Conditions: Kidney Transplant; Complications Postoperative Residual Curarization Postoperative Residual Weakness
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 84
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare two medications that reverse muscle paralysis at the end of kidney transplant surgery with the goal of reducing residual muscle weakness and insufficient respiratory function after surgery.

Detailed description:
This is a prospective randomized double-blind single center study on patients with severe kidney failure undergoing kidney transplantation surgery. Patients will have their muscles paralyzed during general anesthesia for surgery. At the end of surgery, muscle paralysis will be reversed with either neostigmine (control group) or sugammadex (intervention group). Residual muscle weakness and respiratory function will be monitored after surgery with a quantitative train-of-four (qTOF) monitor and a noninvasive continuous ventilation monitor. The investigators hypothesize that patients receiving sugammadex will have less residual muscle weakness and better respiratory function than patients receiving neostigmine. Respiratory and kidney function parameters and any adverse events will be collected during the hospital stay. Patients will contacted for a study follow up around 2 weeks after their surgery.

Arms:
arm 1: Sugammadex arm 2: Neostigmine

Interventions: intervention 1: Sugammadex intervention 2: Neostigmine
Intervention descriptions: intervention 1: Administration of Sugammadex intravenously at a dose appropriate for the reversal of neuromuscular blockade (usually 2-4 mg/kg) at the end of the surgery before tracheal extubation intervention 2: Administration of Neostigmine intravenously at a dose appropriate for the reversal of neuromuscular blockade (usually 0.03-0.07 mg/kg) at the end of the surgery before tracheal extubation

Protocol document:
Prot_SAP_000.pdf: 
 
COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490 TELEPHONE: 303-724-1055 Fax: 303-724-0990 
 
Protocol #: 18-2707 
Project Title: 
A double-blind, randomized, parallel study to compare the efficacy of sugammadex 
versus neostigmine for reversal of neuromuscular blockade at the end of kidney 
transplantation surgery in patients with severe kidney dysfunction. 
Principal Investigator: Ana Fernandez-Bustamante M.D., Ph.D. 
Version # and Date: #3 – 09/18/2020 
 
Hypotheses and Specific Aims 
Clinical Hypotheses 
Sugammadex, compared to neostigmine, reduces inadequate neuromuscular blockade reversal (NMBR) 
and its related hypoventilation, as measured by reducing the frequency of patients with one or more 
episodes of hypoventilation, by at least 50% during the first 3h after the end of kidney transplantation 
surgery (or until meeting discharge criteria from the PACU if sooner than 3h) after adjusting for 
quantitative train-of-four (qTOF) T4/T1 monitoring and morphine equivalents received. Hypoventilation 
events are defined by the presence of ³1 minute-long events of minute ventilation (MV) <40% of the 
expected MV for each patient (expMV). 
Sugammadex, compared to neostigmine, reduces inadequate NMBR and its related hypoventilation, as 
measured by reducing the frequency of patients with one or more episodes of hypoventilation, by at least 
50% for up to 3 days after kidney transplantation surgery after adjusting for qTOF T4/T1 monitoring and 
morphine equivalents received. 
Our overall hypothesis is that sugammadex will provide improved NMBR and postoperative ventilation 
than neostigmine. Prevention of hypoventilation with sugammadex may contribute to reduce patient’s 
reported dyspnea scores (PROMIS® Dyspnea Functional Limitation questionnaire scores), decrease 
PPCs possibly related to inadequate NMBR after kidney transplantation surgery (i.e. respiratory 
insufficiency, gastric aspiration, pneumonia), improve kidney graft outcomes, reduce hospital resources 
utilization and estimated healthcare costs. A study powered to test these as a hypothesis would require a 
substantially larger sample size and it may be pursued in the future. 
 
Objectives 
 
Primary objective: To test the efficacy of NMBR with sugammadex, compared to neostigmine, to reduce 
inadequate NMBR and its related hypoventilation during the immediate postoperative period after kidney 
transplantation surgery, after adjusting for qTOF recovery and morphine equivalents received. We define 
hypoventilation as the incidence of ³1 minute-long events of MV <40% of expMV. Minute ventilation will 
be measured continuously with a noninvasive respiratory volume monitor for the first 3h after the end of 
surgery or until meeting discharge criteria from the post-anesthesia care unit (PACU) (if sooner than 3h). 
 
Secondary objective: To test the efficacy of NMBR with sugammadex, compared to neostigmine, to 
reduce inadequate NMBR and its related hypoventilation during the first 3 postoperative days in patients 
after kidney transplantation surgery, after adjusting for qTOF recovery and morphine equivalents 
received. We define hypoventilation as the incidence of ³1 minute-long events of MV <40% of expMV. 
Minute ventilation will be measured continuously with a noninvasive respiratory volume monitor for up to 
3d after surgery or until meeting end of monitoring criteria (if sooner than 3d) 
 
Additional secondary objectives: To test if NMBR with sugammadex, compared to neostigmine, reduces 
patient’s reported dyspnea scores (with the validated Patient-Reported Outcomes Measurement 
Information System, PROMIS®, assessment), decreases postoperative pulmonary complications (PPCs) 


possibly related to inadequate NMBR after kidney transplantation surgery (i.e. respiratory insufficiency, 
gastric aspiration, pneumonia), improves kidney graft outcomes and reduces hospital resources utilization 
(i.e. hospital length of stay, ICU admission) and estimated healthcare costs. 
 
II. Background and Significance/Preliminary Studies: 
 
Inadequate neuromuscular blockade reversal (NMBR) leads to different degrees of residual muscle 
weakness at extubation and during the post-anesthesia care unit (PACU) in up to 70% of patients[1-3]. 
Estimates of inadequate NMBR depends on the methods of diagnosis and definitions used (i.e. 
quantitative vs. qualitative TOF, T4/T1 threshold), surgery type, and patient comorbidities. Even mild 
incomplete NMBR (e.g. T4/T1 0.7-0.8) impairs ventilatory compensation to hypoxia and coordination of 
the upper airway muscles[4-6]. Therefore it increases the risk for postoperative atelectasis, aspiration, 
and pneumonia[7-9]. The use of any NMB agent, lack of TOF monitoring or NMBR administered, and 
NMBR with neostigmine, as opposed to NMBR with sugammadex, are strongly associated with PPCs. 
These PPCs include mild (e.g. atelectasis, lung edema, hypoxemia requiring oxygen supplementation) 
and major complications (e.g. pneumonia, re-intubation)[7, 10-12]. Mild PPCs (e.g. atelectasis) are often 
underestimated, but we have recently shown their association with worse clinical outcomes[13]. In this 
multicenter study in American Society of Anesthesiologists (ASA) class 3 patients undergoing non- 
cardiothoracic surgery, mild PPCs (including atelectasis) were associated with increased early 
postoperative mortality, ICU admission and hospital stay[13]. However, the existing data on the 
association between inadequate NMBR and quantitative assessment of ventilation is scarce. Only one 
study[14] analyzed respiratory muscle weakness after either sugammadex or placebo with pulmonary 
function tests (maximum inspiratory and expiratory pressures, forced vital capacity and forced expiratory 
volume in 1 second). Pulmonary function tests are certainly quantitative but depict the pulmonary function 
at only one time point[14]. Respiratory function during the first hours after general anesthesia is 
influenced by a series of factors, from residual NMB to sedation by residual anesthetics and opioid 
analgesics, pain-induced hypoventilation, respiratory obstruction due to sleep apnea, and others. In fact, 
patients with severe kidney dysfunction present an increased risk to the respiratory depression induced 
by opioids due to their reduced pharmacokinetic elimination[15]. The diagnosis of respiratory depression 
in the PACU routinely depends on the development of hypoxemia, even though this is a well-known late 
sign of hypoventilation. There is increasing evidence suggesting the value of continuous noninvasive 
quantitative expiratory volume monitoring in patients at increased risk for multifactorial hypoventilation[16- 
20]. Investigators have reported up to 76% of patients after general anesthesia present at least one 
hypoventilation event, defined as a ³1 minute-long episode of minute ventilation (MV) <40% of expected 
(expMV) for the patient’s age, gender, height and weight or body surface area[21]. The effect of 
sugammadex on the quantitative assessment of hypoventilation in postoperative patients adjusted for 
TOF monitoring or opioid consumption has not been evaluated. 
 
There is insufficient information on the use of sugammadex for NMBR in patients with kidney dysfunction. 
The clearance of sugammadex is proportional to creatinine clearance (ClCr), and thus delayed with 
kidney dysfunction[22-25]. However, no safety adverse events related to inadequate NMBR or delayed 
recurrence of NMB have been observed in patients with kidney dysfunction receiving sugammadex[26]. 
Nonetheless, patients with kidney impairment often receive the cholinesterase inhibitor neostigmine for 
NMBR. Neostigmine provides a slower and less effective NMBR than that achieved with sugammadex in 
the overall population, and its overdose is itself associated with increased muscle weakness[3, 10, 27-31] 
and postoperative pulmonary morbidity[1, 12]. It is critical to investigate the effect of sugammadex as 
NMBR in patients with kidney dysfunction. 
Thus, we are proposing to randomize patients with severe kidney dysfunction (ClCr <30 mL/min) 
undergoing kidney transplantation surgery to receive either NMBR with sugammadex (intervention) or 
neostigmine (control) following qTOF monitoring-guided and FDA-approved doses. Despite their severe 
kidney disease these patients are receiving a kidney transplantation surgery. The exact kidney function 
during the first hours after reperfusion of the graft kidney in the receiving patient is unknown. Thus the 
clearance and duration of effect of sugammadex in kidney transplant recipients during the early 
postoperative period is unknown but relevant. Their kidney function is expected to improve over the 
following days to months after transplant, and considered stable 6-12 months after transplant. 


III. Research Methods 
 
A. Outcome Measure(s) 
 
The primary outcome will be the frequency of patients with one or more ³1 minute-long episodes of 
hypoventilation within 3 hours after the end of surgery or until meeting discharge criteria from the 
PACU (if sooner than 3h), assessed with a continuous noninvasive respiratory volume monitor that 
will be blinded to care providers. 
 
Additional outcomes will include: intraoperative minutes from NMBR administration to qTOF T4/T1 
>0.9, to extubation, and total in operating room time; incidence of residual NMB in PACU based on 
qTOF; number of events and accumulated minutes of hypoventilation in PACU; frequency of patients 
with ³1 events of delayed postoperative hypoventilation (daily for up to 3 postoperative days) and 
accumulated minutes of hypoventilation; delayed recurrence of NMB based on qTOF; presence of 
pre-defined postoperative pulmonary complications during hospital stay and by the postoperative day 
14±3; standardized Patient-Reported Outcomes Measurement Information System (PROMIS®) 
dyspnea functional limitations questionnaire score compared to patient’s baseline; pre-defined kidney 
graft outcomes; hospital resources utilization (e.g. hospital length of stay, ICU admission) and their 
cost estimates. 
 
B. Description of Population to be Enrolled 
We will include adults (³ 18 years and ≤ 90) diagnosed with severe kidney dysfunction (defined by 
plasma creatinine clearance <30 mL/min) and planning on kidney transplantation surgery at the 
University of Colorado Hospital. Exclusion criteria: patients unable to sign the informed consent, 
pregnant women, Body Mass Index (BMI) > 40, pre-existing oxygen or ventilatory dependency (24h 
use of oxygen or other noninvasive or invasive ventilatory support), or patients with any pulmonary, 
neuromuscular or other disease that severely limits their respiratory functional status (e.g. unable to 
achieve 4 Metabolic Equivalent of Tasks, METs, such as climbing up 1 flight of stairs[32]), or any 
contraindication for any of the study-related medications or interventions. 
C. Study Design and Research Methods 
We have designed a prospective randomized double-blind single center study on 100 patients with 
severe kidney failure undergoing kidney transplantation surgery. Patients will be randomized to 
receive either NMB with rocuronium and sugammadex for NMBR (intervention group) or NMB with 
rocuronium and neostigmine for NMBR (control group). Respiratory function will be objectively 
monitored starting in PACU and during the first 3 postoperative days or until end of monitoring criteria 
are met. A blinded assessor will record the frequency of hypoventilation events as well as the 
accumulated minutes of hypoventilation. Quantitative TOF monitoring will be evaluated by a blinded 
investigator. Additional data related to patient’s comorbidities, morphine equivalents (mg/kg) received, 
validated dyspnea patient-reported scores, pulmonary complications, kidney graft relevant data and 
outcomes, and hospital resource utilization and estimated costs will also be collected. 
After signing informed consent, patients will be randomized to receive, during kidney transplant 
surgery, NMB with rocuronium and NMBR with either sugammadex (intervention group) or 
neostigmine (control group). Both groups will receive intraoperative NMB agents and reversal 
medications as guided by qTOF monitoring and following FDA-approved doses (see details below). In 
the PACU, we will perform continuous monitoring of their MV during their PACU stay and assess 
qTOF at selected time points in all patients. Institutional discharge criteria from PACU is based on an 
Aldrete’s score[33] ³8 assuming there are no discharge concerns by the patient’s healthcare 
providers (PACU nurse, anesthesiologist and/or surgeon). After discharge from PACU and during the 
first 3 postoperative days (or until end of monitoring criteria if sooner) we will maintain the continuous 
MV monitoring and daily quantitative TOF assessment, collect opioids received and data relevant to 
pulmonary complications, kidney graft outcomes and estimated healthcare costs. At the postoperative 
surgery clinic visit or by phone interview we will collect patient’s subjective dyspnea scores and 
compare to their baseline (with a validated questionnaire), as well as updated PPCs, kidney graft 
outcomes, hospital resources utilization and estimated healthcare costs. 
 


Patient scheduled, screened
Consent obtained
Quant TOF 
monitoring-guided
rocuronium/
sugammadex
Randomization
Control
Intervention
Preop 
clinic
Operating Room
Hospital
Data collection: comorbidities, PROMIS® 
dyspnea questionnaire
Quant TOF 
monitoring-guided
rocuronium/ 
neostigmine
PACU
f/u call 
or clinic
Last daily monitoring 
(Postop Day 3 or sooner if end of monitoring criteria met)
Outcomes 
•PROMIS® dyspnea questionnaire
•Postoperative pulmonary complications, kidney outcomes
•Hospital resources utilization and estimated cost
Postop Day 14±3
•Quant TOF (selected time 
points)
•Continuous noninvasive 
blinded monitoring of minute 
volume ventilation 
Data collection
• Time NMBR dosing-to-T4/T1 >0.9
• Time NMBR dosing-to-extubation
• Total OR time, medications, fluids, etc.
Outcomes
•Freq of hypoventilation in 
PACU (primary) (events with 
≥1min of MV <40% of expMV)
•Incidence of residual NMB 
(quant TOF T4/T1 < 0.9)
•Accumulated events/minutes 
of hypoventilation
•Same outcomes as above, 
2/day


Preoperative phase 
Screening for eligibility and consenting will take place once the patient has been accepted for 
kidney transplantation at the University of Colorado Hospital by the Transplant Surgery team. 
Randomization will occur after patients consent for the study. Only the PI will remain unblinded to 
the group allocation (see below). 
Preoperative data will be collected by the blinded investigator (study coordinator), including 
baseline vital signs (including room air SpO2), comorbidities, medications, and kidney graft 
relevant factors. The baseline dyspnea scores will be assessed by asking patients to complete 
the PROMIS® v1.0 Dyspnea Functional Limitations Short Form 10a_9-2-2016 questionnaire 
(available at 
http://www.healthmeasures.net/administrator/components/com_instruments/uploads/PROMIS%2 
0SF%20v1.0-Dyspnea%20Functional%20Limitations%2010a_9-2-2016.pdf). This is a validated 
and standardized short questionnaire to quantitate if sugammadex used for NMBR reduces the 
subjective dyspnea scores relative to baseline. 
 
 
Intraoperative phase 
 
We will perform a prospective parallel randomized study of rocuronium/sugammadex 
(intervention) vs. rocuronium/neostigmine (control) for NMB and NMBR at the end of kidney 
transplantation surgery. This will be performed by the unblinded investigator, following the 
following protocol(s): 
 
• 
A quantitative TOF (qTOF) monitor (the Stimpod NMS450®, Xavant Technology Ltd., South 
Africa, the acceleromyography-based monitor available at UCH, and/or the TwitchViewTM, 
Blink Device Company, Seattle, WA, an electromyography-based monitor) will guide the NMB 
and NMBR management in all study patients. Quantitative NMB monitoring are considered 
superior to the more routinely-used but subjective qualitative TOF monitors[34, 35]. The 
qTOF monitor will be placed in the ulnar nerve territory to stimulate the adductor pollicis 
muscle[36] immediately after loss of consciousness during induction of anesthesia. The exact 
location of monitoring will be marked and used for qTOF measurements in the postoperative 
period. 
• 
NMB brief protocol: Rocuronium will be the NMB agent used in both groups as guided by the 
qTOF and following standard dosing protocols in order to achieve adequate NMB to allow the 
intubation and surgical procedure (routinely T4/T1 <T3 until closure of surgical incision). 
Rocuronium dosing: 0.6-1.2 mg/kg for intubation, 0.08-0.2 mg/kg bolus for maintenance with 
recovery of second twitch (T2) in qTOF. 
• 
NMBR brief protocol: The sugammadex (intervention) or neostigmine (control) will be 
administered at the end of the surgery. The goal will be to administer the appropriate NMBR 
medication when ³2 twitches are objectivized with the qTOF monitor. NMBR drugs and 
dosing for each group will follow standard of care FDA-approved doses, as follows: 
Sugammadex 2 mg/kg will be administered when spontaneous recovery has reached the 
reappearance of the second twitch in response to TOF stimulation. 
 
Sugammadex dosing 
(mg/kg) 
Neostigmine dosing (mg/kg) 
T4 recovered 
2 
0.03-0.05 (max 5 mg) 
T2/T3 recovered 
2 
0.05-0.07 (max 5 mg) 
T0/T4 with 1-2 post- 
tetanic twitches 
present or T1 
recovered 
 
4 or wait 
 
Wait 
Overdosing of neostigmine will be avoided to prevent neostigmine-induced muscle weakness. 
Neostigmine will be administered simultaneously with the appropriate glycopyrrolate dose (0.2 
mg per 1.0 mg of neostigmine). 


Extubation will be performed following the usual standard of care criteria of adequate level of 
consciousness, presence of airway protection reflexes and spontaneous ventilation parameters 
in addition to quantitative TOF T4/T1 >0.9. The following times (minutes) will be recorded: 
NMBR administration-to-T4/T1 >0.9, NMBR administration-to-extubation, total operating room 
time. 
Postoperative in-hospital phase 
The blinded investigator will collect the following study-related information: 
• 
Continuous respiratory volume monitoring: From the moment of arrival to the PACU, the 
patient will be continuously monitored with the FDA-approved noninvasive respiratory volume 
monitor ExSpiron® (Respiratory Motion, Inc.) available at UCH. This electrical impedance- 
based monitor uses a sensor that is applied to the chest’s skin at three pre-determined 
locations: sternal notch, xyphoid and right mid-axillary line at the level of the xyphoid. By 
monitoring the thoracic impedance to a high frequency current it continuously assesses the 
estimated volume between three thoracic points of reference. It provides 5-second updates of 
average respiratory rate, tidal volume and MV volume (= respiratory rate * tidal volume). 
Calibration is no longer required, but it requires the user to enter some patient’s information 
(gender, and height + weight, or body surface area) for the mathematical calculation of tidal 
volume and minute volume for that particular patient. By calculating the expected minute 
volume (expMV = tidal volume times respiratory rate) based on patient’s characteristics it 
provides the option to compare the observed estimated MV and detect hypoventilation 
events. The settings of hypoventilation events are customizable by duration and the percent 
of expected MV below which the MV is observed. This monitor will be blinded to healthcare 
providers to avoid biasing routine standard of care. Continuous data from this monitor 
(respiratory rate, tidal volume and MV volume) are automatically stored and will be exported 
at the end of PACU and daily for up to 3 days or sooner if the patient fulfills the following end 
of monitoring criteria: is discharged from the hospital; or is freely ambulating (defined as 
patient walking outside of the hospital room ³2 times a day) and shows no signs or symptoms 
of respiratory complications, swallowing problems or muscle weakness. While attached to the 
monitor, this will be secured to a wheeled pole to facilitate the process for patient mobilization 
and ambulation. Once the respiratory volume data is exported, we will measure the incidence 
of hypoventilation as defined below (primary outcome) during PACU and daily for up to 3 
postoperative days, as well as characterize the distribution of respiratory volume parameters 
(average, median, percentiles) during PACU and daily for up to 3 postoperative days. 
• 
The blinded investigator will assess the presence of residual NMB with the quantitative TOF 
monitor by calculating the average of 3 measurements of qTOF T4/T1 (40mA or adequate to 
achieve TOF response while comfortable for the patient) within 15min of PACU arrival and 
hourly until up to 3h after the end of surgery or sooner if the patient meets PACU discharge 
criteria. We will record the initial PACU TOF and calculate the PACU average TOF. After 
transfer to the postoperative floor, the blinded investigator will assess residual or recurrent 
NMB with the qTOF monitor twice a day, with 3 repetitions each time, and each assessment 
separated by ³6h. This will be maintained for up to 3 days after the end of surgery or until 
end of monitoring criteria are met. 
• 
The individual doses of administered opioids received by the patient during the study (PACU 
and daily for up to 3 postoperative days or until the end of monitoring criteria are met) will be 
recorded and converted to morphine equivalents[21] to statistically evaluate the effect of 
opioid administration on hypoventilation events. 
• 
Nursing-charted episodes of respiratory depression during the PACU stay will also be 
recorded. Postoperative pulmonary complications (as defined elsewhere[13]) during PACU 
and up to 3 postoperative days will be collected. 
 
Postoperative end of study follow-up 
At postoperative day 14±3 during the patient’s visit to the transplant surgery clinic or via a phone 
call, the PROMIS® Dyspnea Functional Limitations Short Form questionnaire will be repeated 


and normalized to the patient’s baseline. Any postoperative pulmonary complications[13] and 
hospital resources utilization occurring from the hospital discharge until this end of study follow-up 
will be collected from the patient and the medical record, and the estimated costs based on 
average hospital daily stay depending on type of care unit or reported cost of complications 
calculated. 
Any signs and symptoms of hypersensitivity (e.g. rash, anaphylaxis) detected during PACU and 
up to 3 postoperative days will be collected from the patient and patient’s providers. The 
relationship of these signs and symptoms to sugammadex will be assessed by the patient’s 
providers and also by the study safety officer. Their confirmatory diagnostic testing and 
management will be performed at the discretion of the patient’s providers. 
We hypothesize that the intervention group will present a ³50% reduction in the incidence of 
hypoventilation for the first 3h after the end of kidney transplantation surgery or until meeting 
discharge criteria from the PACU (if sooner than 3h), as defined by the incidence of ³1 minute- 
long events of observed MV of <40% of expMV detected with a noninvasive respiratory volume 
monitor after adjusting for qTOF T4/T1 and morphine equivalents received. 
 
 
Tele-communication for screening, e-consenting and any eligible study-related visits 
 
In line with current efforts to minimize face-to-face contact with potential candidates and/or study 
participants in response to the COVID-19 pandemic, we will maximize when possible HIPPA- 
compliant methods of tele-communication for any study-related tasks. HIPPA-compliant 
applications (i.e. REDCap, Qualtrics, MS Office, Zoom, Skype, or Vidyo) will be used for 
prospective study participants for electronic screening, consenting and any eligible study-related 
visits. The first goal of tele-communication with eligible candidates is to provide a detailed 
overview of the study protocol and consent form to be signed by study participant and PI (or 
research study staff). 
 
a. 
After subject screening, a phone call will be made to introduce the purpose of the study 
and to request prospective study participation, upon verbal consent, a personal e-mail 
address will be requested. 
 
b. 
After phone call, consent study forms in .pdf format will be sent via e-mail to prospective 
study participant with a follow up 30-minute video meeting request. 
 
c. 
During 30-minute video meeting, detailed e-consent guidance will be provided to 
prospective study participant. 
 
d. 
Participant will document and sign informed consent electronically or by printing the 
consent form, signing with pen, and then scanning and emailing back to study team. 
After signed informed consent, all study-related visits will be evaluated for possible use of tele- 
communication. The study intervention during surgery and those postoperative in-hospital visits to 
assess respiratory function and residual NMB are not eligible for tele-communication, but all other 
visits for data collection from the participant (e.g. PROMIS questionnaires, end-of-study follow-up) 
will be attempted via tele-communication as described above. 
 
D. Description, Risks and Justification of Procedures and Data Collection Tools: 
• 
Insufficient neuromuscular blockade reversal (NMBR): Insufficient neuromuscular 
blockade reversal at the end of surgery can lead to postoperative complications related to 
neuromuscular weakness. Complications due to insufficient NMBR range from mild 
subjective sensation of muscle weakness and up to respiratory failure requiring reintubation 
and mechanical ventilation, including problems with swallowing, speech or vision, airway 
aspiration of gastric contents, hypoventilation and increased requirement of oxygen 
supplementation and pneumonia. The use of sugammadex in this population with severe 


kidney disease has not been sufficiently studied but previous small studies have not 
observed early or delayed events of insufficient NMBR in patients with severe kidney 
disease. The long-term goal of this study is to reduce insufficient NMBR after kidney 
transplant surgery, and its contribution to hypoventilation and other complications. 
• 
Adverse effects related to NMBR agents, including sugammadex (intervention 
patients) and neostigmine (control patients): The most common adverse effects to 
sugammadex include: nausea, vomiting, pain, hypotension and headache. The most 
common adverse effects for neostigmine include: salivation, fasciculation, bowel cramps and 
diarrhea. A recent Cochrane systematic review with meta-analysis and trial sequential 
analysis found that the overall risk of adverse effects, including residual NMBR, 
nausea/vomiting and bradycardia is lower for sugammadex than for neostigmine, and the risk 
of severe adverse reactions is similar after sugammadex and neostigmine[30]. 
• 
Local skin irritation to respiratory volume sensor. The ExSpiron sensor has three 
electrode pads to be placed against the patient’s skin at the sternal notch, xiphoid and right 
mid-axillary line at the level of the xiphoid. The risk of this bio-impedance-based monitor is 
minimum, with some possible irritation of the skin in susceptible patients. This monitor has 
been used with no adverse events[16-21, 37, 38]. 
• 
Discomfort during neuromuscular blockade monitoring: Monitoring of NMB with a Train- 
Of-Four (TOF) monitor consists of provoking muscle twitches that can be uncomfortable in 
awake patients, proportionally to the amplitude of the electrical signal used. In awake the 
TOF monitoring is usually well tolerated at 30-40 mA, which is the amperage we are planning 
on using. This has been used without problems by us and others[3, 29, 39], but we will 
reduce the amperage if uncomfortable for a study patient. 
• 
Risk to privacy: There is a small risk of loss of privacy of confidential data collected from 
study participants. We will collect the minimum patient information required for the study and 
use RedCap for data collection and storage. The paper copies of study data and the 
electronic master file will be stored behind locked doors in the PI’s office and protected by the 
security measures established by the University of Colorado network. 
 
E. Potential Scientific Problems: 
 
This study has been designed to detect differences in the incidence of hypoventilation (primary 
outcome) but the sample size may be insufficient to detect differences in clinically relevant 
complications secondary to hypoventilation. Such a study would require a larger study sample. 
 
F. Data Analysis Plan: 
 
The investigator and statistician will be responsible for analyzing the study data. The PI will be 
unblinded in order to follow the intraoperative study protocol. The study coordinator will be blinded 
to the randomization allocation, and will be responsible for performing the preoperative (baseline) 
and postoperative assessments. The official clinical database will not be unblinded until the data 
is clean and complete and the last independent safety review has been performed, and the study 
database is locked. The groups will be blindly labeled in the study website and only the PI and the 
safety review monitor will have access to the group codes. 
 
Variables/Time Points of Interest 
 
Frequency of patients with one or more episodes of hypoventilation events in PACU (primary 
outcome). This will be obtained from the noninvasive respiratory monitor that provides a continuous 
assessment of the patient’s respiratory rate, tidal volume and minute volume. This continuous 
monitoring will be performed continuously during the PACU stay. When meeting PACU discharge 
criteria based on institutional standard of care (based on an Aldrete’s score[33] ³8 with patient’s 
nurse and anesthesiologist agreement and no surgical concerns), the every 5-second information 
will be exported, and the periods with MV <40% of expMV for that patient that last ³1 minute will 


be identified and counted. For the primary outcome patients will be classified as presenting or not 
at least one event of hypoventilation, summarized per group and compared. 
 
Frequency of patients with one or more episodes of hypoventilation events daily for 3 first 
postoperative days or sooner if patient meets end of monitoring criteria. Similar as before, 
hypoventilation will be assessed once daily for up to 3 days, or less if the patient is discharged 
from the hospital or is freely ambulating (ambulates outside of the hospital room ³2 times a day) 
with no signs or symptoms of respiratory complications. 
 
Additional assessments of hypoventilation (e.g. accumulated minutes of hypoventilation) will be 
performed during PACU and daily for up to 3 postoperative days. 
 
Incidence of residual or recurrent NMB in PACU. This will be determined from the quantitative 
TOF measurements and calculated as the average qTOF T4/T1 at 40 mA from 3 repetitions at 
selected time points: 15min after arrival to PACU, hourly and before transfer to floor. A patient will 
be classified as presenting an episode of residual NMB if the average T4/T1 at any time point 
during PACU is <0.9. In addition, a percentage of timepoints with an average T4/T1 <0.9 will be 
analyzed as an accumulated time with residual or recurrent NMB. This variable will be used as 
covariate in the logistic regression analysis (see below). An average TOF of 3 repetitions <0.4 will 
be considered a severe residual or recurrent NMB. Patient’s safety will be prioritized and thus an 
average TOF of 3 repetitions <0.9 will be immediately reported to the patient’s care team in 
addition to following the appropriate study regulatory safety communications of adverse events. 
 
Incidence of residual or recurrent NMB in the postoperative floor. This will be calculated as 
described before (T4/T1 <0.9, considered severe if T4/T1 <0.4), as an average of 3 repetitions 
obtained on two occasions separated by ³6h daily on postoperative days 1-3 or until the end of 
monitoring criteria have been met. 
 
Morphine equivalents will be calculated from individual opioid doses administered to each patient 
following standard conversion formulas[21, 40]. This morphine equivalent dose will be calculated 
for the PACU period and daily for 3 first postoperative days or until the end of monitoring criteria 
have been met, and used as covariate in the logistic regression analysis. 
 
Time from NMBR administration to quantitative TOF T4/T1 >0.9 (minutes, one decimal). The 
quantitative TOF will be repeated at 80 mA every 30 seconds from the moment the NMBR 
medication (sugammadex or neostigmine) has been completely administered intravenously. 
 
Time from NMBR administration to extubation (minutes, once decimal). 
 
Time of total operating room time (minutes), counting from in-room time stamp to out-of-room 
time stamp. 
 
The PROMIS® v1.0 Dyspnea Functional Limitations Short Form 10a_9-2-2016 questionnaire is a 
validated and standardized short questionnaire to quantitate if sugammadex used for NMBR 
reduces the subjective dyspnea scores relative to baseline. It will be completed by the patient in 
the preoperative phase and during the postoperative follow up. It is available at 
http://www.healthmeasures.net/administrator/components/com_instruments/uploads/PROMIS%2 
0SF%20v1.0-Dyspnea%20Functional%20Limitations%2010a_9-2-2016.pdf). 
 
 
Postoperative Pulmonary Complications (PPCs) following previous definitions[13, 41, 42], 
including: 
 
Respiratory Failure, defined as[41]: “When postoperative PaO2 <60mmHg on room air, a ratio 
of PaO2 to inspired oxygen fraction <300 or arterial oxyhemoglobin saturation measured with 
pulse oximetry (SpO2) <90% and requiring oxygen therapy”. 


Unplanned intubation with postoperative mechanical ventilation (POMV), defined as placement 
of a breathing tube that was not intended or planned, excluding instances of intubation during 
an unplanned return to the operating room. Also excluded those patients that were transferred 
intubated and ventilated to the intensive care unit (ICU) from the operating room. 
 
ARDS, based on the Berlin definition[43] 3 mutually exclusive categories of ARDS based on 
degree of hypoxemia: mild (200 mmHg < PaO2/FIO2 ≤ 300 mmHg), moderate (100 
mmHg < PaO2/FIO2 ≤ 200 mmHg), and severe (PaO2/FIO2 ≤ 100 mmHg) and 4 ancillary 
variables for severe ARDS: radiographic severity, respiratory system compliance (≤40 mL/cm 
H2O), positive end-expiratory pressure (≥10 cm H2O), and corrected expired volume per minute 
(≥10 L/min). 
 
Pneumonia – or “Respiratory infection” as defined per NSQIP criteria[42]: “having at least 1 
definitive chest radiologic examination and at least 1 sign of pneumonia (fever, leukocytosis, or 
altered mental status with no other cause), as well as at least 1 microbiologic laboratory finding 
(positive cultures from blood, bronchoalveolar lavage, or pleural fluid specimens) or at least 2 
symptoms (purulent sputum, worsening cough, dyspnea or tachypnea, rales or rhonchi, or 
worsening gas exchange)”. 
 
Pneumothorax defined as in: “Air in the pleural space with no vascular bed surrounding the 
visceral pleura”. 
 
Atelectasis, defined as[41]: “Lung opacification with a shift of the mediastinum, hilum, or 
hemidiaphragm toward the affected area, and compensatory overinflation in the adjacent 
nonatelectatic lung” (based on radiology reports/medical chart). 
 
Pleural effusion, defined as[41]: “Chest x-ray demonstrating blunting of the costophrenic angle, 
loss of the sharp silhouette of the ipsilateral hemidiaphragm in upright position, evidence of 
displacement of the adjacent anatomical structures, or (in the supine position) a hazy opacity in 
one hemithorax with preserved vascular shadows“ (based on radiology reports/medical chart). 
 
Bronchospasm, defined as: “Presence in medical chart of bronchospasm and/or wheezing plus 
the use of bronchodilators (not bronchodilators alone)”. 
 
These pulmonary complications will be identified with information obtained directly from the patient’s 
medical chart. All testing will be performed by and at the discretion of the patient’s physicians. No 
tests will be ordered specifically for this clinical study. The clinical severity of pulmonary and non- 
pulmonary complications will be graded following accepted scales[44, 45]. 
 
Kidney graft outcomes, including postoperative ClCr, daily urine output, need for dialysis 
postoperatively, diagnosis of delayed graft function, kidney graft rejection. Postoperative hemodialysis 
is not usually planned and typically reserved for patients with immediate donor graft failure who 
exhibit signs of congestive heart failure within the first week after transplantation. The need of rescue 
hemodialysis within the first week after kidney transplantation is an accepted and simple definition of 
delayed kidney graft function[46]. 
 
Hospital resources utilization: hospital floor length of stay (LOS) (days, rounded to half a day), ICU 
admission and LOS, estimated cost based on average daily cost at a postoperative UCH floor or ICU 
and/or based on reported estimated costs per PPC[47, 48] 
 
Hypersensitivity adverse events: hypersensitivity signs and symptoms, including but not limited to 
rash, bronchospasm or anaphylaxis, will be obtained for up to 3 postoperative days directly from the 
patient and the patient’s providers. Their relationship to sugammadex will be assessed by the 
patient’s physicians and the study safety officer. Their confirmatory testing and management will be 
performed strictly at the discretion of the patient’s physicians. 


Statistical Methods 
 
The primary hypothesis is that the frequency of patients with one or more episodes of hypoventilation 
events in PACU (% of patients) is lower in the sugammadex group compared to neostigmine 
(controls). This will be analyzed by logistic regression which includes as covariates group allocation, 
total morphine equivalents, and TOF T4/T1 response, and other observed significant and clinically 
relevant differences between the groups. The odds ratio for the group covariate will be the primary 
outcome of interest, with the other covariates included in the model to adjust for potential confounders 
related to hypoventilation. 
The secondary analysis comparing delayed efficacy of sugammadex to neostigmine in reducing the 
incidence of hypoventilation during the first 3 postoperative days will assume the same model and 
covariates as the primary hypothesis. To compare the incidence of PPCs a logistic regression model 
will be used with the binary outcome of any PPC and will include covariates for group and total 
morphine equivalents. Hospital length of stay and costs will be compared between groups using a 
linear regression model including covariates for group, total morphine equivalents, presence of 
respiratory comorbidities and other clinical differences that may influence the outcome. Continuous 
outcomes may be transformed if they violate the normality assumption (e.g., a log-transformation). 
 
Multiplicity 
 
Given only one primary outcome and hypothesis, there is a not a concern for multiplicity. Secondary 
analyses are considered exploratory in this protocol. 
 
Power/Sample Size: 
 
Based upon a sample size of 40 patients per group, this study has 90% power to detect a 50% 
difference in hypoventilation incidence in the PACU (from 76% as reported in previous studies[21] to 
38%, alpha 0.05), assuming a potential dropout of up to 6 patients per group. The 50% reduction is 
considered clinically relevant for a decrease in the frequency of hypoventilation, a precursor of more 
clinically significant complications such as hypoxemia, reintubation or pneumonia. Quantifying the 
contribution of hypoventilation into more severe complications is challenging, and details of duration 
and severity of hypoventilation are not well known. Thus, only a significant reduction in 
hypoventilation incidence (i.e. 50%) may be accepted as relevant. This trial will provide additional 
detailed information that may provide more insight on the clinical consequences of hypoventilation 
(e.g. potential association between accumulated minutes of MV <40% expMV and decrease in 
SpO2/FiO2 over the following 30 min). 
 
A sample size of 40 patients per group would also have approximately 80% power (78%) to detect a 
difference in case the incidence of any hypoventilation events is 60%, instead of the literature-based 
76%. The table below provides the sample size per group to achieve a variety of assumptions for the 
primary outcome, alpha, and power: 
 
Incidence 
Group 1 
Incidence 
Group 2 
 
Alpha 
 
Power 
Sample Size per 
Group 
1. 0.76 
2. 0.38 
3. 0.01 
4. 0.8 
5. 39 
6. 0.76 
7. 0.38 
8. 0.05 
9. 0.8 
10. 26 
11. 0.76 
12. 0.38 
13. 0.01 
14. 0.9 
15. 48 
16. 0.76 
17. 0.38 
18. 0.05 
19. 0.9 
20. 34 
 
Although our sample size has been designed based on the frequency of hypoventilation in patients 
during the PACU stay, we have also estimated the power that a sample size of n=40 patients per 
group would have to detect a difference on the incidence of residual NMB. In a preliminary sample of 
25 patients after general anesthesia and neostigmine used for NMBR at our institution, 9 patients had 
a quantitative TOF T4/T1 <0.9 in the PACU (36%). This matches the incidence range 10-50% of TOF 
<0.9 observed in other studies[8, 10, 49]. The reported frequency of qTOF <0.9 after 15min of 


sugammadex administration in other surgical populations is <8%[34, 39, 50, 51]. With this incidence 
of residual NMB, our proposed sample size would have 90% power to detect a reduction to residual 
NMB to an incidence of 5% (alpha 0.05): 
 
G. Summarize Knowledge to be Gained 
 
This study will fill an important gap of knowledge with immediate clinical applications: 1) determine 
the efficacy of sugammadex, compared to neostigmine, for NMBR in patients with severe kidney 
dysfunction undergoing a kidney transplant; and 2) characterize the effect of sugammadex and 
neostigmine on postoperative ventilation, dependent and independent to residual or recurrent NMB 
and other contributing factors (e.g. opioids). Our study will describe the effect of NMBR on objective 
and quantitative assessments of qTOF and minute volume ventilation. Additional measures will 
include patient’s subjective dyspnea scores (with a validated questionnaire), PPCs and kidney graft 
outcomes, hospital resource utilization and estimated healthcare costs. 
 
H. References 
 
• 
1. 
Fuchs-Buder, T., R. Nemes, and D. Schmartz, Residual neuromuscular blockade: 
management and impact on postoperative pulmonary outcome. Curr Opin Anaesthesiol, 2016. 
29(6): p. 662-667. 
• 
2. 
Hayes, A.H., et al., Postoperative residual block after intermediate-acting neuromuscular 
blocking drugs. Anaesthesia, 2001. 56(4): p. 312-8. 
• 
3. 
Fortier, L.P., et al., The RECITE Study: A Canadian Prospective, Multicenter Study of the 
Incidence and Severity of Residual Neuromuscular Blockade. Anesth Analg, 2015. 121(2): p. 
366-72. 
• 
4. 
Herbstreit, F., J. Peters, and M. Eikermann, Impaired upper airway integrity by residual 
neuromuscular blockade: increased airway collapsibility and blunted genioglossus muscle activity 
in response to negative pharyngeal pressure. Anesthesiology, 2009. 110(6): p. 1253-60. 
• 
5. 
Eriksson, L.I., Reduced hypoxic chemosensitivity in partially paralysed man. A new 
property of muscle relaxants? Acta Anaesthesiol Scand, 1996. 40(5): p. 520-3. 
• 
6.       Eriksson, L.I., et al., Functional assessment of the pharynx at rest and during swallowing 
in partially paralyzed humans: simultaneous videomanometry and mechanomyography of awake 
human volunteers. Anesthesiology, 1997. 87(5): p. 1035-43. 
• 
7. Grosse-Sundrup, M., et al., Intermediate acting non-depolarizing neuromuscular blocking 
agents and risk of postoperative respiratory complications: prospective propensity score matched 
cohort study. BMJ, 2012. 345: p. e6329. 
• 
8. 
Murphy, G.S., et al., Residual neuromuscular blockade and critical respiratory events in 
the postanesthesia care unit. Anesth Analg, 2008. 107(1): p. 130-7. 
• 
9. 
Berg, H., et al., Residual neuromuscular block is a risk factor for postoperative pulmonary 
complications. A prospective, randomised, and blinded study of postoperative pulmonary 
complications after atracurium, vecuronium and pancuronium. Acta Anaesthesiol Scand, 1997. 
41(9): p. 1095-1103. 
• 
10. 
Errando, C.L., et al., Residual neuromuscular blockade in the postanesthesia care unit: 
observational cross-sectional study of a multicenter cohort. Minerva Anestesiol, 2016. 82(12): p. 
1267-1277. 
• 
11. 
McLean, D.J., et al., Dose-dependent Association between Intermediate-acting 
Neuromuscular-blocking Agents and Postoperative Respiratory Complications. Anesthesiology, 
2015. 122(6): p. 1201-13. 
• 
12. 
Sasaki, N., et al., Effects of neostigmine reversal of nondepolarizing neuromuscular 
blocking agents on postoperative respiratory outcomes: a prospective study. Anesthesiology, 
2014. 121(5): p. 959-68. 
• 
13. 
Fernandez-Bustamante, A., et al., Postoperative Pulmonary Complications, Early 
Mortality, and Hospital Stay Following Noncardiothoracic Surgery: A Multicenter Study by the 
Perioperative Research Network Investigators. JAMA Surg, 2017. 152(2): p. 157-166. 


• 
14. 
Piccioni, F., et al., An acceleromyographic train-of-four ratio of 1.0 reliably excludes 
respiratory muscle weakness after major abdominal surgery: a randomized double-blind study. 
Can J Anaesth, 2014. 61(7): p. 641-9. 
• 
15. 
Tawfic, Q.A. and G. Bellingham, Postoperative pain management in patients with chronic 
kidney disease. J Anaesthesiol Clin Pharmacol, 2015. 31(1): p. 6-13. 
• 
16. Mehta, J.H., et al., The relationship between minute ventilation and end tidal CO2 in 
intubated and spontaneously breathing patients undergoing procedural sedation. PLoS One, 
2017. 12(6): p. e0180187. 
• 
17. 
Williams, G.W., 2nd, et al., A Comparison of Measurements of Change in Respiratory 
Status in Spontaneously Breathing Volunteers by the ExSpiron Noninvasive Respiratory Volume 
Monitor Versus the Capnostream Capnometer. Anesth Analg, 2017. 124(1): p. 120-126. 
• 
18. 
Voscopoulos, C., et al., A risk stratification algorithm using non-invasive respiratory 
volume monitoring to improve safety when using post-operative opioids in the PACU. J Clin Monit 
Comput, 2017. 31(2): p. 417-426. 
• 
19. 
Gonzalez Castro, L.N., et al., Quantification of respiratory depression during pre- 
operative administration of midazolam using a non-invasive respiratory volume monitor. PLoS 
One, 2017. 12(2): p. e0172750. 
• 
20. 
Cavalcante, A.N., et al., Low minute ventilation episodes during anesthesia recovery 
following intraperitoneal surgery as detected by a non-invasive respiratory volume monitor. J Clin 
Monit Comput, 2017. 
• 
21. 
Galvagno, S.M., Jr., et al., Evaluation of respiratory volume monitoring (RVM) to detect 
respiratory compromise in advance of pulse oximetry and help minimize false desaturation 
alarms. J Trauma Acute Care Surg, 2016. 81(5 Suppl 2 Proceedings of the 2015 Military Health 
System Research Symposium): p. S162-S170. 
• 
22. 
Min, K.C., et al., Pharmacokinetics of sugammadex in subjects with moderate and severe 
renal impairment. Int J Clin Pharmacol Ther, 2017. 55(9): p. 746-752. 
• 
23. 
Staals, L.M., et al., Reduced clearance of rocuronium and sugammadex in patients with 
severe to end-stage renal failure: a pharmacokinetic study. Br J Anaesth, 2010. 104(1): p. 31-9. 
• 
24. 
Panhuizen, I.F., et al., Efficacy, safety and pharmacokinetics of sugammadex 4 mg kg-1 
for reversal of deep neuromuscular blockade in patients with severe renal impairment. Br J 
Anaesth, 2015. 114(5): p. 777-84. 
• 
25. 
Staals, L.M., et al., Multicentre, parallel-group, comparative trial evaluating the efficacy 
and safety of sugammadex in patients with end-stage renal failure or normal renal function. Br J 
Anaesth, 2008. 101(4): p. 492-7. 
• 
26. 
de Souza, C.M., et al., Efficacy and safety of sugammadex in the reversal of deep 
neuromuscular blockade induced by rocuronium in patients with end-stage renal disease: A 
comparative prospective clinical trial. Eur J Anaesthesiol, 2015. 32(10): p. 681-6. 
• 
27. 
Illman, H.L., et al., The duration of residual neuromuscular block after administration of 
neostigmine or sugammadex at two visible twitches during train-of-four monitoring. Anesth Analg, 
2011. 112(1): p. 63-8. 
• 
28. Khuenl-Brady, K.S., et al., Sugammadex provides faster reversal of vecuronium-induced 
neuromuscular blockade compared with neostigmine: a multicenter, randomized, controlled trial. 
Anesth Analg, 2010. 110(1): p. 64-73. 
• 
29. 
Gaszynski, T., T. Szewczyk, and W. Gaszynski, Randomized comparison of 
sugammadex and neostigmine for reversal of rocuronium-induced muscle relaxation in morbidly 
obese undergoing general anaesthesia. Br J Anaesth, 2012. 108(2): p. 236-9. 
• 
30. 
Hristovska, A.M., et al., Efficacy and safety of sugammadex versus neostigmine in 
reversing neuromuscular blockade in adults. Cochrane Database Syst Rev, 2017. 8: p. 
CD012763. 
• 
31. 
Kaufhold, N., et al., Sugammadex and neostigmine dose-finding study for reversal of 
residual neuromuscular block at a train-of-four ratio of 0.2 (SUNDRO20)dagger. Br J Anaesth, 
2016. 116(2): p. 233-40. 
• 
32. 
Jette, M., K. Sidney, and G. Blumchen, Metabolic equivalents (METS) in exercise testing, 
exercise prescription, and evaluation of functional capacity. Clin Cardiol, 1990. 13(8): p. 555-65. 


• 
33. 
Aldrete, J.A., The post-anesthesia recovery score revisited. J Clin Anesth, 1995. 7(1): p. 
89-91. 
• 
34. 
Brull, S.J. and A.F. Kopman, Current Status of Neuromuscular Reversal and Monitoring: 
Challenges and Opportunities. Anesthesiology, 2017. 126(1): p. 173-190. 
• 
35. 
Murphy, G.S., Neuromuscular Monitoring in the Perioperative Period. Anesthesia & 
Analgesia, 2018. 126(2): p. 464-468. 
• 
36. 
Thilen, S.R. and S.M. Bhananker, Qualitative Neuromuscular Monitoring: How to 
Optimize the Use of a Peripheral Nerve Stimulator to Reduce the Risk of Residual 
Neuromuscular Blockade. Curr Anesthesiol Rep, 2016. 6: p. 164-169. 
• 
37. 
Mehta, J.H., et al., Assessment of perioperative minute ventilation in obese versus non- 
obese patients with a non-invasive respiratory volume monitor. BMC Anesthesiol, 2017. 17(1): p. 
61. 
• 
38. 
Voscopoulos, C., et al., Non-invasive respiratory volume monitoring to detect apnea in 
post-operative patients: case series. J Clin Med Res, 2014. 6(3): p. 209-14. 
• 
39. 
Brueckmann, B., et al., Effects of sugammadex on incidence of postoperative residual 
neuromuscular blockade: a randomized, controlled study. Br J Anaesth, 2015. 115(5): p. 743-51. 
• 
40. 
Thiele, R.H., et al., Standardization of care: impact of an enhanced recovery protocol on 
length of stay, complications, and direct costs after colorectal surgery. J Am Coll Surg, 2015. 
220(4): p. 430-43. 
• 
41. 
Canet, J., et al., Prediction of postoperative pulmonary complications in a population- 
based surgical cohort. Anesthesiology, 2010. 113(6): p. 1338-50. 
• 
42. 
Cassidy, M.R., et al., I COUGH: reducing postoperative pulmonary complications with a 
multidisciplinary patient care program. JAMA Surg, 2013. 148(8): p. 740-5. 
• 
43. 
ARDS Definition Task Force, T., Acute Respiratory Distress Syndrome: The Berlin 
definition. JAMA: The Journal of the American Medical Association, 2012. 307(23): p. 2526-2533. 
• 
44. 
Clavien, P.A., et al., The Comprehensive Complication Index (CCI(R)): Added Value and 
Clinical Perspectives 3 Years "Down the Line". Ann Surg, 2017. 265(6): p. 1045-1050. 
• 
45. 
Dindo, D., N. Demartines, and P.-A. Clavien, Classification of Surgical Complications. 
Annals of Surgery, 2004. 240(2): p. 205-213. 
• 
46. 
Mallon, D.H., et al., Defining delayed graft function after renal transplantation: simplest is 
best. Transplantation, 2013. 96(10): p. 885-9. 
• 
47. 
Shander, A., et al., Clinical and economic burden of postoperative pulmonary 
complications: patient safety summit on definition, risk-reducing interventions, and preventive 
strategies. Crit Care Med, 2011. 39(9): p. 2163-72. 
• 
48. 
Lawrence, V.A., et al., Incidence and hospital stay for cardiac and pulmonary 
complications after abdominal surgery. J Gen Intern Med, 1995. 10(12): p. 671-8. 
• 
49. Esteves, S., et al., Incidence of postoperative residual neuromuscular blockade in the 
postanaesthesia care unit: an observational multicentre study in Portugal. Eur J Anaesthesiol, 
2013. 30(5): p. 243-9. 
• 
50. 
Della Rocca, G., et al., Reversal of rocuronium induced neuromuscular block with 
sugammadex or neostigmine: a large observational study. Acta Anaesthesiol Scand, 2013. 57(9): 
p. 1138-45. 
• 
51. 
Ledowski, T., et al., Introduction of sugammadex as standard reversal agent: Impact on 
the incidence of residual neuromuscular blockade and postoperative patient outcome. Indian J 
Anaesth, 2013. 57(1): p. 46-51.