Secondary Logo

Intermediate-Acting Nondepolarizing Neuromuscular Blocking Agents and Risk of Postoperative 30-Day Morbidity and Mortality, and Long-term Survival

Bronsert, Michael R. PhD, MS*†; Henderson, William G. PhD, MPH*†‡; Monk, Terri G. MD, MS§‖; Richman, Joshua S. MD, PhD; Nguyen, Jennifer D. MD#; Sum-Ping, John T. MD**; Mangione, Michael P. MD††; Higley, Binh MD#; Hammermeister, Karl E. MD*†‡‡

doi: 10.1213/ANE.0000000000001848
Anesthetic Clinical Pharmacology: Original Clinical Research Report
Free
SDC

BACKGROUND: Nondepolarizing neuromuscular blocking drugs (NNMBDs) are commonly used as an adjunct to general anesthesia. Residual blockade is common, but its potential adverse effects are incompletely known. This study was designed to assess the association between NNMBD use with or without neostigmine reversal and postoperative morbidity and mortality.

METHODS: This is a retrospective observational study of 11,355 adult patients undergoing general anesthesia for noncardiac surgery at 5 Veterans Health Administration (VA) hospitals. Of those, 8984 received NNMBDs, and 7047 received reversal with neostigmine. The primary outcome was a composite of respiratory complications (failure to wean from the ventilator, reintubation, or pneumonia), which was “yes” if a patient had any of the 3 component events and “no” if they had none. Secondary outcomes were nonrespiratory complications, 30-day and long-term all-cause mortality. We adjusted for differences in patient risk using propensity matched (PM) followed by assessment of the association of interest by logistic regression between the matched pairs as our primary analysis and multivariable logistic regression (MLR) as a sensitivity analysis.

RESULTS: Our primary aim was to assess the adverse outcomes in the patients who had received NNMBDs with and without neostigmine. Administration of an NNMBD without neostigmine reversal compared with NNMBD with neostigmine reversal was associated with increased odds of respiratory complications (PM odds ratio [OR], 1.75 [95% confidence interval [CI], 1.23–2.50]; MLR OR, 1.71 [CI, 1.24–2.37]) and a marginal increase in 30-day mortality (PM OR, 1.83 [CI, 0.99–3.37]; MLR OR, 1.78 [CI, 1.02–3.13]). However, there were no statistically significant associations with nonrespiratory complications or long-term mortality. Patients who were administered an NNMBD followed by neostigmine had no differences in outcomes compared with patients who had general anesthesia without an NNMBD.

CONCLUSIONS: The use of NNMBDs without neostigmine reversal was associated with increased odds of our composite respiratory outcome compared with patients reversed with neostigmine. Based on these data, we conclude that reversal of NNMBDs should become a standard practice if extubation is planned.

Supplemental Digital Content is available in the text.Published ahead of print February 24, 2017.

From the *Adult and Child Consortium for Health Outcomes Research and Delivery Science; Surgical Outcomes and Applied Research; Department of Biostatistics and Informatics, University of Colorado School of Medicine, Aurora, Colorado; §Department of Anesthesiology and Perioperative Medicine, University of Missouri, Columbia, Missouri; Department of Anesthesiology, Durham VA Medical Center, Durham, North Carolina; Department of Surgery, University of Alabama Birmingham, Birmingham VA Medical Center, Birmingham, Alabama; #Department of Anesthesiology, Baylor College of Medicine, Michael E. DeBakey VA Medical Center, Houston, Texas; **Department of Anesthesiology and Pain Management, University of Texas, Southwestern Medical Center, VA North Texas Health Care System, Dallas, Texas; ††Department of Anesthesiology, University of Pittsburgh School of Medicine, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; and ‡‡Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado.

Published ahead of print February 24, 2017.

Accepted for publication November 21, 2016.

Funding: The project was supported by an Anesthesia Patient Safety Foundation (APSF) grant funded by Covidien and based upon work supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development Grant Number IIR 05-229, Washington, DC. The opinions expressed are those of the authors and not necessarily those of the Department of Veterans Affairs or the United States government.

Conflicts of Interest: See Disclosures at the end of the article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Michael Bronsert, PhD, MS, Adult and Child Consortium for Health Outcomes Research and Delivery Science, Mail Stop F443, UPI Building, 13199 East Montview Blvd, Suite 300, Room 338, Aurora, CO 80045. Address e-mail to Michael.Bronsert@UCDenver.edu.

Nondepolarizing neuromuscular blocking drugs (NNMBDs) competitively block the action of acetylcholine at the postsynaptic receptors on the motor nerve end plate. These agents are used in the majority of surgical procedures conducted under general anesthesia to enhance muscle relaxation for tracheal intubation and to inhibit spontaneous ventilation or muscle contraction during surgery. An acetylcholinesterase inhibitor, such as neostigmine, is commonly used to reverse the muscle paralysis near the end of the surgical procedure.

Back to Top | Article Outline

Rationale

There is evidence, largely obtained from observations in the postanesthesia care unit, that muscle paralysis persists in a substantial proportion of patients regardless of whether or not a neuromuscular function monitor was used or a reversal agent was given.1–3 The presence of residual paralysis after extubation may place patients at an increased risk of developing complications because normal protective airway mechanisms may be inhibited.4 A recent review concluded that, “… residual neuromuscular block is an important patient safety issue and that neuromuscular management affects postoperative outcomes.”5 A large observational study, which used propensity matched (PM) to adjust for the differences in risk, reported a significantly increased risk of reintubation and unplanned admission to the intensive care unit within 7 days of surgery for patients who received an intermediate-acting NNMBD matched to patients who did not receive any NNMBDs (odds ratio [OR], 1.40, 95% confidence interval [CI 1.09–1.80]).6 Importantly, the use of neostigmine was also associated with an increased risk of reintubation after surgery (OR, 1.78 [CI, 1.38–2.26]). We have been unable to find additional contemporary studies with adequate statistical power of adverse outcomes occurring beyond 1 week postoperatively associated with NNMBDs.

Back to Top | Article Outline

Objective and Hypotheses

The overall objective of the present observational study was to assess the relationship between the intraoperative use of an NNMBD and its reversal with acetylcholine esterase inhibitors and the primary outcome of 30-day respiratory complications and secondary outcomes of 30-day nonrespiratory complications, 30-day mortality and long-term all-cause mortality in patients undergoing major surgery in 5 Veterans Health Administration (VA) hospitals. We tested the following 3 hypotheses: (1) patients receiving an NNMBD are more likely to have an adverse outcome than those who do not; (2) among patients receiving an NNMBD, reversal is associated with a lower risk of adverse outcomes; and (3) there is no difference in the odds of adverse outcomes between patients receiving an NNMBD with reversal and those not receiving an NNMBD.

Back to Top | Article Outline

METHODS

Data Sources

Intraoperative data were obtained from 5 VA hospitals with anesthesia information management systems (AIMS) for the years 2003 to 2008. AIMS are specialized forms of the electronic health record used to record and store large amounts of physiological and operative data during the intraoperative period, including drugs administered.

Patient demographics and comorbidities, intraoperative, and 30-day postoperative outcomes were collected from the VA Surgical Quality Improvement Program (VASQIP) database. The VASQIP is a surgical quality improvement program, in existence in the VA since 1991, that collects data on preoperative risk factors, characteristics of the operation, and 30-day postoperative mortality and morbidity outcomes for the majority of major surgical operations performed in the VA healthcare system.7–11 These data are used to risk-adjust hospital-level operative morbidity and mortality for use as measures of quality of care. The VASQIP data are collected by a specially trained nurse at each VA medical center. A previous study documented that the VASQIP data are complete and reliable.12 Long-term vital status data were obtained from the VA vital status data sets, which merge death records from 4 national sources.13

AIMS and VASQIP databases were linked by patient social security number and surgery date, whereas the long-term vital status was linked by social security number. Only those operations that had both the AIMS and VASQIP data available were retained for analysis. The patient sample was limited to those who had general anesthesia for at least part of their surgery. For patients with more than 1 operation recorded in the database, only the first operation for each patient was retained for analysis.

The study was approved by the University of Colorado Multiple Institutional Review Board (IRB), Denver, Colorado; the IRB at the Durham, NC, VA Medical Center; the IRB at each of the 5 participating VA medical centers (Dallas, Houston, Pittsburgh, Seattle, and Washington, DC); and the VA Surgical Quality Data Use Group.

Back to Top | Article Outline

Neuromuscular Blocking and Reversal Agents

Patients, who were administered one or more of the intermediate-acting nondepolarizing agents, vecuronium, cisatracurium, and rocuronium, were considered to have received an NNMBD, whereas patients receiving any other nondepolarizing NNMBD were excluded. Patients who received one or more of the NNMBDs and were administered neostigmine, edrophonium, physostigmine, or pyridostigmine were considered to have received a reversal agent. Patients who received the short-acting depolarizing muscle relaxant succinylcholine (commonly used during intubation only) but did not receive an NNMBD had outcome rates similar to patients who did not receive any muscle relaxant and were included in the no NNMBD group. Patients who received a reversal agent but no NNMBD were excluded. At our VA hospitals, it is routine practice to utilize nerve stimulators and titrate NNMBD and neostigmine reversal as clinically appropriate based on monitored twitch results. Although these data were not collected in the current study, we made the assumption that all patients were monitored for neuromuscular function, and the goal was either to give enough muscle relaxant to achieve either 1 to 2 twitches on a train-of-four or adequate muscle relaxation for the surgical procedure.

Back to Top | Article Outline

Outcomes

The primary outcome for this study was a composite of 3 respiratory complications: (1) inability to wean from the ventilator within 48 hours following surgery, (2) reintubation within 30 days postoperatively, and (3) postoperative pneumonia within 30 days after surgery. A composite variable was used to increase the event rate and statistical power of the study, and the 3 individual outcomes that make up the respiratory complication have been shown to be correlated.14 The 3 secondary outcomes were: (1) 30-day all-cause mortality; (2) late all-cause mortality (includes 30-day mortality and all reported deaths before January 24, 2013, or last date of utilization of service for patients who did not die); and (3) one or more of the following nonrespiratory complications: superficial surgical site infection (SSI), dehiscence, deep wound SSI, organ/space SSI, systemic sepsis, urinary tract infection, acute renal failure, progressive renal insufficiency, cardiac arrest, myocardial infarction, deep vein thrombosis, pulmonary embolism, bleeding requiring >4 units pack red blood cells, cerebrovascular accident/stroke, coma, and peripheral nerve injury.

Back to Top | Article Outline

Risk Adjustment Variables

We included all preoperative and operative risk variables listed in Supplemental Digital Content (Supplemental Table 1, http://links.lww.com/AA/B610) as risk-adjustment variables; patients having missing values for nonlaboratory variables were excluded (1.0% [111/11,583]). Because of its established strong relationship with surgical outcomes,15 we imputed missing values for serum albumin using the Buck method;16 we assumed normal values for other laboratory measures that were missing.

Back to Top | Article Outline

Statistical Analysis

For each hypothesis and each of the 4 outcomes, we risk-adjusted the outcomes by 2 different methods: (1) PM cohorts as the primary analysis, and (2) multivariable logistic regression (MLR) as a sensitivity analysis.17 A propensity score for each patient for each of the 3 hypotheses was calculated using an MLR model in which the dependent variable was treatment group and the independent variables were the preoperative and operative adjustment variables listed in the Supplemental Digital Content (Supplemental Table 1, http://links.lww.com/AA/B610). Separate propensity models were developed for each of the 3 hypotheses. For each model, the β-coefficients were combined with the patients’ values for each covariate to generate model-specific propensity scores for each patient. These patient-level propensity scores were then used to match treated patients to nontreated patients to produce the propensity-matched cohorts using the 1-to-1 greedy matching method.18 The matching algorithm first matches pairs within 8 decimal places of the propensity score. If there are no matches at 8 decimals, then the matching algorithm moves to 7 decimal places, and so on down to one decimal place. For hypothesis 1, we matched patients who received an NNMBD to patients who did not. For hypothesis 2, we matched patients who received an NNMBD but no reversal agent to patients who received an NNMBD followed by a reversal agent. For hypothesis 3, we matched patients who received an NNMBD followed by a reversal agent to patients who did not receive an NNMBD. The quality of the matching process was assessed by comparing the standardized differences between the treatment groups for the covariates before and after matching.18,19 It is generally considered that the groups are well balanced if the absolute values of the standardized differences are less than 0.1.

We performed MLR analysis to test our hypotheses regarding the association between treatment and the binary outcomes of respiratory and nonrespiratory complications and 30-day mortality. Generalized estimating equation models were used to test our hypotheses for the propensity-matched cohort to account for correlation within each matched pair. A Cox proportional hazards model20,21 was used to test the association between treatment and long-term all-cause mortality. Models adjusting for clustering effect of VA site were not performed because previous studies have shown that accounting for clustering with hierarchical modeling does not have a clinically important effect.22,23

For all outcomes and risk-adjusted results, statistical significance and CIs were adjusted for multiple comparisons (ie, 4 outcomes and 2 risk-adjustment methods) using the Bonferroni method by multiplying the P values or dividing the α levels by the number of comparisons. All statistical tests were considered to be significant at a 2-sided P < .05. All analyses were performed using SAS software version 9.4 (SAS Inc, Cary, NC).

For hypothesis 1, we have a power of 80% to detect an OR of 2.2 for PM and 1.2 for MLR and a power of 90% to detect an OR of 2.3 for PM and 1.2 for MLR. For hypothesis 2, we have a power of 80% to detect an OR of 1.6 for PM and 1.2 for MLR and a power of 90% to detect an OR of 1.7 for PM and 1.2 for MLR. For hypothesis 3, we have a power of 80% to detect an OR of 2.3 for PM and 1.2 for MLR and a power of 90% to detect an OR of 2.4 for PM and 1.2 for MLR. All 3 power analyses assumed an α of 0.006 for the respective sample sizes and assuming a multiple correlation coefficient of 0.95 or less.24

Back to Top | Article Outline

RESULTS

Patient Inclusion

There were 11,583 general anesthesia patients with both VASQIP data and data on the use of NNMBDs and reversal agents from the AIMS data files of the 5 participating hospitals. Exclusions from this sample were those who received only atracurium, mivacurium, or pancuronium (74, 0.6%); received a reversal agent but no NNMBD (43, 0.4%); or were missing key data (dyspnea [105, 0.9%], alcohol consumption [3, 0.03%], and work relative value unit [3, 0.03%]), leaving 11,355 patients used for the analyses of morbidity and mortality.

Back to Top | Article Outline

Sample Characteristics

The Supplemental Digital Content (Supplemental Table 1, http://links.lww.com/AA/B610) shows that the mean age was 59.1 years and, consistent with a VA population, this was a largely male cohort (92.1%). The majority (70.6%) of patients were ASA class III or higher (ie, III, IV, or V) and had an operation with a median time of 2.1 (interquartile range 1.3–3.2) hours. A total of 30.5% of the operations were general surgery, 22.9% orthopedic, 10.7% peripheral vascular, 9.9% urologic, 9.0% neurosurgical, 5.2% thoracic, and 11.8% other specialties.

Back to Top | Article Outline

NNMBD and Reversal Agents Received

Among patients receiving an NNMBD, vecuronium was administered in 36.9% (3313/8984), cisatracurium in 34.8% (3129/8984), rocuronium in 14.7% (1322/8984), and more than one type of NNMBD in 13.6% (1220/8984). All but 3 patients who received a reversal agent were administered neostigmine, and 0.1% (8/7047) of patients received more than one reversal agent. Among patients not receiving an intermediate duration of action NNMBD, 30.2% (717/2371) received the short-acting depolarizing neuromuscular blocking agent succinylcholine.

Back to Top | Article Outline

Unadjusted Outcomes

Table 1

Table 1

As shown in Table 1, unadjusted rates of adverse outcomes were substantially higher in patients receiving an NNMBD compared with those not, and among patients receiving an NNMBD, the rate of adverse outcomes was substantially higher in those who did not receive a reversal agent.

Back to Top | Article Outline

Neuromuscular Blocking and Reversal Agent Allocation

The Figure shows the allocation of NNMBD and reversal agent for the 3 hypotheses. The first hypothesis (patients receiving an NNMBD are more likely to have an adverse outcome than those who do not) was tested by comparing adverse outcomes rates between the 8984 patients who received an NNMBD with or without neostigmine (box 1) with the 2371 patients who did not receive an NNMBD (Figure, box 2). The second hypothesis (among patients receiving an NNMBD, reversal is associated with a lower risk of adverse outcomes) was tested by comparing adverse outcomes rates for the 1937 patients who received an NNMBD but no reversal agent (Figure, box 4) with the 7047 patients who received an NNMBD followed by a reversal agent (Figure, box 3). The third hypothesis (that there is no difference in the odds of adverse outcomes between patients receiving an NNMBD with reversal and those not receiving an NNMBD) was tested by comparing adverse outcomes rates between the 7047 patients receiving an NNMBD followed by a reversal agent (Figure, box 3) to the 2371 patients who received no NNMBD (Figure, box 2).

Figure. F

Figure. F

Hypothesis 1: Patients receiving an NNMBD are more likely to have an adverse outcome than those who did not.

Table 2 shows that there was no significant association between receiving an NNMBD with or without reversal and respiratory complications for PM (1.63 [0.88–3.03]), but there was for MLR (2.00 [1.14–3.51]). Both PM and MLR analyses found no significant association between receiving an NNMBD and nonrespiratory complications, 30-day all-cause mortality, and late all-cause mortality.

Table 2

Table 2

The Supplemental Digital Content (Supplemental Table 2, http://links.lww.com/AA/B610) compares characteristics between patients receiving no NNMBD and those receiving an NNMBD before and after PM. There were 2071 matched pairs of patients created by matching on the propensity to receive an NNMBD, which is 87% (2071/2371) of the smaller of the unmatched cohorts. In the unmatched samples, 19 of 45 (42.2%) characteristics had standardized differences >0.1 between the patients receiving and not receiving an NNMBD. When the samples were matched by propensity to have an NNMBD, none of the 45 characteristics had standardized differences >0.1.

Hypothesis 2: Among patients receiving an NNMBD, reversal is associated with lower odds of adverse outcomes.

Table 3 shows there was a very strong, statistically significant association between receiving an NNMBD without reversal agent and having one or more respiratory complications compared with patients who received NNMBD followed by a reversal agent (PM 1.75 [1.23–2.50] and MLR 1.71 [1.24–2.37]; P < .001 and P < .0001). There was also a marginal association (PM 1.83 [0.99–3.37] and MLR 1.78 [1.02–3.13]; P = .06 and P = .04) with 30-day all-cause mortality. The association between not receiving a reversal agent and nonrespiratory complications and late all-cause mortality was not statistically significant.

Table 3

Table 3

The Supplemental Digital Content (Supplemental Table 3, http://links.lww.com/AA/B610) compares characteristics between patients receiving an NNMBD with reversal and those receiving an NNMBD without reversal. A total of 7047/8984 (78.4%) of the patients had their NNMBD reversed. Only 9.5% (184/1937) of the patients not receiving a reversal agent could not be propensity matched with a patient receiving a reversal agent. In the unmatched samples, 26 of 45 (57.8%) characteristics had standardized differences >0.1, but in the propensity matched samples none of the 45 characteristics had standardized differences >0.1.

Hypothesis 3: There is no difference in the odds of adverse outcomes between patients receiving an NNMBD with reversal and those not receiving an NNMBD.

Table 4 shows that although NNMBD with reversal was associated with adverse outcomes before covariate adjustment, the only statistically significant result in adjusted analyses was for MLR for 30-day all-cause mortality (1.11 [1.10–1.12]; P < .0001). However, there was no statistical association seen for 30-day all-cause mortality for PM (1.06 [0.44–2.55]; P = 1.0).

Table 4

Table 4

The Supplemental Digital Content (Supplemental Table 4, http://links.lww.com/AA/B610) presents the differences in characteristics between patients who received an NNMBD and reversal agent and those who received neither. In the unmatched samples, the standardized differences were >0.1 for 42.5% (19 of 45) of the characteristics. When the samples were matched by propensity to have an NNMBD plus reversal agent versus neither, none of the 45 characteristics had standardized differences >0.1. A total of 18.0% (427/2371) of the patients receiving neither treatment were not able to be matched with a patient receiving NNMBD followed by a reversal agent.

Back to Top | Article Outline

DISCUSSION

Summary of Findings

Among patients receiving an NNMBD, not using a reversing agent was associated with increased odds of respiratory complications, a marginal association with 30-day all-cause mortality, but no association with nonrespiratory complications or long-term all-cause mortality (Table 3). Not administering a reversal agent was associated with an estimated 70% to 75% increase in odds for respiratory complications (failure to wean from the respirator within 48 hours or reintubation or pneumonia within 30 days). Numerous studies have documented that it is not possible to determine if neuromuscular function has recovered to more than a train-of-four ratio > 0.4 using clinical evaluation (head lift, hand grip) or tactile or visual evaluation with a qualitative neuromuscular function monitor.25,26 It is, therefore, likely that the clinicians who did not reverse NNMBD were relying on one of these techniques to evaluate neuromuscular recovery and that their patients suffered from the consequences of residual blockade including the presence of incomplete neuromuscular recovery resulting in a decrease in normal protective airway mechanisms.4

We documented the success of the PM by showing that the absolute values of the standardized differences were <0.1 in all 45 patient characteristics used in the propensity analyses for all 3 hypotheses (Supplemental Digital Content, Supplemental Tables 2–4, http://links.lww.com/AA/B610). Additionally, the matched pairs groups included 82% to 90% of the patients in the smaller of the unmatched cohorts, meaning that we did not lose too many of the patients in the smaller of the 2 treatment groups by PM, and these analyses should be representative of the full cohort of the smaller of the 2 treatment groups.

Back to Top | Article Outline

Other Studies

We have been unable to identify randomized trials of adequate sample size addressing the safety of NNMBD with and without administration of a reversal agent. We have identified 4 contemporary (within the last decade) observational studies on this issue. The first is a case control study conducted by Arbous et al.27 About one-third of patients undergoing anesthesia in the Netherlands between 1995 and 1996 were selected (869,483) on the basis of demographic regions. The cases were 807 patients who either died or remained comatose in the 24 hours following surgery. Controls were patients who had not died or remained comatose within this period and were matched to the cases by gender and similar age within a 5-year window. It is not surprising that the baseline characteristics varied hugely between cases and controls; for example, 69.8% of cases were in American Society of Anesthesiologists (ASA) IV or V compared with 1.7% of controls. Perhaps more important is the difference in use of regional anesthesia, in which NNMBDs are not used: 9.8% in cases and 34.9% in controls. This raises serious questions regarding the validity of the reported OR of 0.10 for the use of “reversal of anesthesia (for muscle relaxants and the combination of muscle relaxants and opiates).” In addition, a strong protective association of 0.10 would be most unusual in this circumstance.

A large observational cohort study of the effects of NNMBDs on outcomes in patients operated on at the Massachusetts General Hospital was reported by Grosse-Sundrup et al6 in 2012. Risk adjustment was performed by matching patients 1-to-1 by their propensity to receive an NNMBD, one of whom received an NNMBD, whereas the other did not. Postoperative hypoxia (<90% saturation) and reintubation requiring unplanned admission to the intensive care unit within 7 days of surgery were significantly increased in the group receiving an NNMBD; respective ORs were: 1.36 (95% CI, 1.23–1.51) and 1.40 (1.09–1.80). These authors attributed the increased respiratory problems after reversal of NNMBDs with neostigmine to neostigmine-induced neuromuscular blockade. There was no difference in mortality between the 2 groups. In contrast to our findings, neostigmine administration was not significantly associated with reintubation (1.36 [0.69–2.70]). In the current report, we demonstrate a statistically significantly increased odds in our composite respiratory complication (which includes reintubation out to 30 days postoperatively) in patients who received an NNMBD without a reversal agent compared with those who did (Table 3). Our findings are in agreement with previous reports indicating that neostigmine-induced “paradoxical weakness” is an uncommon occurrence.28,29 It is possible that our results differ because although Grosse-Sundrup et al matched on the propensity to receive an NNMBD, we found no evidence that they matched patients on the propensity to receive neostigmine. Moreover, in a follow-up letter to the British Medical Journal, Meyer et al30 report that they performed a secondary analysis of the same data set, in which one of the pair received neostigmine and the other did not. There were no differences in reintubation (1.11 [0.87–1.43]) or oxygen desaturation to <80% (1.09 [0.88–1.37]) between patients receiving neostigmine after an NNMBD and those who did not. Our data show markedly different results; not administering a reversal agent to antagonize the neuromuscular blockade with neostigmine was associated with a 70% to 75% greater risk of a respiratory complication (Table 3).

A second large cohort study of the effects of NNMBDs on respiratory outcomes in patients operated on at the Massachusetts General Hospital was reported by McLean et al in 2015.31 They analyzed 48,499 patients who received intermediate-acting NNMBDs and found a statistically significant association with a dose-dependent increased risk of postoperative respiratory complications (1.28 [1.04–1.57]). In addition, they also found a statistically significant association of NNMBD reversal with neostigmine and dose-dependent increases in the risk of postoperative respiratory complications (1.51 [1.25–1.83]). However, they found that after “appropriate” neostigmine reversal (neostigmine ≤ 60 μg/kg after recovery to a train-of-four count of 2), the dose-dependent association of NNMBDs and respiratory complications was eliminated (0.98 [0.63–1.52]). Our data show similar results in that patients who received an NNMBD, and then subsequently received a reversal agent, had similar adverse outcomes as patients who did not receive an NNMBD (Table 4).

A final observational cohort study of the effects of NNMBD on postoperative pneumonia in patients operated on at the Vanderbilt University Medical Center was reported by Bulka et al32,33 in 2016. In this study, the authors used their National Surgical Quality Improvement Program database for the years of 2005 to 2013 to propensity match 1455 surgical patients who received an NNMBD to 1455 patients who did not and 1320 surgical patients who received an NNMBD and reversal to 1320 patients who received an NNMBD but did not receive a reversal agent. They found that there was a statistically significant increase in the incident rate ratio for postoperative pneumonia for patients receiving an NNMBD compared with patients who did not (1.79 [1.08–3.07]) and for patients who received an NNMBD but did not receive a reversal agent compared with patients who received an NNMBD and a reversal agent (2.26 [1.65–3.03]). Our data show similar results in that patients who received an NNMBD and did not subsequently receive a reversal agent had greater risk of a respiratory complication.

Back to Top | Article Outline

Strengths and Weaknesses

The strengths of our study are: (1) the use of 2 methods of risk adjustment because MLR uses the entire sample, whereas PM uses a subset of patients; (2) the ability to assess the association between administration of an NNMBD with or without a reversal agent and multiple adverse outcomes (30-day respiratory, 30-day nonrespiratory complications, 30-day all-cause mortality, as well as late all-cause mortality); and (3) a large sample size (11,355 patients) with very little missing data on risk factors or outcomes.

Possible weaknesses are as follows: The VA population is not representative of the overall US population, particularly with regard to predominantly male gender, older age, and greater comorbidity. Like most risk-adjustment techniques in observational studies, PM models are unable to adjust for unmeasured confounders. We do not have data on intraoperative monitoring of train-of-four count and timing of reversal agent administration relative to the last NNMBD dose given; these are data that can help further elucidate whether or not the omission of a reversal agent is appropriate. In addition, we do not know how often a peripheral nerve stimulator was utilized or what doses of neostigmine were administered. There was a lack of intensive care unit data to determine whether patients were kept intubated at the end of the surgery. The surgeries were performed between 2003 and 2008. The last weakness would be of great concern had there been a temporal change in anesthesia practice, particularly regarding the use of the reversal agents of NNMBD; however, there have been few changes in the medications used for neuromuscular blockade, with the exception of sugammadex,34 which received Food and Drug Administration approval for use in the United States in 2016. The rate of use of a reversal agent (neostigmine) in our study (78.4%) was not greatly different from that reported by Grosse-Sundrup et al for surgery between 2006 and 2010 (63.9% [20,459/32,002]).

Back to Top | Article Outline

CONCLUSIONS

The use of NNMBDs without neostigmine reversal was associated with increased odds of postoperative respiratory complications and a marginal association with 30-day postoperative mortality. Based on these data, we conclude that reversal of NNMBDs should become a standard practice if extubation is planned.

Back to Top | Article Outline

DISCLOSURES

Name: Michael R. Bronsert, PhD, MS.

Contribution: This author helped with study design, critical review, analysis, and writing.

Conflicts of Interest: None.

Name: William G. Henderson, PhD, MPH.

Contribution: This author helped with study design, critical review, and writing.

Conflicts of Interest: None.

Name: Terri Monk, MD, MS.

Contribution: This author helped with study design, critical review, and writing.

Conflicts of Interest: Terri Monk is a consultant and is on the speaking bureau for Merck Pharmaceuticals.

Name: Joshua S. Richman, MD, PhD.

Contribution: This author helped with critical review and study design.

Conflicts of Interest: None.

Name: Jennifer D. Nguyen, MD.

Contribution: This author helped with critical review and study design.

Conflicts of Interest: None.

Name: John T. Sum-Ping, MD.

Contribution: This author helped with critical review and study design.

Conflicts of Interest: None.

Name: Michael P. Mangione, MD.

Contribution: This author helped with critical review and study design.

Conflicts of Interest: None.

Name: Binh Higley, MD.

Contribution: This author helped with critical review and study design.

Conflicts of Interest: None.

Name: Karl E. Hammermeister, MD.

Contribution: This author helped with study design, critical review, writing, and grant funding.

Conflicts of Interest: None.

This manuscript was handled by: Ken B. Johnson, MD.

Back to Top | Article Outline

REFERENCES

1. Plaud B, Debaene B, Donati F, Marty J. Residual paralysis after emergence from anesthesia. Anesthesiology. 2010;112:1013–1022.
2. Donati F. Residual paralysis: a real problem or did we invent a new disease? Can J Anaesth. 2013;60:714–729.
3. Naguib M, Kopman AF, Ensor JE. Neuromuscular monitoring and postoperative residual curarization: a meta-analysis. Br J Anasesth. 2007;98:302–316.
4. Murphy GS, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS. Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesth Analg. 2008;107:130–137.
5. Murphy GS, Brull SJ. Residual neuromuscular block: lessons unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg. 2010;111:120–128.
6. Grosse-Sundrup M, Henneman JP, Sandberg WS, et al. Intermediate acting non-depolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study. BMJ. 2012;345:e6329.
7. Khuri SF, Daley J, Henderson W, et al. The National Veterans Administration Surgical Risk Study: risk adjustment for the comparative assessment of the quality of surgical care. J Am Coll Surg. 1995;180:519–531.
8. Daley J, Khuri SF, Henderson W, et al. Risk adjustment of the postoperative morbidity rate for the comparative assessment of the quality of surgical care: results of the National Veterans Affairs Surgical Risk Study. J Am Coll Surg. 1997;185:328–340.
9. Daley J, Forbes MG, Young GJ, et al. Validating risk-adjusted surgical outcomes: site visit assessment of process and structure. National VA Surgical Risk Study. J Am Coll Surg. 1997;185:341–351.
10. Khuri SF, Daley J, Henderson W, et al. Risk adjustment of the postoperative mortality rate for the comparative assessment of the quality of surgical care: results of the National Veterans Affairs Surgical Risk Study. J Am Coll Surg. 1997;185:315–327.
11. Khuri SF, Daley J, Henderson W, et al. The Department of Veterans Affairs’ NSQIP: the first national, validated, outcome-based, risk-adjusted, and peer-controlled program for the measurement and enhancement of the quality of surgical care. National VA Surgical Quality Improvement Program. Ann Surg. 1998;228:491–507.
12. Davis CL, Pierce JR, Henderson W, et al. Assessment of the reliability of data collected for the Department of Veterans Affairs national surgical quality improvement program. J Am Coll Surg. 2007;204:550–560.
13. Sohn MW, Arnold N, Maynard C, Hynes DM. Accuracy and completeness of mortality data in the Department of Veterans Affairs. Popul Health Metr. 2006;4:2.
14. Meguid RA, Bronsert MR, Juarez-Colunga E, Hammermeister KE, Henderson WG. Surgical Risk Preoperative Assessment System (SURPAS): I. Parsimonious, clinically meaningful groups of postoperative complications by factor analysis. Ann Surg. 2016;263:1042–1048.
15. Gibbs J, Cull W, Henderson W, Daley J, Hur K, Khuri SF. Preoperative serum albumin level as a predictor of operative mortality and morbidity: results from the National VA Surgical Risk Study. Arch Surg. 1999;134:36–42.
16. Buck SF. A method of estimation of missing values in multivariate data suitable for use with an electronic computer. J Roy Stat Soc. 1960; 22: 302–307.
17. Austin PC. A comparison of 12 algorithms for matching on the propensity score. Stat Med. 2014;33:1057–1069.
18. Rosenbaum PR. Observational Studies. 2002.New York, NY: Springer-Verlag.
19. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009;28:3083–3107.
20. Cox DR. Regression models and life-tables. J Roy Stat Soc. 1972; 43: 187–220.
21. Bewick V, Cheek L, Ball J. Statistics review 12: survival analysis. Crit Care. 2004;8:389–394.
22. Cohen ME, Dimick JB, Bilimoria KY, Ko CY, Richards K, Hall BL. Risk adjustment in the American College of Surgeons National Surgical Quality Improvement Program: a comparison of logistic versus hierarchical modeling. J Am Coll Surg. 2009;209:687–693.
23. Hannan EL, Wu C, DeLong ER, Raudenbush SW. Predicting risk-adjusted mortality for CABG surgery: logistic versus hierarchical logistic models. Med Care. 2005;43:726–735.
24. Hsieh FY. Sample size tables for logistic regression. Stat Med. 1989;8:795–802.
25. Beemer GH, Rozental P. Postoperative neuromuscular function. Anaesth Intensive Care. 1986;14:41–45.
26. Pedersen T, Viby-Mogensen J, Bang U, Olsen NV, Jensen E, Engbaek J. Does perioperative tactile evaluation of the train-of-four response influence the frequency of postoperative residual neuromuscular blockade? Anesthesiology. 1990;73:835–839.
27. Arbous MS, Meursing AE, Van Kleef JW, et al. Impact of anesthesia management characteristics on severe morbidity and mortality. Anesthesiology. 2005;102:257–268.
28. Song IA, Seo KS, Oh AY. Timing of reversal with respect to three nerve stimulator end-points from cisatracurium-induced neuromuscular block. Anaesthesia. 2015;70:797–802.
29. Choi ES, Oh AT, Seo KS, et al. Optimum dose of neostigmine to reverse shallow neuromuscular blockade with rocuronium and cisatracurium. Anaesthesia. 2016;71:443–449.
30. Meyer MJ, Bateman BT, Kurth T, Eikermann M. Neostigmine reversal doesn't improve postoperative respiratory safety. BMJ. 2013;346:f1460.
31. McLean DJ, Diaz-Gil D, Farhan HN, Ladha KS, Kurth T, Eikermann M. Dose-dependent association between intermediate-acting neuromuscular-blocking agents and postoperative respiratory complications. Anesthesiology. 2015;122:1201–1213.
32. Bulka CM, Terekhov MA, Martin BJ, Dmochowski RR, Hayes RM, Ehrenfeld JM. Nondepolarizing neuromuscular blocking agents, reversal, and risk of postoperative pneumonia. Anesthesiology. 2016;125:647–655.
33. Murphy GS, Kopman AF. To reverse or not to reverse. The answer is clear. Anesthesiology. 2016;125:611–614.
34. Keating GM. Sugammadex: a review of neuromuscular blockade reversal. Drugs. 2016;76:1041–1052.

Supplemental Digital Content

Back to Top | Article Outline
© 2017 International Anesthesia Research Society