Predicted lines fit from full (dashed line) and parsimonious (solid line) logistic regression models incorporating significant group, time, and the group by time interaction effects (but no potential confounders) are depicted.
Figure 2: Outcomes.
Observed proportions prior to and after the institutional transition from neostigmine to sugammadex, together with predicted lines fit from full and parsimonious logistic regression models for four outcome variables: A) composite respiratory outcome (re-intubation for respiratory failure or newly initiated non-invasive ventilation), B) hypoxic events defined as SpO2<90% following transfer out of the post-anesthesia care unit at any time during hospitalization, The red dotted line indicates the three month institutional transition period (wash-out / wash-in) from neostigmine to sugammadex. The Y-axis shows the proportions corresponding to values on a logit scale.
Table 2, right panel contains adjusted OR, 95% Confidence Limits, and p-values from the full and selected parsimonious models for each primary and secondary outcome, incorporating 11 covariates. Neither for β2, the immediate effect of the introduction of sugammadex on the composite respiratory outcome (p=0.893, OR=0.795 [95% CI, 0.523–1.208]), nor for β3, the change in slope of the composite respiratory outcome over time after introducing sugammadex (p=0.312, OR=0.986 [95% CI, 0.959–1.013]), was statistical significance detected in the full model. Although non-significant, the slope in the intervention period is trending negative, numerically (β3) and visually (Figure 2A).
The estimate of β2 was significant in the parsimonious model (p<0.001, OR=0.667 [95% CI, 0.536–0.830]) after the non-significant estimates (β1, β3) were removed. The slope in the intervention period, β1, was not found to differ from zero (p=0.939, OR=1.001 [95% CI, 0.982–1.019]).
For the composite respiratory outcome, we also report estimates for the covariates from the full and selected parsimonious models in Table 3. Six covariates were similarly significantly related to the composite respiratory outcome in both models: ASA physical status (p<0.001), weight (p=0.002), age (p=0.005), men versus women (p=0.023), duration of surgery (p<0.001), and cardiothoracic surgery (p<0.001).
Table 3.
Multiple logistic regression of primary outcome by group adjusting for other characteristics.
| Characteristic | Model | Odds ratio | 95% Confidence Limits | p-value |
|---|---|---|---|---|
| β0 | F | <0.001 | ≤0.001 | <0.001 |
| P | <0.001 | ≤0.001 | <0.001 | |
| β1 | F | 1.001 | 0.982–1.019 | 0.939 |
| P | n/a | n/a | n/a | |
| β2 | F | 0.795 | 0.523–1.208 | 0.283 |
| P | 0.667 | 0.536–0.830 | <0.001 | |
| β3 | F | 0.986 | 0.959–1.013 | 0.3119 |
| P | n/a | n/a | n/a | |
| Age | F | 1.011 | 1.003–1.019 | 0.005 |
| P | 1.011 | 1.003–1.019 | 0.005 | |
| Weight | F | 1.008 | 1.003–1.013 | 0.002 |
| P | 1.008 | 1.003–1.013 | 0.002 | |
| Men vs Women | F | 1.309 | 1.039–1.650 | 0.023 |
| P | 1.309 | 1.039–1.650 | 0.023 | |
| ASA physical status | F | 2.731 | 2.225–3.315 | <0.001 |
| P | 2.726 | 2.246–3.309 | <0.001 | |
| Hispanic | F | 1.069 | 0.668–1.679 | 0.808 |
| P | 1.066 | 0.672–1.691 | 0.786 | |
| OSA | F | 1.090 | 0.842–1.412 | 0.512 |
| P | 1.094 | 0.845–1.417 | 0.494 | |
| Intraoperative Oral Morphine Equivalents | F | 0.997 | 0.995–1.000 | 0.051 |
| P | 0.997 | 0.995–1.000 | 0.051 | |
| Race* | ||||
| Not provided | F | 0.826 | 0.583–1.170 | 0.282 |
| P | 0.826 | 0.583–1.169 | 0.280 | |
| Other or more than one race | F | 1.312 | 0.785–2.194 | 0.301 |
| P | 1.304 | 0.780–2.181 | 0.311 | |
| Black or AA | F | 1.082 | 0.518–2.262 | 0.833 |
| P | 1.099 | 0.526–2.294 | 0.802 | |
| Asian, AI, AN, NH, OPI | F | 1.383 | 0.934–2.049 | 0.106 |
| P | 1.386 | 0.936–2.053 | 0.103 | |
| Duration of surgery – minutes | F | 1.002 | 1.001–1.003 | <0.001 |
| P | 1.002 | 1.001–1.003 | <0.001 | |
| Surgical subspecialty^ | ||||
| Cardiothoracic Surgery | F | 3.274 | 1.700–6.306 | <0.001 |
| P | 3.288 | 1.708–6.330 | <0.001 | |
| Orthopedic Surgery | F | 1.486 | 0.762–2.900 | 0.245 |
| P | 1.495 | 0.766–2.917 | 0.238 | |
| General Surgery | F | 1.510 | 0.803–2.837 | 0.201 |
| P | 1.518 | 0.808–2.852 | 0.194 | |
| Interventional Radiology, GI, Cardiology, others | F | 1.767 | 0.875–3.568 | 0.113 |
| P | 1.771 | 0.877–3.575 | 0.111 | |
| Vascular surgery, Transplant Surgery | F | 1.607 | 0.765–3.376 | 0.210 |
| P | 1.602 | 0.763–3.364 | 0.213 | |
| ENT, ophthalmology, Plastic, OMF, Dental | F | 2.049 | 0.980–4.281 | 0.057 |
| P | 2.061 | 0.987–4.305 | 0.054 | |
| Urology | F | 1.210 | 0.581–2.517 | 0.611 |
| P | 1.212 | 0.583–2.522 | 0.607 | |
| Neurosurgery | F | 1.337 | 0.676–2.641 | 0.404 |
| P | 1.342 | 0.680–2.652 | 0.396 | |
| Epidural | F | 1.079 | 0.766–1.520 | 0.664 |
| P | 1.079 | 0.776–1.519 | 0.664 | |
AA: African American, AI: American Indian, AN: Alaska Native, NH: Native Hawaiian. OPI: other Pacific Islander, ASA: American Society of Anesthesiology physical status (ranks from 1–6, a status of 1 presents a healthy person, 4 presents a person with severe systemic disease which is a constant threat to life), OSA: obstructive sleep apnea (formal diagnosis or sleep apnea documented in standardized anesthesia preoperative assessment), OME: oral morphine equivalents, OB/Gyn: obstetrics/gynecology, GI: gastroenterology, IR: Interventional Radiology, ENT: Ear, Nose and Throat Surgery, OMF: Oral and Maxillofacial Surgery.
Race was compared to White or Caucasian.
Surgical subspecialties were compared to OB/Gyn, F: full model, P: parsimonious model.
Results from full and parsimonious regression models for secondary outcomes pre- and post-sugammadex introduction are summarized in Table 2. The odds of ICU admission did not differ significantly between groups, regardless of whether the full or parsimonious model was used. The odds of a hypoxic event were less common post-sugammadex compared to before in the full model (β2: p=0.002, OR=0.717 [95% CI, 0.584–0.880]) and the parsimonious model (β2: p=0.002, OR=0.718 [95% CI, 0.585–0.882], Figure 2B). The odds for in-hospital mortality were not significantly lower in the post-sugammadex group in the full or the parsimonious model. Overall low mortality rates led to possible conversion issues. However, simplified models without the previously included 11 confounders produced results similar to those reported in Table 2.
Discussion
Unadjusted results revealed a 31%-reduction in the incidence of composite respiratory outcome with a 34%-reduction in newly initiated NIV in patients undergoing general anesthesia after a system-wide change to sugammadex from neostigmine. The reduction in intercept/level from pre- to post-sugammadex was not significant in a full logistic regression model that includes all parameter estimates, regardless of statistical significance. However, our observation is supported by non-significant within-group time trends and a significant reduction in intercept/level from pre- to post-sugammadex in a parsimonious logistic regression model adjusting for covariates. In addition, regardless of the full or parsimonious modeling approach, reversal with sugammadex was associated with an immediate reduction in the odds for hypoxic events.
While previously published literature has reported a decrease in signs of residual or recurrent muscle paralysis, it did not demonstrate a reduction in re-intubation or NIV: A meta-analysis from 2015 showed no difference in critical respiratory events, which included among others hypoxemic events defined as SpO2<90% despite oxygen therapy, re-intubation or NIV (relative risk of 0.13 [95% CI, 0.02–1.06], p=0.06).20 A 2016 meta-analysis reported a significant difference in respiratory adverse events (OR 0.36 [95% CI, 0.14–0.95], p=0.04) but did not separate between mild or severe PPCs.21 These findings were mostly driven by one prospective study which found a decreased proportion of hypoxia.28 In 2017, a Cochrane-analysis found no significant differences in overall serious adverse events including respiratory depression and respiratory failure (relative risk of 0.54 [95% CI, 0.13–2.25], p=0.71).11 Notably, the largest study reporting on composite serious adverse events incorporated in the Cochrane analysis included 154 patients.11,29 In our study, only 4.9% of all patients required newly initiated NIV, even fewer patients required re-intubation for respiratory failure (0.8%). Hence, other studies comparing neostigmine with sugammadex were likely insufficiently powered to detect a significant difference in the incidence of PPCs.
Our study included 7,316 patients and, to our knowledge, is the first of its size to evaluate the associations between NIV or re-intubation and a system-wide change from neostigmine to sugammadex. The switch after the wash-out wash-in period was near-complete: Only one patient in the pre-sugammadex cohort received sugammadex and only 23 patients in the post-sugammadex group (0.6%) received neostigmine. A systematic transition to sugammadex is therefore feasible and could likely be reproduced elsewhere. The decreased odds of the composite respiratory outcome identified by the parsimonious model can likely be explained by the faster onset and longer lasting reversal of NMB with sugammadex compared to neostigmine.8 A decreased rate of residual or recurrent paralysis in the PACU is associated with improved airway protection and could have translated into a lower incidence of PPCs.2,3,30 Considering the long-term consequences of PPCs including 46,200 related deaths and 4.8 million additional hospitalization days in the United States alone, our results are highly relevant for patient safety and public health.31
Although the odds for the secondary outcome post-operative hypoxic events were lower post-sugammadex, the odds for ICU admission were non-significantly different and, no significant change in the in-hospital mortality odds was detected. The reduction of the primary outcome was driven by a decline in the necessity for NIV, not re-intubation for respiratory failure. Given the incidence of 0.8% for re-intubation, our study was not powered to detect a difference for such an infrequent outcome. Patient and procedural characteristics, which were associated with increased likelihood of the composite respiratory outcome in our study included increasing ASA physical status, weight, age, duration of surgery and cardiothoracic surgery. Indeed, these findings are consistent with previously published work.26,32–34 Other known predictors for re-intubation, which were tested in our study but did not show an association with the composite respiratory outcome, included vascular, abdominal, neurological, and transplant surgeries.34
Our study has several limitations: First, a before-after study is not designed as a randomized controlled trial and unaccounted confounding remains possible.35 Investigating relatively uncommon outcomes requires large sample sizes and performing a large randomized controlled trial would be extremely resource intensive. To mitigate for seasonality and other time-varying confounders, the time periods for both groups started in August and ended in May.23,24 We attempted to further address this limitation with an ITS design, which reflects the next most robust research design to study longitudinal effects of non-randomized interventions.23 However, approaches for analyzing data from an ITS design vary, and in this case these different approaches led to different conclusions regarding the composite respiratory outcome. Since we hypothesized that the overall odds for the composite respiratory outcome would decrease with sugammadex administration (Figure 2A), we followed recommendations to exclude the non-significant estimates for slope and interaction terms.24 However, others contend that groups usually do not depict outcomes parallel over time and other (unaccounted) factors do typically change over time. Hence, even a slight interaction, regardless of statistical significance, should not be ignored, but rather considered in the inference.25 Therefore we chose to present both, our originally planned parsimonious model and a full logistic regression model (including the β1 and β3 estimates) to permit a more complete interpretation of the data. Interestingly, although the β2 estimate changes from non-significant to highly significant when one compares the results of the full to the parsimonious model, all other covariates remain essentially unchanged (Table 3). We would argue that the estimated (and very non-significant) difference in slopes is “overpowered” by a much larger and clear difference in means between the periods (Figure 2A), and hence would favor the parsimonious model in this case. Regardless, part of the difference in estimates between the two models is that the standard error was cut in half for the parsimonious model, in addition to the increase in the log-OR.
Second, although group assignment was not randomized in this ITS design but determined by the date of surgery, demographic and perioperative characteristics were evenly distributed, including weight and gender, which are known risk factors for residual paralysis.36 The only relevant exceptions included the ASA physical status (p=0.013), which was higher in the post-sugammadex group, supplementary epidural anesthesia (p=0.001), which was more frequent in the pre-sugammadex group and the intraoperative dose of oral morphine equivalents (p<0.001), which was higher in the pre-sugammadex group. We speculate that the lower opioid use in the post-sugammadex group could have been due to institutional and nation-wide effort to lower the use of opioids, for example in patients with OSA.37 The different composition of performed procedures may also explain why patients in the pre-sugammadex group received a higher dose of oral morphine equivalents: the pre-sugammadex group had a higher rate of procedures performed by General Surgery (29.2% vs 25.7%) and Cardiothoracic Surgery (9.7% vs 8.3%), but a lower rate of less invasive procedures performed by Interventional Radiology, Gastroenterology, Cardiology and other minor procedures (5.2% vs 7.6%). Hence, the procedure performed and the amounts of opioids administered were included in the logistic regression model. Some of the aforementioned differences in demographic and perioperative characteristics are small and therefore of clinically questionable relevance. However, a higher frequency of the composite respiratory outcome would be expected in patients with higher ASA status, patients not receiving epidural anesthesia, and patients receiving more opioids. Indeed, in the multivariable logistic regression analysis, a higher ASA physical status was associated with higher odds of the composite respiratory outcome, which correlates with previous findings showing an association between ASA physical status and PPC.34,38 The total dose of intraoperative opioids or supplementation of epidural anesthesia, on the other hand, had no effect on the composite respiratory outcome (p=0.051 and p=0.664, respectively). Finally, it should be mentioned that other demographic or intraoperative predictors of postoperative respiratory complications such as the rate of congestive heart failure, other chronic pulmonary disease, and emergency procedures were not included in our regression models, and we can therefore not guarantee that all relevant confounders were captured.34,39
Third, our composite primary outcome was limited to re-intubation for respiratory failure and new NIV. Yet, mortality is increased also with other adverse PPCs such as ARDS (50%), pneumonia (9.1%), or pleural effusions (7.0%).26 Given our sample size and data collection approach using EMR-sources, reliable detection of these outcomes was not feasible. The high post-operative mortality associated with newly initiated NIV and re-intubation provided the rationale for choosing our composite outcome.26
Lastly, NIV is not always prescribed for respiratory failure. Although we defined new NIV exclusive of patients with known pre-operative NIV use, we cannot exclude that NIV was initiated for newly suspected OSA.40 However, the incidence of patients with a diagnosis of OSA or at high-risk for OSA which were identified during the preoperative anesthesia assessment showed no significant differences between groups.
Conclusion
This interrupted time series study of 7,316 patients undergoing general anesthesia with pharmacologic reversal of NMB reveals that the institutional transition from neostigmine to sugammadex was associated with a decrease in the odds of a composite primary outcome of either new NIV or re-intubation for respiratory failure. A system-wide transition from neostigmine to sugammadex as the preferred reversal agent for rocuronium- and vecuronium-induced NMB may lead to a reduction of adverse respiratory outcomes.
Key Points.
Question
Were proportions of re-intubation for respiratory failure or initiation of new non-invasive ventilation reduced after a system-wide transition from neostigmine to sugammadex for reversal of rocuronium or vecuronium?
Findings
In this interrupted time series study design that included 7,316 patients, the composite primary outcome of re-intubation for respiratory failure or new non-invasive ventilation occurred in 6.1% of the pre-sugammadex group and 4.2% of the post-sugammadex group.
Meaning
A system-wide transition of the standard pharmacologic reversal agent from neostigmine to sugammadex was associated with a decrease in the odds of adverse post-operative respiratory outcomes.
Acknowledgments
Financial Disclosures: This work was supported by the National Institutes of Health (NIH), Award Number K23DA040923 to Karsten Bartels. The content of this report is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The NIH had no involvement in study design, collection, analysis, interpretation of data, writing of the report, or the decision to submit the article for publication.
Glossary of Terms
- NIH
National Institutes of Health
- CI
confidence interval
- PPC
postoperative pulmonary complication
- NMB
neuromuscular blockade
- NIV
non-invasive ventilation
- STROBE
Strengthening the Reporting of Observational Studies in Epidemiology
- ITS
interrupted time series
- ASA
American Society of Anesthesiologists
- OSA
obstructive sleep apnea
- ICU
intensive care unit
- PACU
post-anesthesia care unit
- EMR
electronic medical record
- OR
odds ratio
Footnotes
Conflict of Interest: The authors report no conflicts of interest.
Clinical trial number and registry URL: not applicable
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