Supplemental Digital Content

Figures

Figure S1. Quality assessment for the 20 studies included in the meta-analysis

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Figure S2. Spontaneous recovery, rNMB incidence at PACU entry

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Figure S3. TOFR<0.90, rNMB incidence at PACU entry

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Figure S4. Results of sensitivity analysis (restricted to rocuronium NMB)—Moderate block

rNMB: Residual neuromuscular block; m: Minutes after antagonist administration

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Figure S5. Results of sensitivity analysis (restricted to rocuronium NMB)—Deep block

rNMB: Residual neuromuscular block; m: Minutes after antagonist administration

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Tables

Table S1: Search strategy for clinical burden# Searches Results

1 exp neuromuscular blocking/ or exp neuromuscular blocking agent/ or exp Neuromuscular Blockade/ or exp Neuromuscular Blocking Agents/ or neuromuscular block*.ti,ab. 102397

2

(Atracurium or Relatrac or Tracrium or Cisatracurium or Nimbex or Doxacurium Nuromax or Mivacurium or Mivacron or Pancuronium or Pavulon or Pipecuronium or Pipecurium or Arduan or Rocuronium or Esmeron or Esmerone or Zemuron or Tubocurarine or Tubocurare or d-Tubocurare or d-Tubocurarine or vecuronium or Norcuron or succinylcholine or Succinyldicholine or Suxamethonium or Myorelaxin or Suxamethonium or Succinylcholine or Listenon or Anectine or Celocurine or Ditilin or Lysthenon or Quelicin or Succicuran or suxamethonium or decamethonium).mp.

84265

3 (residual curarization or residual curarisation or delirium or Delayed Emergence from Anesthesia).mp. 478224 (rnmb or residual nmb or residual neuromuscular block or residual neuromuscular blockade).mp. 9585 Residual paralysis.mp. 5026 residual block*.mp. 3497 Anesthesia Recovery Period.mp. 70518 exp anesthetic recovery/ 7308

9 (adverse effects or contraindications or adverse drug reaction or drug toxicity or poisoning or clinical trial or drug interaction or drug effects or poisoning or toxicity).fs,xs. and residual*.mp. 48496

10 1 or 2 12647611 3 or 4 or 5 or 6 or 7 or 8 or 9 11056512 10 and 11 594613 (recover* or recovery tim*).mp. 143079314 (train of four or tof or tofr).mp. 7640115 exp Anaphylaxis/ or exp atelectasis/ or exp Pneumonia/ or (pneumonia or atelectasis or anaphyla*).ab,ti. 542076

16

exp Cardiovascular Diseases/ or exp Cardiovascular Disease/ or exp heart muscle ischemia/ or exp Myocardial Ischemia/ or exp Heart Failure/ or exp heart failure/ or exp ventilator induced lung injury/ or exp Ventilator-Induced Lung Injury/ or exp Pneumonia, Ventilator-Associated/ or exp ventilator associated pneumonia/ or exp hypotension/ or exp Hypotension/ or (afib or a-fib or artrial fibrillation or tachycardia* or atrioventricular or cardiac arrest or shortness of breath or respiratory failure or heart attack or myocardial ischemia or ischemic heart or cardiac failure or heart failure or cardiac insufficiency or heart insufficiency or myocardial insufficiency or myocardial failure or ventilator failure or low blood pressure or hypotensi*).mp.

6203802

17 (residual curarization or residual curarisation or delirium or Delayed Emergence from Anesthesia or porc or residual paresis).mp. 49071

18 ((discharg* or pacu or post anesthesia care) and time).ab,ti. 14825319 (discharge and (ready or readiness or tim*)).ab,ti. 13201820 (exp time factor/ or exp time factors/) and (exp patient discharge/ or exp hospital discharge/) 357521 (extubat* and (dose or dosing or dosage or administration or tim*)).ab,ti. 1960722 exp time/ and (exp intubation/ or exp reintubation/ or exp extubation/) 676223 ((intubat* or reitubat* or re-intubat*) and tim*).ab,ti. 40459

24 exp immunopathology/ or exp Immune System Diseases/ or (immune disorder* or immune disease* or autoimmune disorder* or autoimmune disease*).ab,ti. 3049786

25 ((exp vomiting/ or exp nausea/ or exp nausea/) and vomiting/) or (nausea* or vomit* or emesis).mp. 481736

26 exp length of stay/ or (los or length of stay).mp. or exp hospital readmission/ or (readmission* or readmit* or re-admit* or re-admission*).ti,ab. or exp patient readmission/ 472084

27 pain*.mp. or exp pain/ 2379812

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28 (hypertens* or elevated blood pressure).mp. or exp elevated blood pressure/ or exp hypertension/ 140131029 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 1283553030 12 and 29 5521

31

(real world or postmarketing or post-marketing or observational* or retrospective* or prospective* or case control or cohort study or real world or cross sectional or longitudinal* or Epidemiologic Studies or clinical study or randomi* or rct or clinical Study or observational study or Observational Study or systematic* or meta-analy* or metaanaly* or meta analysis or systematic review or Meta-Analysis).mp.

10411194

32 30 and 31 276833 exp case report/ or exp case reports/ or case report.ti. 422939434 32 not 33 275535 limit 34 to yr="2003 -Current" 177736 remove duplicates from 35 1294

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Table S2: Search strategy for humanistic burden# Searches Results

1 exp neuromuscular blocking/ or exp neuromuscular blocking agent/ or exp Neuromuscular Blockade/ or exp Neuromuscular Blocking Agents/ or neuromuscular block*.ti,ab. 102397

2

(Atracurium or Relatrac or Tracrium or Cisatracurium or Nimbex or Doxacurium Nuromax or Mivacurium or Mivacron or Pancuronium or Pavulon or Pipecuronium or Pipecurium or Arduan or Rocuronium or Esmeron or Esmerone or Zemuron or Tubocurarine or Tubocurare or d-Tubocurare or d-Tubocurarine or vecuronium or Norcuron or succinylcholine or Succinyldicholine or Suxamethonium or Myorelaxin or Suxamethonium or Succinylcholine or Listenon or Anectine or Celocurine or Ditilin or Lysthenon or Quelicin or Succicuran or suxamethonium or decamethonium).mp.

84265

3 (residual curarization or residual curarisation or delirium or Delayed Emergence from Anesthesia).mp. 478224 (rnmb or residual nmb or residual neuromuscular block or residual neuromuscular blockade).mp. 9585 Residual paralysis.mp. 5026 residual block*.mp. 3497 Anesthesia Recovery Period.mp. 70518 exp anesthetic recovery/ 7308

9 (adverse effects or contraindications or adverse drug reaction or drug toxicity or poisoning or clinical trial or drug interaction or drug effects or poisoning or toxicity).fs,xs. and residual*.mp. 48496

10 1 or 2 12647611 3 or 4 or 5 or 6 or 7 or 8 or 9 11056512 10 and 11 5946

13(utility or quality of life or qaly or qalys or sedation status or glasgow or ramsay or questionnaire* or survey* or assessment or tool or outcome measures or patient reported outcome or patient reported outcomes or utilities).mp.

7948538

14 (quality of life or qol or utility or validation or algorithm or economic* or pharmacoeconomic* or cost or costs or patient reported outcomes or patient reported outcome or pro).mp. 4733401

15 (utility or disutility or disutilities or utilities).mp. 438830

16

(real world or postmarketing or post-marketing or observational* or retrospective* or prospective* or case control or cohort study or real world or cross sectional or longitudinal* or Epidemiologic Studies or clinical study or randomi* or rct or clinical Study or observational study or Observational Study or systematic* or meta-analy* or metaanaly* or meta analysis or systematic review or Meta-Analysis).mp.

10411194

17 14 or 15 or 16 1378637518 12 and 13 and 17 83619 limit 18 to yr="2003-Current" 70420 remove duplicates from 19 607

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Table S3: Search strategy for economic burden# Searches Results

1 exp neuromuscular blocking/ or exp neuromuscular blocking agent/ or exp Neuromuscular Blockade/ or exp Neuromuscular Blocking Agents/ or neuromuscular block*.ti,ab. 102397

2

(Atracurium or Relatrac or Tracrium or Cisatracurium or Nimbex or Doxacurium Nuromax or Mivacurium or Mivacron or Pancuronium or Pavulon or Pipecuronium or Pipecurium or Arduan or Rocuronium or Esmeron or Esmerone or Zemuron or Tubocurarine or Tubocurare or d-Tubocurare or d-Tubocurarine or vecuronium or Norcuron or succinylcholine or Succinyldicholine or Suxamethonium or Myorelaxin or Suxamethonium or Succinylcholine or Listenon or Anectine or Celocurine or Ditilin or Lysthenon or Quelicin or Succicuran or suxamethonium or decamethonium).mp.

84265

3 (residual curarization or residual curarisation or delirium or Delayed Emergence from Anesthesia).mp. 478224 (rnmb or residual nmb or residual neuromuscular block or residual neuromuscular blockade).mp. 9585 Residual paralysis.mp. 5026 residual block*.mp. 3497 Anesthesia Recovery Period.mp. 70518 exp anesthetic recovery/ 7308

9 (adverse effects or contraindications or adverse drug reaction or drug toxicity or poisoning or clinical trial or drug interaction or drug effects or poisoning or toxicity).fs,xs. and residual*.mp. 48496

10 1 or 2 12647611 3 or 4 or 5 or 6 or 7 or 8 or 9 11056512 10 and 11 5946

13 (cost or economic or pharmacoeconomic* or icer or utilization or hcru or length of stay).mp. or exp economics/ or exp economic aspect/ 3470664

14 (burden or observational or real world or cost of illness or cost effectiveness or cost utility or cost benefit or cost minimization or budget or systematic review or meta-analysis or metaanaly*).mp. 1864525

15 budget.mp. 5847116 14 or 15 186452517 12 and 13 and 16 14018 limit 17 to yr="2003 -Current" 11619 remove duplicates from 18 98

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Table S4: Inclusion criteria for clinical, economic and humanistic burden of rNMB

Inclusion Criteria

Population(s)

All patients undergoing any type of surgery and prescribed the following neuromuscular blocking (NMBa) agents

o atracuriumo cisatracuriumo doxacuriumo mivacuriumo pancuroniumo pipecuroniumo rocuroniumo tubocurarineo vecuroniumo succinylcholine (suxamethonium)o decamethonium

Interventions

NMB antagonists, including, but not limited to: o sugammadexo neostigmineo pyridostigmine

No NMB antagonistsComparators Same as interventions Outcomes (16+) rNMBb and Clinical Outcomes

rNMB as Quantitative Outcomes: Train of four (TOFc) ratio post-operative/at post-anaesthesia care unit

o rNMB based on TOF ratio using quantitative/qualitative method after surgeryo rNMB based on TOF ratio using quantitative/qualitative method at PACUo Time to NMB Recovery i.e. time for TOF ratio ≥ 0.9

rNMB as Qualitative Outcomes: Time (from NMB agent administration, NMB antagonist administration) to tracheal

extubation Length of stay in ORd

Readmission Time to PACU discharge / time to PACU discharge readiness Adverse events (AEse) (30 days post-operation; upon arrival at PACUf)

o residual neuromuscular block / post-operative residual curarization (PORCg)o Paino Cardiac disorders (atrial fibrillation, atrioventricular block, tachycardia, ventricular

fibrillation, myocardial ischemia, heart failure)o Immune disorderso Hypertension/Hypotensiono Respiratory disorders (laryngospasm, dyspnea, wheezing, pulmonary edema,

bronchospasm, pneumonia, atelectasis)o Nausea and vomiting

a Neuromuscular blockingb Residual NMBc Train-of-four ratiod Operation theatree Adverse events;f Post-Anesthesia care unitg Post-operative residual curarization

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Inclusion Criteriao Reintubation

Severe AEs (≤30 days post-operation OR upon arrival at PACU)o Pulmonary complications (pneumonia, atelectasis)o Respiratory failure and/or Ventilatory Failureo Anaphylaxis o Cardiac disorders (cardiac arrest, bradycardia)

rNMB and Economic Outcomes Healthcare resource utilization Direct costs of initial hospitalization and readmissions;

o All-cause medicalo Pharmacyo Inpatiento Post-Anaesthesia care unit (PACU)

Indirect costs ofo Caregivero Productivityo Absenteeism

ICERh

PACU, ICUi length of stay (LOSj) Hospital LOS

rNMB and Humanistic Outcomes Utility from patient reported survey / questionnaires Reported utilities from adverse events (AEs) and serious adverse events (SAEsk) Disutility Quality of life (cognitive, functional or pain scales) Neurological/sedation status (Glasgow Coma scale (GCSl)/ Ramsay scale)

Time Publications from 2003 and after Time period for outcomes post-operation – ≤ 30 days

Study design

Clinical studies (randomised or non-randomised, blinded or open-label) Observational studies Real world data including registries Systematic reviews or meta-analyses of RCTsm (for reference checking only)

Other Language: English only Countries: Global

h Institute for Clinical and Economic Reviewi Intensive care unitj Length of stayk Serious Adverse Eventsl Glasgow Coma scalem Randomized controlled trials

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Table S5. Studies not included in the meta-analysis

Study ID Blinding

N Randomize

d

N Complete

d

Population InterventionNMB

Monitoring Age ASA Surgical Procedures Country NMB Agent(s)

mg/kgNMB Antagonist

Comparison: NMB Agent vs. Other NMB Agents (without NMB Antagonist)

Gueret 2004** S 87 87 15 to 85 NR Cardiac surgery France ATRA; CIS None AMGMaybauer 2007** A+S+P 400 338 ≥ 18 I-III Elective abdominal surgery Germany CIS; ROC None AMGMurphy 2003** A 82 79 ≥ 18 NR Cardiac surgery US ROC; PAN None AMG

Comparison: NMB Agent vs. Other NMB Agent(s) (with NMB Antagonist)Choi 2016*** None 112 97 20 to 70 I-II Elective ear surgery Italy ROC; CIS NEO 0.01,

0.02, 0.04AMG

Ghosh 2006** A+S+P 240 240 ≥ 18 I-II Elective surgical procedures India PAN; ATRA; VEC

NEO 0.025-0.03

AMG

Sagir 2013** A+S+P 60 60 ≥ 60 II-III Elective abdominal surgery Turkey ROC; VEC, CIS NEO 0.05 AMGComparison: NMB Agent + NMB Antagonist vs. NMB Agent + Another Antagonist

Abdullatif 2018****

None 60 55 18-60 I-III Liver resection Egypt ROC SUG 2.0; NEO 0.05

KMG

Breuckmann 2015* A 154 154 ≥ 18 I-III Elective abdominal surgery Austria, Poland, Sweden ROC SUG 2.0-4.0; NEO 0.017-0.084

AMG

Flockton 2008** None 84 73 ≥ 18 I-III Elective surgical procedures European Countries ROC; CIS SUG 2.0; NEO 0.05

AMG

Koc 2012** None 33 33 18-65 I-III Elective surgical procedures Turkey ROC SUG 2.0; NEO 0.05

AMG

Pongracz 2013** A+S+P 80 75 18 to 65 I-III Elective surgical procedures Hungary ROC SUG 0.5, 1.0, 2.0; NEO 0.05

AMG

Woo 2014** A 128 118 > 18 I-III Elective surgical procedures Korea ROC SUG 2.0; NEO 0.05

AMG

Comparison: Doses of NMB AntagonistAmao 2012** A 86 77 ≥ 18 II-III Elective surgery with

pulmonary disease Canada, US ROC SUG 2.0,

4.0AMG

Drobnik 2010** A 91 89 18 to 64 I-II General anesthesia for surgery Europe ROC SUG 1.0, 4.0

AMG

Koo 2018** A+S+P 108 108 > 19 I-II TURBT South Korea ROC SUG 2.0, 4.0

AMG

Abbreviations:

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A: assessor of outcomes; AMG: acceleromyography; ASA: American Society of Anesthesiologist Physical Status; ATRA: atracurium; CIS: cis-atracurium; KMG: kinemyography; MMG: mechanomyography; NEO: neostigmine; NMB: neuromuscular blocking agents; NR: Not Reported; P: patient; PLA: placebo; ROC: rocuronium; SUG: sugammadex; S: surgeon; TURBT: Transurethral Resection of Bladder Tumor; UK: United Kingdom; US: United States; VEC: vecuroniumReason for excluding from the meta-analysis: * Outcome reported for mixed moderate and deep depth** TOFR<0.9 at a pre-specified timepoint not reported*** Not enough information provided to conduct analysis**** Timepoint not reported

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Table S6. Meta-analysis of rNMB incidence at PACU entry and timepoints after antagonist administration, base-case results

TOFRa < 0.9Sugammadex Neostigmine

Number of studies

Number of study arms

Pooled Incidence with 95% CIb

I2

(%)# of

studies# of study

armsPooled Incidence with

95% CII2

(%)

Moderate block

PACUc entry 2 5 0.3 (0.0, 2.8) 0.0 2 3 42.5 (6.7, 83.5) 94.52 min 3 3 19.2 (0.0, 57.8) 95.0 4 4 100 (98.9, 100) 0.03 min 3 3 11.2 (3.3, 22.4) 76.4 4 4 97.8 (94.7, 99.7) 32.24 min 2 2 9.9 (0.8, 25.9) 75.9 3 3 94.3 (82.7, 100) 80.15 min 4 4 2.6 (0.0, 8.8) 71.9 6 8 71.2 (54.5, 85.6) 88.96 min 2 2 2.8 (0.0, 16.7) 81.8 3 3 82.3 (71.4, 91.2) 60.210 min 3 4 0.7 (0.0, 5.2) 70.1 7 12 31.8 (18, 47.3) 90.415 min 2 2 2.8 (0.0, 16.7) 81.8 4 4 39.4 (12.3, 70.5) 93.920 min 2 2 2.1 (0.0, 12.5) 74.3 3 3 36.7 (4.8, 77.1) 96.230 min 3 4 0.5 (0.0, 3.9) 58.9 5 7 14 (4.5, 27) 88.460 min 2 2 2.1 (0.0, 12.5) 74.3 2 2 19 (5.1, 38.5) 75.8

Deep block

2 min 5 7 87 (71.9, 97.3) 84.6 3 3 100 (96.5, 100) 0.03 min 6 8 69.8 (47.1, 88.5) 92.3 3 3 100 (96.5, 100) 0.04 min 6 8 44.7 (18.9, 72) 93.9 3 3 100 (96.5, 100) 0.05 min 6 8 35.6 (10.9, 64.9) 95.6 3 3 100 (96.5, 100) 0.06 min 5 7 17.1 (3, 37.7) 90.3 3 3 100 (96.5, 100) 0.010 min 6 8 11.3 (1, 28.1) 89.1 3 3 100 (96.5, 100) 0.015 min 5 5 1.1 (0.0, 7.1) 69.5 3 3 99.1 (93.7, 100) 0.020 min 4 4 0.7 (0.0, 4.7) 47.1 3 3 99.1 (93.7, 100) 0.030 min 5 5 0.4 (0.0, 2.9) 40.5 3 3 95 (83.9, 100) 42.160 min 4 4 0.4 (0.0, 3) 14.7 4 4 39.3 (18.5, 62.3) 75.8

a Train-of-four ratiob Confidence Intervalc Post anesthesia care unit

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Table S7. Meta-analysis of rNMB incidence at PACU entry and timepoints after antagonist administration, sensitivity analysis results (restricted to rocuronium NMB)

TOFR < 0.9a

Sugammadex Neostigmine

# of studies # of study arms

Pooled Incidence with 95% CIb I2 (%) # of studies # of study

armsPooled Incidence

with 95% CI I2 (%)

Moderate block

PACUc entry 2 5 0.3 (0.0, 2.8) 0.0 2 2 22.7 (10.6, 37.4) 34.52 min 2 2 6.6 (0.0, 35.5) 89.9 3 3 100 (98.6, 100) 0.03 min 2 2 7.6 (3.9, 12.3) 0.0 3 3 98.5 (96.2, 99.9) 0.04 min 1 1 4.3 (0.1, 12.4) NA 2 2 95.9 (76.6, 100) 89.15 min 2 3 0.7 (0.0, 2.8) 0.0 3 4 80.2 (73.3, 86.4) 36.46 min 1 1 0 (0.0, 3.6) NA 2 2 79.5 (64.1, 91.6) 68.8

10 min 2 3 0 (0.0, 0.8) 0.0 5 6 38.5 (23.8, 54.2) 85.415 min 1 1 0 (0.0, 3.6) NA 3 3 29 (5.4, 60.6) 92.020 min 1 1 0 (0.0, 3.6) NA 2 2 24 (0.0, 72.8) 96.430 min 2 3 0 (0.0, 0.8) 0.0 4 5 10.3 (3, 20.9) 81.360 min 1 1 0 (0.0, 3.6) NA 1 1 11.1 (3.3, 22.2) NA

Deep block

2 min 4 6 90.3 (73.7, 99.7) 85.1 2 2 100 (95.4, 100) 0.03 min 5 7 73.1 (47.2, 93.1) 93.0 2 2 100 (95.4, 100) 0.04 min 5 7 46 (15.3, 78.3) 94.8 2 2 100 (95.4, 100) 0.05 min 5 7 35.5 (7.7, 69.5) 96.1 2 2 100 (95.4, 100) 0.06 min 4 6 15.4 (0.8, 39.6) 90.9 2 2 100 (95.4, 100) 0.0

10 min 5 7 10 (0, 29.4) 89.9 2 2 100 (95.4, 100) 0.015 min 4 4 0 (0, 1.3) 0.0 2 2 98.4 (90.9, 100) 0.020 min 3 3 0 (0, 1.5) 0.0 2 2 98.4 (90.9, 100) 0.030 min 4 4 0 (0, 0.9) 0.0 2 2 91 (78.7, 98.9) 14.360 min 3 3 0 (0, 1.5) 0.0 3 3 40.6 (13.1, 71.5) 83.7

Train-of-four ratiob Confidence Intervalc Post anesthesia care unit

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