An Anesthesia-Centered Bundle to Reduce Postoperative Pulmonary Complications: The PRIME-AIR Study
Phase: NA
Conditions: Postoperative Pulmonary Complications
Sponsor: Columbia University

PRIME-AIR Standalone Protocol 
NCT04108130
Document date: 02.02.2023

 
1  
  
  
IRB PROTOCOL  
  
PRIME-AIR study  
  
  
  
I. BACKGROUND AND SIGNIFICANCE  
  
Postoperative pulmonary complications (PPCs) are a major cause of morbidity 
and mortality for patients undergoing the estimated 51 million annual inpatient 
surgeries in the US1–3. National estimates suggest 1,062,000 PPCs per year, with 
46,200 additional deaths, and 4.8 million additional days of hospitalization2. Abdominal 
surgery is associated with the largest absolute number of PPCs4. Our long-term goal is 
to develop and implement perioperative strategies to eliminate PPCs.  
  
Whereas PPCs are as significant and lethal as cardiac surgical complications1,5, 
research in the field has received much less attention, and strategies to minimize them 
are limited. Indeed, the recommendations of the American College of Physicians to 
mitigate PPCs highlight the lack of evidence guiding current intraoperative anesthetic 
practice and perioperative care5,6. In contrast, we and others have evidence to suggest 
a crucial role of perioperative interventions such as ventilatory strategies7–10, and 
administration and reversal of neuromuscular blocking agents11,12 in reducing PPCs, 
consistent with the beneficial effects of lung protective ventilation in the acute 
respiratory distress syndrome (ARDS)13. Surgical patients differ substantially from 
ARDS patients as most have no or limited lung injury at the onset of surgery. Yet, during 
and after abdominal surgery, systemic inflammation due to surgical trauma14 and 
translocation of endotoxin15 and bacteria16 predispose to indirect lung injury; while 
resorptive and compression atelectasis from limited diaphragmatic excursion, surgical 
retractors, muscle paralysis, high inspired oxygen fractions, prolonged supine position, 
and pain17–19 predispose to direct lung injury20. The ensuing multiple-hit facilitates the 
onset of clinical or sub-clinical lung injury that places patients at risk for PPCs19,21,22 .  
  
Recent major trials on PPCs focused on mechanical ventilation. Futier et al.7 
demonstrated the benefit of intraoperative lung recruitment and low stretch on a 
composite of pulmonary and extrapulmonary outcomes. Hemmes et al.23  found no 
effect of intraoperative constant high vs. low positive end-expiratory pressure (PEEP) on 
PPCs. While the first trial highlighted the relevance of ventilatory strategies to 
postoperative outcomes, the second led to the controversial recommendation that low 
PEEP should be the standard of care in abdominal surgery23,24 , a practice anticipated to 
worsen lung collapse. No trial addressed the effects of neuromuscular blocking agents 
on PPCs. This evidence gap and the resulting wide and unexplained variability in 
current anesthetic practices is a major public health issue as some practices within 
usual care appear to be suboptimal and even potentially injurious8,11,12 25.   

 
2  
  
Accordingly, solid evidence to guide optimal perioperative anesthetic care to 
prevent PPCs is greatly needed.   
  
We propose to conduct a large prospective multicenter randomized controlled pragmatic 
trial with a blinded assessor to compare PPCs in patients undergoing major open 
abdominal surgery receiving an individualized management bundle versus usual care. 
We hypothesize that this anesthesia-centered bundle, based on our recent findings 
and focused on perioperative lung protection, will minimize multiple and synergistic 
factors responsible for the multiple-hit perioperative pulmonary dysfunction and result in 
decreased incidence and severity of PPCs.  
  
II. SPECIFIC AIMS  
We will leverage the experience achieved in a successful pilot collaboration among US 
academic centers26 to study this hypothesis by pursuing the following aims:  
Specific Aim 1: To compare the number and severity of PPCs in patients 
receiving an individualized perioperative anesthesia-centered bundle to those in 
patients receiving usual anesthetic care during open abdominal surgery. The 
anesthesia-centered bundle will consist of: (a) mechanical ventilation utilizing 
individualized PEEP with recruitment maneuvers to maximize respiratory system 
compliance and minimize driving pressures; (b) individualized use of neuromuscular 
blocking agents and their reversal; and (c) postoperative lung expansion to maintain 
lung recruitment following surgery. We will use the patient classification of PPC severity 
during the first 7 days after surgery as the primary outcome in order to specifically 
assess the effect of our intervention not only on PPC incidence but also on severity 
distribution.  
Specific Aim 2: To assess the effect of the proposed bundle on plasma levels 
of lung injury biomarkers. We hypothesize that our intervention will minimize lung 
mechanical injury and systemic inflammation by reducing overinflation and atelectasis. 
Thus, we anticipate that plasma levels of biomarkers of inflammation, epithelial, and 
endothelial cell injury will be lower in the intervention arm as previously described with 
lung protective ventilation for ARDS27,28, and in our pilot29 and others30 data for PPCs. 
The mechanistic insights from this aim will facilitate bundle dissemination and support 
adoption as it has for lung protective ventilation for ARDS.28,31,32, In the process, we will 
create a novel biobank uniquely focused on PPCs, and gain mechanistic insights on 
early perioperative lung protection.   
  
At the end of this project, we expect that this novel and clinically feasible anesthesia-
centered bundle will change clinical practice and reduce pulmonary morbidity in the 
large population of patients undergoing open abdominal surgery.   
      
III. SUBJECT SELECTION  
This is a multicenter study including 17 US academic medical centers. The 
Massachusetts General Hospital (MGH) will receive and analyze the de-identified data; 
the University of Colorado School of Medicine will receive and analyze all blood 
samples; and Columbia University will function as the clinical coordinating center.   

 
3  
  
We will target adult patients of both genders (N 
=approximately 790 randomized to obtain 750 fully studied 
participants)  
undergoing open abdominal surgery and classified as 
intermediate or high risk for PPCs using the well-established  
and validated ARISCAT risk score for PPCs (Table 1)4.   
   
Inclusion criteria: Participants must meet all of the following 
inclusion criteria to participate in this study:   
• 
Adults (g18 years) scheduled for elective surgery with 
expected duration g2 hours   
• 
Open abdominal surgery including: gastric, biliary, 
pancreatic, hepatic, major bowel, ovarian, renal tract, 
bladder, prostatic, radical hysterectomy, and pelvic 
exenteration   
• 
Intermediate or high risk of PPCs defined by an 
ARISCAT risk scoreg26    
  
Exclusion criteria: Candidates meeting any of the exclusion 
criteria at baseline will be excluded from study participation. 
These criteria are:   
• 
Inability or refusal to provide consent   
• 
Inability or significant difficulty to perform any study 
interventions, including incentive spirometry, 
ambulation and/or maintaining follow-up contact with 
study personnel for up to 90 days after the date of 
surgery.  
• 
Participation in any interventional research study 
within 30 days of the time of the study.   
• 
Previous surgery within 30 days prior to this study.  
• 
Pregnancy   
• 
Emergency surgery   
• 
Severe obesity (above Class I, BMIg35 kg/m2)   
• 
Significant lung disease: any diagnosed or treated respiratory condition that (a) 
requires home oxygen therapy or non-invasive ventilation (except nocturnal 
treatment of sleep apnea without supplemental oxygen), (b) severely limits 
exercise tolerance to <4 METs (e.g., patients unable to do light housework, walk 
flat at 4 miles/h or climb one flight of stairs), (c) required previous lung surgery, or  
(d) includes presence of severe pulmonary emphysema or bullae   
• 
Significant heart disease: cardiac conditions that limit exercise tolerance to <4 
METs   
• 
Renal failure: peritoneal or hemodialysis requirement or preoperative creatinine  
g2 mg/dL   
Table 1. ARISCAT risk 
score for PPCs4  
Variable  
Score 
Age (yr)  
f 50   
51 – 80   
> 80  
  
0  
3  
16  
Preoperative SpO2,  
%  
g 96   
91 – 95  
f 90  
  
  
0  
8  
24  
Respiratory 
infection in the last 
month  
17  
Preoperative 
anemia  
(f 10 g/dL)  
11  
Surgical incision 
Peripheral   
Upper abdominal  
Intrathoracic  
  
0  
15  
24  
Duration of surgery, 
h f 2   
> 2 to 3   
> 3  
 
  
0  
16  
23  

 
4  
  
• 
Neuromuscular disease that impairs ability to ventilate without assistance   
• 
Severe chronic liver disease (Child-Turcotte-Pugh Score >9, Appendix I)   
• 
Sepsis   
• 
Malignancy or other irreversible condition for which 6-month mortality is 
estimated g20%  
• 
Bone marrow transplant  
• 
Pulmonary hypertension 
  
  
IV. SUBJECT ENROLLMENT  
Identification, screening and consent: Participant identification and screening will be 
done in all sites from pre-admission/anesthesia clinic schedules (manual or electronic), 
surgeons9 office schedules, operating room schedules and by communication with the 
relevant nursing and medical staff. Patient advocacy groups are not currently engaged 
because this study does not focus on a patient population with a known disease. 
Instead, our study population is defined by patients with pre-defined risk level for 
postoperative pulmonary complications that are scheduled to undergo abdominal 
surgery. Thus, the anesthesiologists and surgeons performing these procedures and 
their offices9 personnel are the clinical communities critical for successful recruitment 
and retention for this study. We have shown successful recruitment in similar patients 
for the pilot R34 study, with no objection by the health care providers participating in the 
patients9 clinical care in having any patient enrolled in the study.  
  
Once subjects are identified as meeting inclusion criteria, they will be contacted 
according to each site9s procedures including approaches such as in person during 
hospital clinic visits or videoconference through use of a site-specific approved 
HIPAAcompliant telemedicine videoconferencing platform. Besides regular signature of 
the paper consent form, we will also offer the option for electronic consent signature 
(eConsent).   
  
Massachusetts General Hospital (MGH): Once subjects are identified as meeting 
inclusion criteria, the study will be first introduced to them  by a member of the treatment 
team known to the subject. Such introduction will be done through one of the following 
manners: in person, teleconference, phone, IRB approved letter, secure email, 
reproducing the IRB approved letter, distributed flier, or Patient Gateway.  
Provided patients express agreement to be contacted, they will be further approached 
through one of the following methods: (i) in person during a clinic visit, (ii) by HIPAA 
compliant videoconference, or (iii) by phone contact (a likely case at the MGH as 
several patients are referred from and assessed in other hospitals and come to the 
MGH only on the day of surgery specifically to undergo the procedure). Direct contact 
will be sought for patients who answered positively to the Research Opportunities 
Direct to You (RODY) program question. If contact occurs in person during a clinic 
visit, consent will be directly obtained after all questions and concerns are addressed 

 
5  
  
and answered. If subjects prefer, they will be allowed time to consult with their family or 
personal doctors, and consent will only be obtained after patients are comfortable with 
their decision. For patients contacted by mail or phone, once initial contact has been 
made with the subject and the study explained, we will ask permission either to send the 
consent form to the subject via mail or email for their review or to provide them with 
eConsent instructions. If the subject agrees, we will mail or email the consent or provide 
the eConsent instructions and we will follow up with a telephone call to discuss any 
questions or concerns the subject may have.  All questions and concerns will be 
addressed during the follow up call. All subjects will be given the opportunity to speak 
with a doctor during the consent process either in person or through videoconference or 
phone. If the subject then agrees to participate, consent will be obtained in person on 
the day of their surgery or through eConsent utilizing the MGH approved system.  
Pregnant women and children are not being enrolled in this study. No class of subjects, 
including institutionalized individuals, minorities, or other potentially vulnerable 
populations, will be excluded or preferentially targeted. Documentation of reasons for 
ineligibility and for non-participation of eligible candidates will be performed with a 
screening log.   
The subset of patients only physically present in the hospital and able to ultimately sign 
the consent in the day of surgery presents a practical issue as per protocol the 
anesthesia team caring for the patient is assigned according to the group the patient is 
randomized to and the assignment of anesthesiologists to cases is done in the day 
before surgery. To address this, patients in that subset expressing preliminary 
agreement with their participation and not able to sign an eConsent will be 
prerandomized. If assigned to the intervention group, their anesthesia team will be 
assigned accordingly. They will also receive by email the study9s brochure and a link to 
a YouTube explanatory video (provided below). Such material provides brief information 
on postoperative pulmonary complications and methods to reduce them. Consequently, 
it will increase patients9 education on their perioperative care. In fact, similar types of 
materials are commonly used in other institutions for routine clinical care.  
Randomization will be confirmed, and patients considered enrolled in the study only 
when they ultimately sign the informed consent before surgery.  
Brigham and Women’s Hospital (BWH): Participant identification and screening will 
be done at BWH from pre-admission/anesthesia clinic schedules (manual or electronic), 
surgeons9 office schedules, operating room schedules and by communication with the 
relevant nursing and medical staff. Patient advocacy groups are not currently engaged 
because this study does not focus on a patient population with a known disease. 
Instead, our study population is defined by patients with pre-defined risk level for 
postoperative pulmonary complications that are scheduled to undergo abdominal 
surgery. Thus, the anesthesiologists and surgeons performing these procedures and 
their offices9 personnel are the clinical communities critical for successful recruitment 
and retention for this study. We have shown successful recruitment for our past 
interventional trials, with no objection by the health care providers participating in the 
patients9 clinical care in having any patient enrolled in the study.  

 
6  
  
Once subjects are identified as meeting our inclusion criteria, they will be contacted in 
person during their hospital clinic visit or videoconference visit (preferably in the 
preoperative anesthesia test center (PATC) at BWH. Pregnant women and children are 
not being enrolled in this study. No class of subjects, including institutionalized 
individuals, minorities, or other potentially vulnerable populations, will be excluded or 
preferentially targeted. Signed informed consent for participating in the study will be 
obtained prior to randomization and performance of any study procedures either 
inperson or through eConsent utilizing the BWH approved system. Documentation of 
reasons for ineligibility and for non-participation of eligible candidates will be performed 
with a screening log.   
Individuals responsible for screening, and approaching potential participants will be 
members of the research team: attending physicians, certified or in-training 
anesthesiologists, and research nurses, coordinators and assistants. All will have 
appropriate human subjects research training per institutional requirements (e.g., CITI 
training or equivalent). The sites9 research coordinators and assistants are experienced 
in screening and approaching participants and will be closely monitored by the BWH 
site-PI (Dr. Frendl).   
University of Colorado: Participant identification and screening will be done at 
University of Colorado Hospital from pre-admission/anesthesia clinic schedules (manual 
or electronic), surgeons9 office schedules, operating room schedules and by 
communication with the relevant nursing and medical staff. Patient advocacy groups are 
not currently engaged because this study does not focus on a patient population with a 
known disease. Instead, our study population is defined by patients with pre-defined risk 
level for postoperative pulmonary complications that are scheduled to undergo 
abdominal surgery. Thus, the anesthesiologists and surgeons performing these 
procedures and their offices9 personnel are the clinical communities critical for 
successful recruitment and retention for this study. We have shown successful 
recruitment for our past interventional trials, with no objection by the health care 
providers participating in the patients9 clinical care in having any patient enrolled in the 
study.  
Once subjects are identified as meeting our inclusion criteria, they will be contacted in 
person during their hospital clinic visit or videoconference visit (preferably in the 
preoperative center at University of Colorado Hospital). Pregnant women and children 
are not being enrolled in this study. No class of subjects, including institutionalized 
individuals, minorities, or other potentially vulnerable populations, will be excluded or 
preferentially targeted. Signed informed consent for participating in the study will be 
obtained prior to randomization and performance of any study procedures either 
inperson or through eConsent utilizing the University of Colorado approved system. 
Documentation of reasons for ineligibility and for non-participation of eligible candidates 
will be performed with a screening log.   
Individuals responsible for screening, and approaching potential participants will be 
members of the research team: attending physicians, certified or in-training 
anesthesiologists, and research nurses, coordinators and assistants. All will have 
appropriate human subjects research training per institutional requirements (e.g., CITI 

 
7  
  
training or equivalent). The sites9 research coordinators and assistants are experienced 
in screening and approaching participants and will be closely monitored by the 
University of Colorado site-PI (Dr. Fernandez-Bustamante).   
  
  
Duke University Health System:  After obtaining permission from the operating 
surgeon, surgical subjects will be screened for eligibility by the study coordinator by 
reviewing the surgical schedule. If the patient meets eligibility criteria, the study team 
member will first check the Duke office of Clinical Research (DOCR) Opt Out list, to 
ensure that the patient has not opted out of research.  If it is shown that the patient has 
not opted out of research, then they will be contacted by the research coordinator and 
will discuss their willingness to participate in the research protocol either over the phone 
or in person at a clinic visit or videoconference visit.   An IRB approved phone script will 
be used during phone communication. If the subject is in agreement, the coordinator will 
present the research protocol in its entirety to the prospective participant and will 
answer any and all questions as they arise. If the patient decides during the phone call 
that they would like to opt out of research, the study team member will direct the patient 
to contact the Research Navigators to update their status at 919-668-5111.  If the 
patient agrees to participate, the coordinator will ask the subject to sign and date the 
appropriate consent form at their first visit if being contacted over the phone or they will 
sign at the time of consent if in person or through eConsent utilizing the Duke University 
approved system. A copy of this consent form will be given to the subject and a copy of 
the consent form will be added to the patient9s medical record.   
  
Northwestern University/ Northwestern Medicine (NM): Subjects will be identified by 
the primary care surgeon during a preoperative visit or during their visit to the NM 
preoperative clinic or videoconference visit. If they have been identified as meeting the 
inclusion criteria they will be contacted by one of the study team members in person or 
by videoconference or by telephone. For subjects contacted by telephone, study team 
members will use a prepared script to introduce the study including study parameters as 
well as the consent document and the requirements to participate. If the subject 
requests the consent document it will then be e-Mailed via Northwestern Encrypted 
eMail for their perusal or through eConsent utilizing the Northwestern University 
approved system. This will allow additional time for the subject to consult with family 
and personal physicians. A study team member will conduct a follow up telephone call 
to address whether the subject has additional questions regarding the study. The study 
team member will inquire whether the subject would like to participate in the study. On 
the day of surgery the study team member will meet with the subject in the preoperative 
area and will review the inclusion and exclusion criteria. The research study team 
member will also inquire whether the subject has any additional questions regarding the 
study. The study team members will provide ample time to answer any questions posed 
during the questioning. After this review the research study team will obtain written 
informed consent.  Pregnant women and children are not being enrolled in this study. 
No class of subjects, including institutionalized individuals, minorities, or other 
potentially vulnerable populations, will be excluded or preferentially targeted.  

 
8  
  
Documentation of reasons for ineligibility and for non-participation of eligible candidates 
will be performed with a screening log.  
  
Beth Israel Deaconess Medical Center: Subjects will be identified from the 
perioperative information management system (PIMS), surgical consult lists, cardiac 
surgical clinic visit schedules and pre-admission testing (PAT) clinic visit schedules.  
Patients who meet inclusion criteria with no exclusions will be approached for consent 
either in-person or through videoconference visit. The study will be explained in clear, 
layperson language. All study procedures will be disclosed. Risks to the patient will be 
explained; no individual patient benefits will be promised. Patients will be given ample 
time to make a decision regarding participation. The patient will be given the opportunity 
to ask questions and confer with family members and others. If the patient elects to 
consent to the trial, they will sign and date the consent form(s) in the presence of 
authorized research personnel, who will also sign and date or through eConsent utilizing 
the BIDMC approved system.  
Stanford Hospital and Clinics: Once subjects were identified as meeting our inclusion 
criteria by Epic search previously to their surgery. They will be contacted in person 
during a hospital clinic visit (preoperative clinic visit) or by videoconference. Subjects of 
research during the preop clinic visit will be consented after all questions and concerns 
were addressed and answered either in-person or through eConsent utilizing the 
Stanford University approved system. If subjects prefer, they will be allowed time to 
consult with their family or personal doctors, and consent will only be obtained after 
patients are comfortable with their decision. Pregnant women and children are not being 
enrolled in this study. No class of subjects, including institutionalized individuals, 
minorities, or other potentially vulnerable populations, will be excluded or preferentially 
targeted. Documentation of reasons for ineligibility and for non-participation of eligible 
candidates will be performed with a screening log.   
Individuals responsible for screening and approaching potential participants will be 
members of the research team: attending physician and research assistant. All will have 
appropriate human subjects research training per institutional requirements (e.g., CITI 
training or equivalent). The sites9 research assistant is experienced in screening and 
approaching participants and will be closely monitored by the SHC site-PI (Dr. Tanaka).   
UCSF Medical Center at Mission Bay: Once subjects are identified as meeting our 
inclusion criteria, they will be contacted either in person during a hospital clinic visit 
(e.g., to their PCP, surgeon, preoperative clinic visit, provided patients expressed to 
their primary health care providers agreement to be contacted), by phone or by 
videoconference or through mail (via IRB approved MD letter and <opt out= post card), 
or by direct or phone contact.  Direct contact will be sought for patients who answered 
positively to RODY. If contact occurs in person during a clinic visit, consent will be 
directly obtained after all questions and concerns are addressed and answered. If 
subjects prefer, they will be allowed time to consult with their family or personal doctors, 
and consent will only be obtained after patients are comfortable with their decision. For 
patients contacted by mail and phone, once initial contact has been made with the 

 
9  
  
subject, we will ask permission to send the consent form to the subject via mail or email 
or through eConsent utilizing UCSF approved system for their review.  If the subject 
agrees, we will mail or email the consent and follow up with a telephone call to discuss 
any questions or concerns the subject may have. If emailing the consent form, we will 
do so by using encryption via the <Send Secure= function. All questions and concerns 
will be addressed during the follow up call. All subjects will be given the opportunity to 
speak with a doctor during the consent process. If the subject then agrees to participate, 
consent will be obtained in person on the day of their surgery.  Pregnant women and 
children are not being enrolled in this study. No class of subjects, including 
institutionalized individuals, minorities, or other potentially vulnerable populations, will  
be excluded or preferentially targeted. Documentation of reasons for ineligibility and for 
non-participation of eligible candidates will be performed with a screening log.   
Individuals responsible for screening, and approaching potential participants will be 
members of the research team: attending physicians, certified or in-training 
anesthesiologists, and research nurses, coordinators and assistants. All will have 
appropriate human subjects research training per institutional requirements (e.g., CITI 
training or equivalent). The sites9 research coordinators and assistants are experienced 
in screening and approaching participants and will be closely monitored by the UCSF 
site-PIs (Drs. Jae-Woo Lee or Lee-Lynn Chen).  
 
University of Rochester Medical Center  
Participant identification and screening will be done at URMC from 
preadmission/anesthesia clinic schedules (manual or electronic), surgeons9 office 
schedules, and by communication with the relevant nursing and medical staff.  
Once subjects are identified as meeting inclusion criteria, they will be contacted in 
person during their pre-operative visit (preferably in the Center for Perioperative 
Medicine (CPM) or at the surgical clinic visit either in-person or through  
videoconference. Pregnant women and children are not being enrolled in this study. No 
class of subjects, including institutionalized individuals, minorities, or other potentially 
vulnerable populations, will be excluded or preferentially targeted.  Signed informed 
consent for participating in the study will be obtained prior to randomization and 
performance of any study procedures. A URMC approved eConsent platform can be 
used.   
The potential subject will determine whether they prefer to review the consent in person 
or prefer the option of an eConsent at a later time.    
If potential subject prefers to use eConsent, the study team will request verbal 
permission to send the link to the URMC REDCap eConsent via email or text. The 
request will state: <Because URMC can9t control the security of email or text messages 
once we send them, we need your permission to text or email you. Do you want to 
receive the link to the eConsent via text or email?= The permission will be documented. 
The email/text will not include PHI and only includes a link to the URMC REDCap 

 
10  
  
eConsent. To ensure security, 2 step verification is required to access the link, The 
study team will verbally communicate to the subject a passcode required for the 2-step 
verification for the REDCap eConsent process. The subject will receive an email/text 
with a link to the REDCap eConsent and a verbal passcode the user enters on the 
website to initiate and sign the eConsent at home on their computer, phone or electronic 
device.    
The subject will use the link to access the Redcap eConsent system. Once the subject 
completes 2-step verification entering the passcode on the RedCap website, they can 
then initiate the eConsent process. The study team will coordinate a time to review the 
eConsent with subject electronically over the phone and answer any questions the 
subject may have. The subject will then answer comprehension questions to be certain 
the subject understands the clinical study. (If there is any discrepancy in these answers 
the research staff will be notified and they will contact the subject via phone to discuss 
and review the consent and clinical study again.)  
Once comprehension questions are answered correctly, the subject can sign the 
eConsent to acknowledge that they have read and are interested in participating in this 
clinical study.  Subject9s signature on the eConsent will be obtained using an electronic 
signature. Once the consent form is signed and submitted, subjects will be able to 
receive a print out of the paper copy, download a pdf, and/or receive an email with a 
PDF attachment of the signed consent form.  
Documentation of reasons for ineligibility and for non-participation of eligible candidates 
will be performed with a screening log.   
Individuals responsible for screening, and approaching potential participants will be 
members of the research team: attending physicians, advanced care providers (NP, 
PA9s), and research nurses and coordinators. All will have appropriate human subjects 
research training per institutional requirements (e.g., CITI training/GCP).  
Mayo Clinic Rochester: Participant identification and screening will be done at Mayo 
Clinic from pre-admission/anesthesia clinic schedules, surgeons9 office schedules, 
operating room schedules and by communication with the relevant nursing and medical 
staff. Patient advocacy groups are not currently engaged because this study does not 
focus on a patient population with a known disease. Instead, our study population is 
defined by patients with pre-defined risk level for postoperative pulmonary complications 
that are scheduled to undergo abdominal surgery. Thus, the anesthesiologists and 
surgeons performing these procedures and their offices9 personnel are the clinical 
communities critical for successful recruitment and retention for this study. We have 
shown successful recruitment for our past interventional trials, with no objection by the 
health care providers participating in the patients9 clinical care in having any patient 
enrolled in the study. 
Once subjects are identified as meeting our inclusion criteria, they will be contacted in 
person during their preoperative evaluation (POE) appointment at Mayo Clinic 
Rochester. Pregnant women and children are not being enrolled in this study. No class 
of subjects, including institutionalized individuals, minorities, or other potentially 

 
11  
  
vulnerable populations, will be excluded or preferentially targeted. Signed informed 
consent for participating in the study will be obtained prior to randomization and 
performance of any study procedures. Documentation of reasons for ineligibility and for 
non-participation of eligible candidates will be performed with a screening log.  
Individuals responsible for screening and approaching potential participants will be 
members of the research team: attending physicians, certified or in-training 
anesthesiologists, and research nurses, coordinators and assistants. All will have 
appropriate human subjects research training per institutional requirements (e.g., CITI 
training or equivalent). The sites9 research coordinators are experienced in screening 
and approaching participants and will be closely monitored by the Mayo Clinic 
Rochester site-PI (Dr. Sprung).  
Memorial Sloan Kettering Cancer Center: Participant identification and screening will 
be done at MSKCC from Pre-Surgical Testing clinic schedules (electronic), operating 
room schedules and by communication with the relevant nursing and medical staff. 
Individuals responsible for screening will be members of the research team. The study 
population will be defined by patients with pre-defined risk level for postoperative 
pulmonary complications that are scheduled to undergo abdominal surgery. The 
eligibility and exclusion criteria do not discriminate either explicitly or implicitly against 
gender, race or ethnicity.  Pregnant women and children f18 will not be enrolled onto 
the study. 
Once subjects are identified as meeting the inclusion criteria, they will be approached 
during their Pre-Surgical Testing visit at MSKCC by a member of the research team. 
Details pertinent to the trial, expected outcomes, potential risks and adverse outcomes 
will be discussed in detail before enrollment. During the initial conversation between the 
investigator/research staff and the patients, the patient may be asked to provide certain 
health information that is necessary to the recruitment and enrollment process. They will 
use the information provided by the patient and/or medical record to confirm that the 
patient is eligible. 
Signed informed consent for participating in the study will be obtained prior to 
randomization and performance of any study procedures and documented in the 
patient9s chart.  Documentation of reasons for ineligibility and for non-participation of 
eligible candidates will be performed in a screening log and a note to file that will be 
sent to the patient9s electronic medical record. The research staff will destroy all 
information collected on the patient during the initial conversation and medical records 
review, except for any information that must be maintained for the screening log 
purposes. 
University of Massachusetts Medical School- Hospital System:  Participant 
identification and screening will be done from pre-admission/anesthesia clinic schedules 
(manual or electronic), surgeons9 office schedules, operating room schedules and by 
communication with the relevant nursing and medical staff.  Our study population is 
defined by patients with pre-defined risk level for postoperative pulmonary complications 
that are scheduled to undergo abdominal surgery. Thus, the anesthesiologists and 

 
12  
  
surgeons performing these procedures and their offices9 personnel are the clinical 
communities critical for successful recruitment and retention for this study.  
Once subjects are identified as meeting our inclusion criteria, a provider will get a verbal 
consent and a study team member will follow-up with an IRB approved letter and/or 
telephone call (approved phone script) which will provide a brief introduction of the 
study to the patient. If interest is expressed, we will meet with the patient during a clinic 
visit to conduct the informed consent process. Other patients may be approached for 
the first time in the pre-admission clinic or surgeons9 office. Virtual clinical visits and 
electronic consent may be used as a COVID-19 alternative to consent the patient prior 
to surgery. Patients may be consented same day with prior interest and study review. 
All subjects will be given the opportunity to ask the study team questions pertaining to 
the study during the consent process. A provider will be available to consult or review 
the study with the patient. If the patient9s consent process takes place virtually and the 
patient would like to speak to a provider, a University of Massachusetts Medical School 
study team provider will follow-up with the patient via telephone. If the subject then 
agrees to participate, consent will be obtained in person or via an IRB approved 
electronic consent (RedCap). Pregnant women and children are not being enrolled in 
this study. No class of subjects, including institutionalized individuals, minorities, or 
other potentially vulnerable populations, will be excluded or preferentially targeted. 
Documentation of reasons for ineligibility and for non-participation of eligible candidates 
will be performed with a screening log.  
Individuals responsible for screening and approaching potential participants will be 
members of the research team: attending physicians, certified or in-training 
anesthesiologists, and surgeon, research nurses, coordinators and/or assistants. All will 
have appropriate human subjects research training per institutional requirements (e.g., 
CITI training or equivalent).  
Columbia University Irving Medical Center: Participant identification and screening 
will be done at Columbia University Irving Medical Center from pre-
admission/anesthesia clinic schedules, surgeons9 office schedules, operating room 
schedules and by communication with the relevant nursing and medical staff. Patient 
advocacy groups are not currently engaged because this study does not focus on a 
patient population with a known disease. Instead, our study population is defined by 
patients with pre-defined risk level for postoperative pulmonary complications that are 
scheduled to undergo abdominal surgery. Thus, the anesthesiologists and surgeons 
performing these procedures and their offices9 personnel are the clinical communities 
critical for successful recruitment and retention for this study. We have shown 
successful recruitment for our past interventional trials, with no objection by the health 
care providers participating in the patients9 clinical care in having any patient enrolled in 
the study. 
Once subjects are identified as meeting our inclusion criteria, they will be contacted 
during their preoperative evaluation (POE) appointment at Columbia University Irving 
Medical Center. Pregnant women and children are not being enrolled in this study. No 

 
13  
  
class of subjects, including institutionalized individuals, minorities, or other potentially 
vulnerable populations, will be excluded or preferentially targeted. Signed informed 
consent for participating in the study will be obtained prior to randomization and 
performance of any study procedures. Documentation of reasons for ineligibility and for 
non-participation of eligible candidates will be performed with a screening log.  
Individuals responsible for screening and approaching potential participants will be 
members of the research team: attending physicians, certified or in-training 
anesthesiologists, and research nurses, coordinators and assistants. All will have 
appropriate human subjects research training per institutional requirements (e.g., CITI 
training or equivalent). The sites9 research coordinators are experienced in screening 
and approaching participants and will be closely monitored by the Columbia University 
Irving Medical Center, and the site PI, Dr. Wagener. 
 
Cleveland Clinic Foundation: Subjects will be identified using EMR system EPIC, 
searching in the pre-OP visit schedule. Only patients that meet the inclusion criteria will 
be approached in person during the pre-OP visit. Surgeons' agreement was obtained to 
contact their patients. After presentation of the study protocol to the patient and all 
questions and concerns are addressed and answered consent will be directly obtained 
from those patients that agree to participate. All subjects will be given the opportunity to 
speak with a doctor during the consent process. In the case the patients decide to 
review the protocol and/or consent form at home or consult with their family or personal 
doctors, the patients will contact the site-PI with their final decision or he/she will be 
approached again on day of the surgery to inquire their willingness to participate.  If the 
subject then agrees to participate, consent will be obtained in person either during the 
pre-OP visit or the day of their surgery. Pregnant women and children are not being 
enrolled in this study. No class of subjects, including institutionalized individuals, 
minorities, or other potentially vulnerable populations, will be excluded or preferentially 
targeted. Documentation of reasons for ineligibility and for non-participation of eligible 
candidates will be performed with a screening log.  
Study coordinators, Research fellows and research assistants will be responsible for 
screening, and approaching potential participants. All will have appropriate human 
subjects research training per institutional requirements (e.g., CITI training or 
equivalent). The sites9 research coordinator and assistants are experienced in screening 
and approaching participants and will be closely monitored by the CCF site-PI (Dr. 
Marcelo Gamma de Abreu). 
University of Nebraska Medical Center: Subject identification and screening will be 
completed at Nebraska Medicine using surgeons9 clinic schedules, pre-anesthesia clinic 
schedules, operating room schedules and by communication with relevant medical 
staff.  Once subjects are screened and identified as meeting inclusion criteria, the 
research team will introduce the study by the following means: in person, 
teleconference, phone, or OneChart patient portal.   

 
14  
  
Should the potential research candidate express agreement to be contacted, they will 
be approached by the research team (all of whom are trained per institutional 
requirements and have CITI training or equivalent) via the following means: in person 
during a clinic visit, by HIPAA compliant videoconference, or by phone contact.  If 
contact occurs during an in person clinic visit, the potential subject will be allowed time 
to consult with their family or seek medical consultation.  Consent will be obtained only 
after allowed ample time to develop an informed decision.  If contact occurs during a 
videoconference or by phone, the research study team will then ask permission to send 
the potential subject the consent form via email or mail for their review.  A follow up call 
will then be made to address questions and concerns, and the site PI will be made 
available during the entire consent process, either in person or via 
videoconference/phone.  If the potential subject is agreeable to participation, consent 
will be obtained in person prior to surgery, as eConsent cannot be utilized in the state of 
Nebraska for this study. No vulnerable populations, including but not limited to 
minorities, will be preferentially excluded or targeted.  Documentation of potential 
candidate ineligibility or non-participation of eligible candidates will be performed with a 
screening log kept on a secure server. 
There exists a logistical concern for those patients who remotely pre-consent and are 
only available to be physically present in the hospital on the day of surgery. There also 
exists the issue of Anesthesia staff at UNMC not being assigned to cases until the day 
prior to surgery.  In these instances, it will be properly documented and written into the 
IRB application to allow for study staff to pre-randomize the subject prior to obtaining 
written consent on day of surgery so that randomized anesthesia staff can be properly 
assigned to the subject9s case and if subject might randomize to the intervention arm, 
the subject would be able to receive educational materials pertaining to the clinical trial 
prior to the date of surgery.  Subject will specifically receive the study brochure and a 
link to a YouTube explanatory video via email.  The verbal consent would be properly 
documented per IRB requirements and endorsed by a witness.  Although randomization 
may occur prior to a wet signature of the informed consent in this instance, the subject 
will only be considered enrolled in the study once the informed consent is ultimately 
signed with a wet signature on the day of surgery.   
 
Most of the research teams involved in this study have successfully implemented 
previous clinical studies within and outside our network3,10,33–37.   
 
Recruitment sites and Recruitment rate: We currently have 17 sites for enrollment. To 
achieve our goal of 750 studied patients within the period of approximately 36 months, 
an average of 1.5 patients recruited/site/month are required. We have agreed on a 
capitated enrollment model with no maximum of  patients/month per participating center 
as recommended by the DSMB.   
  
Randomization: Two types of randomization are planned in the study: (1) randomization 
of individual patients and (2) randomization of attending anesthesiologists to give either 
the intervention bundle or usual care. Randomization will use a centralized web-based 
system in the Statistics and Data Coordinating Center (SDCC), with stratification by site.  

 
15  
  
Use of a centralized service will reduce the potential for selection bias of participants. 
Randomization of attending anesthesiologists is intended to reduce potential 
contamination in the control group. Only the group allocated to deliver the intervention 
group will be given training in the intervention protocol described below.  
  
Once the patient is enrolled they will be randomly assigned to one of the two groups as 
described below.  
   
  
  
  
  
V. STUDY PROCEDURES  
  
PRIME-AIR is a multicenter, prospective, controlled 
openlabel parallel-group clinical trial to test the effect of an 
individualized perioperative anesthesia-centered bundle on  
the number and severity of postoperative pulmonary  
complications (PPCs). Eligible patients will be adults   
undergoing major open abdominal surgery with intermediate 
or high risk for developing PPCs. These represent a large 
population of abdominal surgery patients sustaining the 
relevance and generalizability of the study. We plan to study 
a total of 750 adult patients undergoing abdominal surgery 
with general anesthesia and mechanical ventilation.  
 
Patients will receive the intervention perioperatively and will be followed by hospital 
visits (in-person or videoconference) and a daily phone call until discharged home or 
until 7 days after surgery. Phone calls or hospital visits (in-person or videoconference) 
will also be done immediately after postoperative days 7, 30 and 90 to determine 
additional complications. 
 
 
Strategy and Experimental Design: We hypothesize that an anesthesia-centered 
bundle, focused on perioperative lung expansion, will minimize the synergistic factors 
responsible for the multiple-hit perioperative pulmonary dysfunction and injury, and will 
result in decreased incidence and severity of PPCs.   
   
We will recruit adult patients with moderate or high risk for PPCs scheduled for major 
open abdominal surgery during 36 months and randomize them 1:1 to either the bundle 
or usual care. Our anesthesia-centered individualized bundle will consist of pre-, intra- 
and postoperative interventions aimed at optimizing perioperative lung expansion.   
  
Fig. 1. Intervention 
categories composing the 
PRIME-AIR bundle to 
reduce PPCs. Light-blue 
= intraoperative, dark 
blue = pre- and 
postoperative.  

 
16  
  
The bundle is summarized in the mnemonic PRIME-AIR: PEEP (positive end-expiratory 
pressure), Recruitment, Incentive spirometry, Muscle relaxant optimization, preoperative 
Education, postoperative early Ambulation, Individualized, and Reinforced.  Specifically, 
the intervention bundle consists of: (1) individualized PEEP with recruitment maneuvers 
to maximize respiratory system compliance and minimize driving pressures; (2) 
protocolized neuromuscular blockade agents administration and reversal based on 
neuromuscular monitoring; (3) postoperative lung expansion interventions (incentive 
spirometry and early ambulation) with adherence enhanced by supervision and 
preoperative education on PPCs and performance of lung expansion maneuvers. This 
is summarized in Fig. 1.  
  
Overview of Patient Flow in the Trial  
(Fig. 2): Trial activities for each 
participant will commence with 
enrollment. This will involve personal or 
phone contact of a member of the study 
team with patients before surgery. After 
signing informed consent (or, for 
participants recruited by phone who will 
be signing the informed consent 
document on the day of surgery, after 
agreeing to participate; please, see 
section IV. Subject Enrollment - MGH), 
patients will be randomized to receive 
the intervention (intervention group) or 
usual perioperative care (control group) 
using a web-based system in the 
SDCC.  The most intense interventional 
phase will occur during hospital 
admission for surgery. Participants will 
receive three daily follow-up visits (in 
person or videoconference) by an 
unblinded investigator until fully 
ambulatory or until 7 days after surgery 
(whichever is longer). Recognizing that 
three visits per day may be difficult for 
specific participants and clinical 
situations, we will consider at least 2 
visits per day as adequate for the 
purposes of the study. Besides the visits by the unblinded investigator,  a daily phone 
call, videoconference, or in-person visit will be done by a blinded investigator until 
discharge or 8 days after surgery. This period will allow for primary and secondary 
outcomes assessment.  
Outcomes will be collected through hospital visits, videoconference or phone calls (if the 
patient is discharged from hospital) immediately after postoperative days (POD) 7, 30 
.  
Fig. 2  Diagram of  PRIME AIR Trial.   Bundle  
interventions are presented in red.  

 
17  
  
and 90. The visit (in-person or videoconference) or phone call for POD7 (with medical 
record review if required) will provide primary and secondary outcomes, and the follow-
ups after POD 30 and 90 will correspond to secondary outcomes. Participation will be 
concluded after the POD 90 follow-up visit (in-person or videoconference) or phone call. 
Windows will be allowed for each postoperative assessment: postoperative days 7 to 14 
for the assessment of POD 7, postoperative days 30 to 45 for POD 30, and 
postoperative days 90 to 120 for POD 90.  
  
  
Study Protocol for the Intervention Group – Perioperative Anesthesia-Centered 
Bundle Elements:  
  
Preoperative Phase:   
  
  
Lung Expansion Education:   
  
Because incentive spirometry and early ambulation depend on patient performance, 
patients in the Intervention group will receive study-specific preoperative education 
consisting of:  
  
  
A. 
Educational printed material and video: These materials will be provided to 
patients before their surgery. The materials will contain written and pictorial information 
on the importance of postoperative pulmonary complications and their prevention with 
adequate lung expansion after surgery using incentive spirometry and early ambulation. 
The effects of anesthesia and surgery on lung volumes and its consequences for lung 
dysfunction and infection will be explained. The educational materials have been 
designed to encourage patients to adhere to interventions by emphasizing that their 
participation is vital to protect their lungs. The written information is included in 
Appendix II and the educational video is available at https://youtu.be/ZcNRZSqjgRw.  
  
B. 
In-person or videoconference education: Reinforcement of these concepts, 
answers to questions and practice with an incentive spirometer will be done at the time 
of visit to the anesthesia/surgery preoperative clinic, as videoconference, or on the day 
of surgery before transport to the operating room and administration of any sedatives. 
Members of the research team will implement this education intervention to maximize 
patient adherence. Family members and caregivers, if present, will be involved in the 
instruction to enhance involvement and further encourage adherence to therapy.   
 
 
Intraoperative Phase:  
  

 
18  
  
Managing anesthesiologists will be those usually composing the team caring for 
abdominal surgery patients at the participating sites. Anesthesiologists will be 
randomized into two groups, caring only for either controls or interventional patients, to 
minimize contamination, i.e., avoid anesthesiologists being exposed to the bundle and 
then treating control patients. The site PI or study coordinator will be available in the 
operating room to monitor and provide support with the interventions. This phase will 
consist of two components (Fig. 1):  
  
A. PEEP and Lung Recruitment - Mechanical Ventilation with Individualized PEEP:   
  
Perioperative lung expansion will be accomplished by PEEP individualization through 
maximization of the patient9s respiratory system compliance (CRS). This corresponds to 
the minimization of driving pressures, i.e., the difference between plateau pressure and 
PEEP during mechanical ventilation. This maximal compliance strategy will be started 
immediately after induction and repeated at least hourly throughout the surgery (see 
Appendix III for additional details).  
   
PEEP individualization will be determined by a recruitment maneuver followed by a 
decremental PEEP titration (Fig. 3). The stepwise recruitment maneuver will consist of 
the increase of PEEP from 5 to 20 cmH2O in 5 cmH2O steps of 30-sec each, as long as 
the patient9s plateau pressure (Pplat) 
=30-32 cmH2O (PEEP can be 
increased by 2-3 cmH2O instead of 
by 5 cmH2O to achieve Pplat =30-32 
cmH2O). Starting at this maximally 
achieved PEEP, PEEP will be 
decreased in 3 cmH2O steps of 45-
75 sec until a maximum CRS is 
identified by a reduction in CRS at a 
lower PEEP following a larger CRS 
at a higher PEEP (Fig. 3). The 
minimum PEEP along the 
decremental steps will be 2 cmH2O. 
Once the PEEP for maximal CRS is 
identified, the largest PEEP level 
achieved during the recruitment 
maneuver will be used for 30-sec 
(in order to reinforce lung 
recruitment), followed by setting 
PEEP as the value that maximized 
CRS. The procedure will be repeated 
on an hourly basis, and  
following any significant event producing a g15% reduction in CRS (e.g., significant 
change in surgical table position, application of surgical retractors, endotracheal tube 
disconnection, endotracheal tube suction). Similar adjustments will be performed in 
  
Fig. 3. Decremental PEEP titration protocol 
following a stepwise recruitment maneuver. 
Respiratory system compliance (CRS) is measured 
at each step  
(●) and the PEEP corresponding to the maximum  
compliance is set as the individualized PEEP. In 
this example, titration would be stopped at 8 
cmH2O and the final PEEP set at 11 cmH2O.  

 
19  
  
case of 15% CRS increases (i.e. removal of retractors) in order to avoid overinflation if 
triggers of lung derecruitment are removed.  
  
Other mechanical ventilation settings will be: volume controlled ventilation, tidal volume  
(VT)=6-8mL/kg of predicted body weight, FIO2 titrated for the target SpO2g96% (FIO2 
increased only to maintain that target while avoiding hyperoxia), I:E ratio 1:2 and 
respiratory rate aiming at normocapnia (PETCO2=32-42 mmHg and/or PaCO2=35-45 
mmHg, if available).   
  
  
B. Muscle relaxant optimization – Individualized 
Administration and Reversal of Neuromuscular 
Blocking Agents:   
  
Only intermediate-acting neuromuscular  
blocking agents will be used (Table 2). Induction 
doses of muscle relaxants will be routine: 
Cisatracurium (f0.2 mg/kg), rocuronium (f1.2 
mg/kg), vecuronium (f0.1 mg/kg). Given the 
difficulty of precise dosing due to 
the presentation of the medications, 
doses 25% higher (or to the next 
round mL, e.g., 10 mg for 
rocuronium, 2 mg for cisatracurium, 
1 mg for vecuronium with usual 
presentations) will be considered as 
consistent with the intent of the 
protocol. Succinylcholine can be 
used and dosed at the anethesia 
team9s discretion. Maintenance 
doses will be administered as 
required by surgical conditions 
and following confirmation of the 
presence of twitches in the train- 
of-four (TOF) stimulation. 
Readministration of muscle relaxants will be avoided as possible when <2 twitches are 
present unless specific clinical conditions such as diaphragmatic contraction indicate 
otherwise. Maintenance doses will be limited to (Table 2): Cisatracurium (f0.03 mg/kg), 
rocuronium (f0.2 mg/kg) and vecuronium (f0.015 mg/kg). As described for the induction 
dose, we will consider doses f25% higher than the target dose or to the next round 
dose in mililiters as consistent with the intent of the protocol. 
 
 
Monitoring of neuromuscular transmission with a peripheral nerve stimulator will be 
applied in all cases using the assessment of muscle response to a TOF stimulation 
Table 2. Maximal intubating and 
maintenance doses of muscle 
relaxants to be used during the 
PRIME-AIR trial.  
  
Dose (mg/kg)  
Intubation Maintenance 
Cisatracurium 
0.2  
0.03  
Rocuronium  
1.2  
        0.2  
Vecuronium  
0.1  
 0.015  
Table 3. Doses of neuromuscular blockade reversal 
based on monitoring of the train-of-four (TOF) ratio 
(T4/T1).113, 171  
Twitches in the TOF  Neostigmine 
dose (mcg/kg) 
Sugammadex dose 
(mg/kg)  
Quantitative 
Monitoring  
Qualitative 
Monitoring  
0  
0  
Wait  
Wait or 4-16  
1  
1  
Wait  
3-4  
2-3  
2-3  
50  
2-3  
T4/T1<0.4 4 with fade 
40  
1-2  
T4/T1=0.4- 
0.9  
4 without 
fade  
15-25  
0.25-2  
T4/T1>0.9 
  
Unnecessary Unnecessary  

 
20  
  
(series of four electric stimuli delivered at 2 Hz). Ulnar nerve stimulation with 
assessment of adductor pollicis response will be preferred. If not achievable, stimulation 
of the temporal branch of the facial nerve with orbicularis oculi response will be 
monitored38. We will encourage use of acceleromyography-guided quantitative TOF 
monitoring. Yet, given current practice, we designed this intervention to allow for use of 
either qualitative (based on visual or tactile assessment of the TOF response) or 
quantitative neuromuscular blockade monitoring. The following principles will be 
followed for neuromuscular blockade reversal management according to type of 
monitoring:   
  
B.1. Quantitative monitor (e.g., acceleromyography): In this case, at least 90% recovery 
of the ratio between the fourth and first twitches (T4/T1>0.9) of the TOF stimulation will 
be ensured before extubation. If this is present before administration of reversal agents, 
no neuromuscular blockade reversal is required. However, up to 1 mg/kg of 
sugammadex is allowed. If it is not present (i.e., T4/T1f0.9), reversal agents will be 
administered based on the TOF quantitative response according to Table 3. As for the 
doses of neuromuscular blockers, we consider doses not more than 25% above the target dose, 
or the next higher dosing interval (50 mg for total dose of sugammadex; 1 mg for total dose of 
neostigmine) as consistent with the protocol. Extubation will only be performed once a 
T4/T1>0.9 is achieved.   
  
B.2. Qualitative monitor (visual or tactile assessment of the TOF response): (i)  
Neostigmine users: administered only when at least two twitches are present in the TOF 
stimulation and based on the doses presented in Table 3; (ii) Sugammadex users: dose 
based on TOF count as recommended following rocuronium- or vecuronium-induced 
neuromuscular blockade (Table 3). As described above for quantitative monitoring, higher 
doses will be considered consistent with the intent of the protocol if not more than 25% above 
the recommended dose or the total dose is not more than the next highest dosing interval. 
 
High-dose neostigmine (g60 mcg/kg) will be systematically avoided since it can increase 
the risk for muscle weakness and postoperative complications12,39.  
 
Additional signs of patient responsiveness, such as ability to follow commands, and 
appropriate hemodynamic, respiratory and temperature parameters will be 
recommended before extubation.  
  
Postoperative Phase:  
  
A. Incentive spirometry: Our protocol has been designed to address concerns that 
incentive spirometry in usual care is not systematically monitored and adherence is 
low32, 5. To maximize adherence and benefit, intervention patients will receive:(1) 
specific preoperative education as described above, (2) clear expectations of 10 
incentive spirometry breaths every hour for at least 10 hours along the day (i.e., 10 
sessions total with 100 incentive spirometry breaths per day); and (3) direct supervision 
of performance targeted to 3 of those 10 sessions, with an expectation that this will be 
done at least twice each day, spaced along awake hours.   

 
21  
  
  
Instructions will be based on the Guidelines of the American Association for Respiratory 
Care (AARC)40. The patient will be instructed to hold the spirometer in an upright 
position, exhale normally, and then place the lips tightly around the mouthpiece. This 
will be followed by a slow inhalation to raise the ball (flow-oriented) or the piston/plate 
(volume-oriented) in the chamber to the set target. At maximum inhalation, the 
mouthpiece is removed, followed by an at least 5-sec breath-hold and normal 
exhalation. Instruction of relatives, guardians, and other health caregivers in the 
technique will be provided to facilitate the patient9s appropriate use of the technique and 
assist with encouraging adherence to therapy.  
  
A member of the research team will be the supervisor aiming to maximize patient9s 
performance through education, reinforcement of expectations, and resolution of 
compliance barriers. Supervision will be started within 2 hours after arrival at the 
postanesthesia care unit and continued in the floor until the patient is able to freely 
ambulate. Free ambulation will be defined as the ability to be out of bed for at least 6 
hours/day and walk at least 75 meters 3 times/day41,42. Postoperative supervision visits 
can also be performed by using a site-specific HIPAA-compliant telehealth 
videoconferencing platform.  
  
Preliminary studies from our group and previous investigations with targeted 
motivational education have shown improved adherence to therapy in respiratory 
conditions with traditionally poor patient compliance43,44.    
                                                   
B. Postoperative Ambulation:  
 
As with incentive spirometry, early ambulation is routinely pursued after surgery but not 
always systematically implemented or reported (although it is more frequently 
systematically used than incentive spirometry in our participating sites). Early 
mobilization and ambulation of intervention patients will be done by health care 
providers participating in the patient9s routine care. The same member of the research 
team supervising incentive spirometry will support ambulation through increased 
education, reinforcement, systematic monitoring (3x/day), and facilitation of barriers 
(e.g., pain) by advising the patient to communicate with the health care team until free 
ambulation. Ambulation after surgery is part of usual care in more than 50% of the 
planned sites (Table 4) and we will encourage early ambulation depending on 
resources routinely available at each individual site (e.g. nursing, physical therapists). 
As tolerated, the following specific expectations for mobilization will be expressed to the 
patient and pursued: postoperative day (POD) 0 (starting from end of surgery until 
midnight) - up in chair with assistance; POD 1 - up in chair 3 times/day for meals, 
ambulation in room or hallway 2 times/day with assistance; POD 2 - out of bed for all 
meals and >6 hours during the day, walking in hallway more than 15 meters 3 times/day 
with assistance; POD 3 - increase ambulation (desirably beyond 75 meters) 3–5 
times/day.   

 
22  
  
  
Protocols to guide the basic requirements for patient care and safety during mobilization 
and ambulation are available in all sites, and followed by postoperative health care 
providers. In the rare circumstances that a contraindication for early mobility is present, 
the intervention will only be implemented when that contraindication is resolved. 
Contraindications include: vasopressor requirement, acute neurologic event, femoral 
catheters, open abdominal wounds, and excessive sedation.  
  
Performance on postoperative incentive spirometry and ambulation will be directly noted 
during the visits (in-person or videoconference) by an unblinded investigator.  Although 
the target is for the unblinded investigator to visit the participant 3 times a day, we will 
consider 2 in-person visits with incentive spirometry to meet the target for the study. 
  
Concomitant Interventions:   
  
  
If pain or other barriers are 
identified that prevent/limit 
adequate performance of 
incentive spirometry or early 
ambulation, the investigator 
will advise the subject to  
report this to their care 
team. Subsequent execution 
of incentive spirometry/ 
ambulation will be pursued 
as soon as feasible.  
  
The following perioperative 
management goals will be 
flexibly defined for 
participants in the 
intervention group to avoid both extremes of clinical practice and practice 
misalignment: (a) anesthesiologists will be advised to use continuous positive airway 
pressure of at least 5 cmH2O during preoxygenation for induction of anesthesia, and 
during the period of spontaneous ventilation preceding removal of the endotracheal 
tube; (b) FIO2 should target normoxia (SpO2g96%). Hyperoxia should be avoided (i.e., 
the lowest range of FIO2 required to achieve that target should be used, and increases 
in FIO2 done only to maintain that target SpO2); (c) fluid administration will be aimed at 
neutral intraoperative fluid balance, and total recommended limit f6 mL/kg/h including 
pre-operative (correction of dehydration) and intraoperative administration.  
Hemodynamic management based on goal directed fluid therapy to guide vasoactive 
medications and avoid excessive fluid administration will be suggested to the primary 
care team as a consideration in high-risk cases if patients present no response after two 
fluid boluses. The primary care team will also be advised to maintain neutral fluid 
Table 4. Usual care for interventions in 14 US academic 
centers  
Usual Care 
Distribution  
Mostly  Frequently  Occasion  Seldom  
% receiving 
intervention  
>80%  50-80%  20-50%  < 20%  
Pre-op Education  
29  
21  
7  
43  
Individualized PEEP  
0  
7  
14  
79  
Reversal protocol  
21  
29  
14  
36  
Reinforced Inc. 
Spirometry  
29  
14  
14  
43  
Consistent Early 
Ambulation  
50  
21  
14  
14  

 
23  
  
balance in the immediate postoperative period (first 24 hours) while oral intake is not 
restarted.  
  
Postoperative Mechanical Ventilation (if applicable): The pre- or intraoperative decision 
to transfer a patient to the critical care unit will be made by clinical staff and recorded. 
To maintain the basic tenet of a recruited lung into the postoperative period, patients 
requiring mechanical ventilation postoperatively will receive at least one PEEP titration 
maneuver per day as described above and in keeping with interventions utilized in ICU 
patients45. This is consistent with the evidence on the beneficial effect of low driving 
pressures to outcomes of surgical8,46 and ICU patients47. Of note, recruitment 
maneuvers and PEEP levels in our protocol are substantially different from those 
utilized in the ART trial and lead to values comparable to the control lower-mortality arm 
of that trial48. We will monitor if the PEEP optimization maneuver and the resulting 
PEEP used at least once a day. In general, this or alternative methods based on 
principles of lung expansion should be attempted if considered feasible by the ICU 
clinical team. Mechanical ventilation in the ICU will be done at the discretion of the 
critical care team. Recruitment maneuvers and PEEP titration are part of the usual care 
of mechanically ventilated ICU patients, and not expected to constitute a significant 
challenge to care providers.  
  
   
Study Protocol for the Control Group:   
  
The control group will consist of a usual care group, managed in a manner consistent 
with routine perioperative medical practice at the participating hospitals and of the 
attending anesthesiologists. This will increase the pragmatic character of the trial, as 
well as generalizability of our results. This design improves safety monitoring by 
providing an ability to detect harmful effects relative to usual care. It also strengthens 
the findings of the trial by emphasizing their pragmatic meaning. Details of usual care in 
participating sites are described in Table 4. This survey of practices in our 14 
participating sites indicated that usual care corresponded to minimal individualization of 
intraoperative PEEP, infrequent use of any systematic management of neuromuscular 
blockade, unusual enforcement of incentive spirometry and rare preoperative education.  
  
Participants in the control group will also be visited (in-person or videoconference) or 
called in the preoperative settings, post-anesthesia care unit, and postoperatively at a 
frequency equivalent to that of the intervention group to reduce the likelihood of bias 
related to less personal attention. At those points, patients will be greeted, and a 
generic conversation held.  
  
  
Study Design Aspects Relevant To All Participants:  
  
With the exception of the specific intervention elements, anesthetic and postoperative 
management will follow each participating site9s routine clinical practice, according to 

 
24  
  
the choices of the primary clinical team caring for the patients. Fluid therapy and 
intraoperative fluid balance (crystalloids, colloids, and volume loss) will be recorded for 
analysis. Participants will receive standard local measures to maintain oxygenation, 
hemoglobin, core temperature, blood pressure and heart rate. Postoperative analgesia 
will be typically provided by epidural infusion (bupivacaine ± opioid) or intravenous 
patient controlled opioid infusion. Oxygen supplementation postoperatively is 
recommended to be administered if SpO2<94% (measured at rest in room air).   
  
Blood Biomarker Analysis and Biobank:   
We will collect blood samples perioperatively at three specific time points (before 
surgical incision, at extubation ±30min at the end of surgery, and 24±12h after 
extubation). Blood collection (10mL at each time point for a total of maximum 30 mL per 
patient) will be synchronized with routine blood draws whenever possible to prevent 
extra needle sticks for the patient. All samples will be sent to the University of Colorado 
for storage as the PRIME-AIR biorepository and they will be analyzed for biomarkers of 
lung injury under the supervision of the study co-PI, Dr. Fernandez-Bustamante. The 
10mL blood samples will be distributed in EDTA tubes (7.5mL) for plasma collection and  
PAXgene tubes (2.5mL) for RNA collection. The EDTA samples will be centrifuged at  
1,000-2,000 rpm for 10 min, plasma volume aliquoted (0.5 mL aliquots), and frozen at 
80°C until analysis. Following conclusion of the study and unless patients have opted 
out, samples of the PRIME-AIR biorepository will be submitted to the NHLBI Biologic 
Specimen and Data Repository (BioLINCC) ) for the creation of a biobank for future 
studies on PPCs.  
  
  
Study Outcomes  
  
Primary Outcome: The primary outcome is the participant9s PPC severity during the 
first 7 days after surgery. PPC severity will be classified from none to Grade 4 (Table 5) 
based on the most serious PPC occurring during those 7 days. Our focus on PPCs as 
the primary outcome is due to their major clinical relevance. This contrasts with previous 
use of composites of pulmonary and extrapulmonary outcomes to assess pulmonary 
interventions7,49,50. By studying the patient severity of PPCs as the primary outcome 
metric, we seek to detect the impact of the bundle not only on the PPC rate but also 
account for the bundle effect on the severity of occurring PPCs. We will utilize an 
established scale of PPC severity7,51,52 (Table 5) that has been slightly modified to 
include PPCs defined in recent large trials4,49,50. These modifications aim to maximize 
event detection by minimizing gaps in the list of conditions composing the primary 
outcome through the addition of two items: (a) Mild hypoxemia (Grade 1),  a usual 
clinical trigger for oxygen therapy in acute patients26,49,49,53, associated by us and others 
with clinically meaningful outcomes and health care utilization; and (b) Respiratory 
infection (Grade 2), included as an important complication in recent large studies on 
PPCs with a broad definition4,23,54. Accordingly, the proposed modifications will enhance 
PPC detection. Indeed, a recent study by one of our collaborators showed an event rate 

 
25  
  
of 48% in the control arm (N=244) in a similar population49. The 7-day postoperative 
period was chosen because it includes the majority of PPCs occurring within the first 
month after surgery7, known to substantially prolong hospital length of stay55; and it was 
used in previous large trials7,23.  
  
  
Table 5. Operational Definitions of PPCs20  
Grade 1  
Mild hypoxemia: SpO2 =90-92% on room air or the equivalent imputed PaO2/FiO2 
ratio when oxygen therapy is provided    
Mild respiratory findings: abnormal lung symptoms/signs (e.g., cough, dyspnea) and 
temperature >37.5°C without other documented cause; chest radiograph 
normal/unavailable  
Grade 2  
Cough: productive, no other cause  
Bronchospasm: new or pre-existent wheezing resulting in therapy change  
Hypoxemia: PaO2<60 mmHg or SpO2< 90% on room air or the equivalent imputed  
PaO2/FiO2 ratio when oxygen therapy is provided   
Respiratory Infection: use of antibiotic for suspected respiratory infection and at least 
one of the following: new or changed sputum, fever>37.5°C, WBC>12,000/mm3 
Atelectasis*: radiological confirmation + either temperature >37.5°C or abnormal 
lung symptoms/signs (e.g., cough, dyspnea) Hypercarbia: transient, requiring 
treatment  
Grade 3  
Pleural effusion: resulting in thoracentesis  
Pneumonia**, suspected: radiological evidence without bacteriological confirmation 
Pneumonia**, proved: radiological evidence and documentation of pathological 
organism  
Pneumothorax: resulting in intervention.  
Ventilatory dependence: (non-invasive or invasive ventilation) < 48h  
Grade 4  
Ventilatory failure: postoperative non-invasive or invasive ventilation dependence 
g48h  
* Atelectasis: lung opacification with shift of the mediastinum, hilum or hemidiaphragm 
towards affected area and compensatory overinflation. ** Pneumonia: new and/or 
progressive pulmonary infiltrates on chest X-ray and two or more of: fever g38°C or 
hypothermia (<36°C); white blood cell count (WBC)/mm3>12000 or <4000; purulent 
sputum and/or onset or worsening cough or dyspnea.    
  
Secondary Outcomes (further defined in Appendices I): We will study Grade 3 and 4 
PPCs (more reliably determined at unsupervised timepoints) at 30 and 90 days to verify 
if short term (7-day) effects persist at meaningful mid-term periods. We will assess a 
sub-set of individual PPCs to identify specific effects, relevant for analysis and clinical 

 
26  
  
management. Because lung injury is associated with extrapulmonary complications7,28, 
we will quantify a subset of those. Given that PPCs have a major effect on 
hospitalization costs58, we intend to collect different measures of health care resource 
utilization. Hypoxemia and hypotension are related to the proposed interventions and 
important intraoperative events requiring quantification. Specifically, the following 13 
secondary outcomes will be assessed:   
  
▪ 
Proportion of participants with highest grade being Grade 1 or 2 through POD 7  
▪ 
Proportion of participants with highest grade being Grade 3 or 4 through POD 7, 
30, 90  
▪ 
Proportion of participants with Hypoxemia by POD 7 (as defined in PPCs Grade 
1 and 2),   
▪ 
Proportion of participants with Atelectasis by POD 7;   
▪ 
Proportion of participants with Pneumonia (suspected and proved) by POD 7;  
▪ 
Proportion of participants with Ventilatory dependence or failure by POD 7;   
▪ 
Proportion of participants with both intraoperative hypoxemia and rescue 
recruitment maneuvers;  
▪ 
Proportion of participants with intraoperative cardiovascular events (hypotension, 
bradycardia, tachycardia, arrhythmias, new ST-segment changes and cardiac 
arrest);    
▪ 
Length of postoperative oxygen therapy/other respiratory support;   
▪ 
Length of hospital stay;   
▪ 
Proportion of participants with any major extrapulmonary complications (as 
defined in Appendix I by established criteria59–61);   
  
Exploratory Outcomes (further defined in Appendices I and IV): These include 7 and 
30-day mortality, as it is affected by PPCs4, and 90-day mortality, important for high-risk 
patient subsets such as the elderly56, and for accurate estimation of mortality after major 
abdominal surgery57. We will assess the subset of individual PPCs not included in the 
secondary outcomes to identify specific effects, relevant for clinical management and 
interpretation of the results. Because lung injury is associated with extrapulmonary 
complications7,28, we will quantify a panel of those as defined in Appendix I. Patient 
reported outcomes are increasingly emphasized as key data to determine management. 
Thus, we will collect those addressing dyspnea and fatigue. Specifically, the following 
exploratory outcomes will be assessed:    
▪ 
All cause mortality at postoperative days 7, 30 and 90;   
▪ 
Each of the individual components of the list of pulmonary complications in the 
primary endpoint not included in the secondary outcomes (Table 5);   
▪ 
Rate of intraoperative muscle weakness;   
▪ 
Dose of intraoperative vasoactive medications, crystalloids and colloids;  
▪ 
Length of stay in the postanesthesia care unit;   
▪ 
Unexpected admission to ICU;   
▪ 
Length of ICU stay;   

 
27  
  
▪ 
Rate of each of the major extrapulmonary complications (defined in Appendix I 
by established criteria59–61);   
▪ 
Rate of hospital readmission(s) after initial discharge;   
▪ 
Patient-Reported Outcomes Measurements (PROMIS®) short forms (Appendix 
IV) addressing: Dyspnea Characteristics, Severity and Functional Limitations; 
and Fatigue, before surgery and 7, 30 and 90 days after surgery.62,63.  
  
Clinically important differences for primary and secondary outcomes: Because a large 
number of patients are affected by PPCs and undergo abdominal surgery, even small 
percent differences in the outcomes to be studied represent a large absolute number of 
patients that could be affected by the studied intervention. Accordingly, we will consider 
clinically significant: (a) a 10% difference in the primary outcome of the study (the row 
mean score test of a Cochran-Mantel-Haenszel, which incorporates both the frequency 
and highest grade of severity of PPCs during the first 7 days after surgery;  (b) 5% 
difference in the rate of composite or isolated PPCs; (c) 5% difference in the rate of 
intraoperative and major extrapulmonary complications; (d) a difference of 12h in the 
length of postoperative oxygen therapy/other respiratory support; (e) a difference of 
half-day in the length of hospital stay.   
  
Plasma biomarkers. We hypothesize that the PRIME-AIR bundle will minimize lung 
mechanical injury and inflammation by reducing overinflation and atelectasis. 
Accordingly, it will reduce plasma levels of biomarkers of inflammatory, epithelial and 
endothelial injury. Plasma will be collected from all patients for analysis of a focused 
panel of plasma biomarkers of inflammation (cytokines IL-6, IL-8); epithelial injury (the 
soluble form of the receptor for advanced glycation end-products, RAGE, and club cell 
protein 16, CC16), and endothelial injury (angiopoietin-2, Ang-2). We will compare 
biomarker levels in the PRIME-AIR bundle vs. control groups before, at the end of and 
24h after surgery. Blood collection in this aim will not only allow for the biomarkers 
analysis, but also for the creation of a biobank for future studies on PPCs.  
  
Blinding: Because the intraoperative and postoperative interventions cannot be 
blinded, each site will have at least 2 members of the research team: one to perform the 
randomization, education, and implementation of the protocol in the operating room and 
postoperative incentive spirometry/mobilization during hospital visits (in-person or 
videoconference); and another, blinded to patient allocation, to assess PPCs and all 
other outcomes .with information obtained from the participant9s medical chart and 
phone calls to the participant (phone script in Attachments/Insight).  Investigators 
performing biomarker assays will also be blinded to study group.  
  
  
VI. STATISTICAL ANALYSIS  
  
A detailed statistical analysis plan (SAP) will be prepared and approved by the core 
study team prior to locking the database for the study. The material below provides an 

 
28  
  
overview of the key features of the SAP.  Should there be any discrepancy between the 
final SAP and material in the protocol, the final SAP will be the definitive version.  
  
Justification of Sample Size. Sample size was estimated using simulations of the 
primary analysis of the primary outcome. Based on these simulations, our sample size 
is 375/group (750 total) being studied. We have formulated the treatment effect in this 
project as a relative percent reduction in PPC rate between groups, not an absolute 
difference between the two groups. With a PPC event rate of 40%, and a treatment 
effect (relative reduction of PPC rate) of 35.29% (so an absolute PPC event rate of 
25.88% in the group receiving the intervention bundle), and no change in the distribution 
of the severity of PPCs, we would have 93% power (α= 0.05, two-sided) for the primary 
analysis. The 35.29% treatment effect was estimated from a Bayesian analysis as the 
lower 10% bound (one-sided) of the highest posterior region based on previous studies 
of aspects of the intervention; this means that we have a 90% expectation that the true 
treatment effect of the entire bundle would be greater than 35.29%. Power increases if 
the PPC event rate is higher than 40%.  
  
Analytic approach - primary endpoints: The primary outcome is the participant's PPC 
severity using a previously published five-point scale7,51,52. Participants are graded from 
0 (no PPC at all) to 4 (most severe PPC) based on the most serious PPC occurring 
during the first seven days after surgery. The analysis will use a Cochran-
MantelHaenszel test (specifically the row mean score test), stratifying by site. This tests 
the null hypothesis that there is no difference between the two treatment groups in the 
distribution of the most severe PPC grade during the first seven days of the study. The 
alternative hypothesis is that there is a difference between the two treatment groups in 
the distribution of the most severe PPC grade during the first seven days of the study. 
The results of this test will determine whether the study can claim that the intervention 
bundle reduced the average level of PPC severity  
  
We will also compare biological measures of lung function and injury between the 
interventions: (1) lung mechanics and gas exchange; and (2) plasma biomarkers of lung 
injury at baseline, end of and 24±4h after surgery (see secondary outcomes).   
  
Minimizing bias in outcome assessment: Study of each subject will involve at least 2 
investigators per center: one to perform the randomization and implementation of the 
protocol in the operating room, and another, blinded to patient allocation, to assess for 
postoperative complications.  
  
Analytic approach - secondary endpoints: The type of variable of the secondary 
outcome determines the approach used, as listed in Table 6 below:  
  
Table 6. Approach for primary analysis according to the type of variable  
Type of Variable  
Approach for Primary Analysis  

 
29  
  
Binary  
For rare events (f 5%): Fisher's Exact  
test   
For more common events (>5%): Logistic 
regression (to allow for stratification by 
site)  
Categorical (> 2 categories)  
Cochran-Mantel-Haenszel test   
Continuous  
van Elteren test (an extension of the 
Wilcoxon Rank Sum test to allow for  
stratification by site)  
Time to death   
Cox Proportional Hazards Model  
Repeated continuous outcomes (e.g. 
PROMIS® measures)  
Mixed model Analysis of Variance  
  
Additional analyses to fully explore the data will be specified in the SAP.  
  
Interim analyses: We will perform two interim analyses after approximately 1/3 and 2/3 
of participants have completed the 7-day follow up. Efficacy will be assessed using a 
Haybittle-Peto boundary of 0.001 at each analysis.  We will be doing a futility analysis at 
the second interim analyses as well.  
  
  
VII. RISKS AND DISCOMFORTS  
The estimated risks and discomforts involved with participation in this study include:  
  
I. Risks of recruitment maneuvers and PEEP titration: The potential main serious 
risks of the proposed bundle are hemodynamic instability, respiratory 
deterioration including pneumothorax. The PEEP values and protocol for 
recruitment maneuvers to be applied in the intervention arm of this study are 
comparable to those from previous studies and intensive care practice in early or 
established lung injury64,65. PEEP levels have been adjusted to lower maximal 
values in the current proposal given that lungs of surgical patients have better 
mechanical properties including recruitability as compared to those of intensive 
care patients. We are also excluding patients with conditions with the potential to 
increase the susceptibility to complications. In addition, ventilator parameters will 
be changed in a manner aimed at minimizing the likelihood of complications, e.g., 
Pplat to be kept under 30-32 cmH2O and PEEP to be changed in a stepwise 
manner aiming at minimizing significant and rapid hemodynamic instability. Given 
the previously observed safety in terms of similar recruitment and PEEP levels in 
critically ill patients66,67, we anticipate safe implementation in patients with less 
critical conditions. Indeed, we have successfully used intraoperative PEEP 
titration in patients comparable to those to be enrolled in the proposed trial during 
our R34 grant, without any serious adverse event. Such expectation of safety is 
reinforced because the intervention will be administered in an intensely 
monitored environment, i.e., operating room.   

 
30  
  
Hemodynamic instability can be triggered by the increased intrathoracic pressure 
during a recruitment maneuver or multiple other reasons during surgery. 
Hemodynamic mild/moderate changes (possible risk) include different degrees of 
hypotension (systolic blood pressure <100 mmHg or mean blood pressure <60 
mmHg), tachycardia (heart rate >100 bpm) or bradycardia (heart rate <60 bpm) 
and/or cardiac arrhythmias. Hemodynamic instability will be defined as systolic 
blood pressure >160 or <80 mmHg, heart rate >140 or <50 bpm, or deviations by 
more than 20% in any of those parameters from patient9s baseline for >3 minutes 
despite treatment (rare risks) or cardiac events (extremely rare) (e.g. significant 
arrhythmias, electrocardiogram ST segment changes). These risks are present 
during recruitment maneuvers and mechanical ventilation performed as standard 
of care during surgery. Our intervention is not expected to significantly increase 
these risks, as we include the assessment of hemodynamic stability before the 
initiation of recruitment maneuvers and careful titration of PEEP level. The 
alternative treatment includes maintaining low levels of PEEP, which can 
contribute to insufficient lung expansion, low oxygenation, and increased risk of 
pneumonia after surgery. Of note, stepwise recruitment as proposed in the 
current protocol is associated with less hemodynamic instability.   
Respiratory deterioration, including: Inadequate oxygenation or desaturation, 
defined as a SpO2<90% or a need to increase FIO2 by 0.2 to maintain the 
targeted SpO2 96%, hypercapnia (PETCO2>45 mmHg, PaCO2>50 mmHg or 
increase by 2mmHg in either parameter compared to before intervention), and 
increase in plateau pressure (Pplat >30-32cmH2O) (possible risks). These risks 
are present during standard of care during surgery and can be related to 
recruitment maneuvers and mechanical ventilation performed but can also be 
due to other factors, e.g., hypotension, and bronchial secretions. Our intervention 
is not anticipated to significantly increase this risk. There are no alternative 
treatments that reliably prevent intraoperative respiratory deterioration, and we 
have designed the appropriate responses in our protocol to respond in the event 
respiratory deterioration occurs.   
Sudden hypoxemia followed by hypotension will lead to the consideration of a 
possible trauma to the airways and pneumothorax (rare risk). The PEEP values 
and protocol for recruitment maneuvers to be used in this study are within ranges 
compatible with those used in previous studies and in clinical practice.  
Specifically, recruitment maneuvers to values of 40 cmH2O have been published, 
whereas in this study values of plateau pressure of 30-32 cmH2O (considered a 
safe limit in patients with acute lung injury) will be used for only 30 seconds. 
PEEP values in the range of 0-20 cmH2O are used in clinical practice. Recent 
studies actually indicated that values of 8-12 cmH2O may be necessary to 
prevent injurious alveolar derecruitment due to abdominal pressure. Such 
pressures are expected to be important in cases of abdominal surgery with 
necessary muscle paralysis for surgery, when pressure applied by abdominal 
contents, surgical retractors and/or operative field manipulation leads to 
compression and derecruitment of the neighboring lung. The alternative 
treatment includes maintaining low levels of PEEP without recruitment 

 
31  
  
maneuvers, which can contribute to lung derecruitment, low oxygenation, and 
increased risk of pneumonia after surgery. Of note, our proposed values for 
recruitment maneuvers are substantially different (lower) from those used in the 
recently published ART trial48.  
II. Risks of neuromuscular blockade monitoring and reversal: insufficient use of 
neuromuscular blockade agents can lead to inadequate surgical conditions, and 
their excessive use and/or insufficient (or excessive) reversal are associated with 
postoperative muscle weakness. Muscle weakness can lead to atelectasis, 
hypoxemia, swallowing problems, aspiration of saliva or gastric contents, 
coughing, pneumonia and need for ventilatory support. These are precisely the 
issues the proposed intervention attempts to address and the risk is 
hypothesized to be reduced in the intervention group. Any sign of muscle 
weakness will be notified to the primary team and recorded. Given that the 
control group will follow usual care practices, any safety issues should be 
detectable during interim analysis. There is no alternative of care since muscle 
paralysis is required for this type of surgery.  
III. Risks of incentive spirometry and early ambulation: pain and lightheadedness 
related to hyperventilation and respiratory alkalosis. Other possible adverse 
effects are fatigue and exacerbation of bronchospasm. Most frequently these 
either do not occur or are mild and resolved by interruption of the procedure. If 
patients develop these symptoms during the study interventions, the intervention 
will be stopped temporarily and symptoms addressed. This may include advising 
the patient to requestpain medication from the primary team or resting 
temporarily. Interventions will be re-attempted when the symptoms resolve and 
patients are agreeable to them. The alternative of not performing or substantial 
delay in those interventions can contribute to insufficient lung expansion, low 
oxygenation, and increased risk of pneumonia after surgery.  
IV. Discomfort and hematoma due to blood sampling: Three blood samples will be 
obtained for the study for the analysis of levels of biomarkers of lung injury. 
These risks are possible if a new vascular access is required but should be a 
minor temporary inconvenience. We will attempt to obtain these blood samples 
from existing vascular lines and/or simultaneous to the collection of other blood 
sample needed for clinical analyses. This risk is also present for routine medical 
care.  
V. Risk to patient privacy: Patient information and blood samples are collected for 
this study. Patient information will be de-identified and assigned a study ID but 
there is a possible risk to the patient9s privacy. A list linking patient names to their 
study ID will be kept separate from the data in secure storage. Deidentified data, 
after review by the NHLBI BioLINCC data repository staff, will be available 
through the NHLBI BioLINCC biorepository. The plan to redact or convert all PHI 
data (e.g. date of hospitalization will be converted to days after randomization; 
rare events will be grouped to minimize the risk of participant identification; site 
will not be identifiable from published or internal data) will be reviewed and 
approved by the NHLBI BioLINCC prior to being implemented. Patients will be 
allowed to opt-out of providing the biorepository of blood samples if they do not 

 
32  
  
desire to participate in the availability of their blood samples for future research 
on pulmonary conditions or other research.  
VI. Risk of anxiety: Potential subjects present a possible psychosocial risk of 
developing anxiety by being asked to participate in a research study. We will 
minimize the risk of anxiety by assuring patients that: the study is based on 
sound medical reasoning and data, the study is entirely voluntary, they may 
withdraw and have usual care at any time, their doctors have the last say in the 
manner their care will be provided, and that their decision of whether or not to 
participate will in no way affect their care.  
VII. 
Risk of distress: Participants are at risk of being distressed by one or more 
items  in the questionnaire. We will minimize the risk of distress by reminding     
participants that they may skip any question if they would prefer not to answer.  
  
We do not know the risk of fetal harm with the study protocol, thus, pregnant patients 
are excluded.  
  
Informed Consent   
  
  
Sites with the capability to create an eConsent with a phone script to consent subjects 
remotely prior to their admission for surgery will be allowed to do so.  When used, this 
process will follow the exact wording as the approved informed consent form (ICF), and 
that ICF will be placed in a HIPAA-compliant platform that creates a secure link. A 
phone script to assess subjects9 interest will be used, and, if subjects are interested, 
they will receive a link to eConsent through secure email.  Once the eConsent is signed, 
a copy will be attached to the patient9s medical record.  
   
Massachusetts General Hospital: Informed consent will be requested after 
confirmation of eligibility of inclusion and exclusion criteria of each potential participant.  
All questions and concerns will be addressed prior to obtaining Informed consent.  
Consent will be obtained in person in a private room by one of the licensed physician 
investigators listed on the protocol. Study nurses, coordinators, or other study staff may 
assist in the consent process by explaining the study to potential participants and 
answering  any questions. All subjects will be given the opportunity to speak to a doctor 
during the consent process either in-person or through videoconference. Participants in 
this study must fulfill study criteria and be able to follow instructions of incentive 
spirometry and ambulation, and thus subjects whose cognitive status makes them 
unable to cooperate will not be eligible to participate. A copy of the informed consent will 
be provided to the patient. The original signed informed consent form will be kept locked 
in a secure location in the PI9s or research coordinator9s office. A MGH approved 
eConsent platform can be used.  When used, this process will follow the exact wording 
as the currently approved ICF, and that ICF will be placed in a HIPAA compliant 
platform that creates a secure link. A phone script to assess subjects9 interest will be 
used, and, if subjects are interested, they will receive a secure link to eConsent through 

 
33  
  
email.  Once the eConsent is signed, a  copy will be attached to the patient9s medical 
record.  
  
Brigham and Women’s Hospital:  
  
Informed consent will be requested after confirmation of eligibility of inclusion and 
exclusion criteria of each potential participant. Informed consent will take place in 
person in a private room of a medical center, or by phone conversation if the participant 
agrees to it or through videoconference. Consent will be obtained by one of the licensed 
physician investigators listed on the protocol. Study nurses, coordinators, or other study 
staff may assist in the consent process by explaining the study to potential participants 
and answering questions. Participants to this study must fulfill study criteria and be able 
to follow instructions of incentive spirometry and ambulation, and thus subjects whose 
cognitive status makes them unable to cooperate will not be eligible to participate in this 
study. A copy of the informed consent will be provided to the patient. The original signed 
informed consent form will be kept locked in a secure location in the BWH SICU 
Translational Research Center office. A BWH approved eConsent platform can be used.  
When used, this process will follow the exact wording as the currently approved ICF, 
and that ICF will be placed in a HIPAA compliant platform that creates a secure link. A 
phone script to assess subjects9 interest will be used, and, if subjects are interested,  
they will receive a secure link to eConsent through email.  Once the eConsent is signed, 
a  copy will be attached to the patient9s medical record.  
  
University of Colorado:  
  
Informed consent will be requested after confirmation of eligibility of inclusion and 
exclusion criteria of each potential participant. Informed consent will take place in 
person in a private room of a medical center, or by phone conversation if the participant 
agrees to it or through videoconference. Consent will be obtained by one of the licensed 
physician investigators listed on the protocol. Study nurses, coordinators, or other study 
staff may assist in the consent process by explaining the study to potential participants 
and answering questions. Participants to this study must fulfill study criteria and be able 
to follow instructions of incentive spirometry and ambulation, and thus subjects whose 
cognitive status makes them unable to cooperate will not be eligible to participate in this 
study. A copy of the informed consent will be provided to the patient. The original signed 
informed consent form will be kept locked in a secure location in the University of  
Colorado anesthesiology research personnel office. A University of Colorado approved 
eConsent platform can be used.  When used, this process will follow the exact wording 
as the currently approved ICF, and that ICF will be placed in a HIPAA compliant 
platform that creates a secure link. A phone script to assess subjects9 interest will be 
used, and, if subjects are interested, they will receive a secure link to eConsent through 
email.  Once the eConsent is signed, a  copy will be attached to the patient9s medical 
record.  
  
  

 
34  
  
Duke University Health System:  
  
The study coordinator or research nurse will confirm subject eligibility of inclusion and 
exclusion criteria.  Once confirmed eligible, the study coordinator or research nurse will 
contact the potential subject either in person or via phone or through videoconference.  
Only key personnel trained in conducting informed consent will discuss the study with 
potential subjects.  The participant will provide consent for themselves.  The participant 
will be allowed as much time as they need to decide to participate or to decline.  The 
consent process will take place in a designated private room or over the phone.  All 
questions about the research study will be answered while with the patient.  Contact 
information and a business card will be provided to the subject in the event there are 
additional questions.  There will be no attempt at coercion or undue influence.  Only 
subjects who are capable of performing the study criteria will be approached.  Once 
consent is signed the original will be maintained in the subject9s study file with a copy 
sent to medical records. A Duke University approved eConsent platform can be used.  
When used, this process will follow the exact wording as the currently approved ICF, 
and that ICF will be placed in a HIPAA compliant platform that creates a secure link. A 
phone script to assess subjects9 interest will be used, and, if subjects are interested, 
they will receive a secure link to eConsent through email.  Once the eConsent is signed, 
a  copy will be attached to the patient9s medical record.  
  
Northwestern University/ Northwestern Medicine (NM):  
  
Written informed consent will be requested after confirmation of eligibility of inclusion 
and exclusion criteria of each potential subject. Questions and concerns will be 
addressed by the research study team prior to obtaining written informed consent.  
Written consent will be obtained in person on the day of surgery in a NM hospital room 
by one of the study team members listed in the EIRB.   
Participants in this study must fulfill study criteria and be able to follow instructions of 
incentive spirometry and ambulation, and thus subjects whose cognitive status makes 
them unable to cooperate will not be eligible to participate. A copy of the written 
informed consent will be provided to the patient. One copy will be forwarded to the 
medical records department of NM and the original signed informed consent form will be 
kept locked in a secure location in Arkes Pavilion 10 Floor Anesthesiology Research 
office in a locked storage room which is key card and hard key controlled. A 
Northwestern University approved eConsent platform can be used.  When used, this 
process will follow the exact wording as the currently approved ICF, and that ICF will be 
placed in a HIPAA compliant platform that creates a secure link. A phone script to 
assess subjects9 interest will be used, and, if subjects are interested, they will receive a 
secure link to eConsent through email.  Once the eConsent is signed, a copy will be 
attached to the patient9s medical record.  
  
Beth Israel Deaconess Medical Center:  
  

 
35  
  
Once a patient is found eligible, he or she will be approached by a member of the 
research team for informed consent either in-person or through videoconference.  
Informed consent will take place in the preoperative setting, in the cardiac surgery clinic, 
inpatient floors or PAT clinic.  The study will be discussed and the consent form 
reviewed. The subjects will have the opportunity to ask any and all questions, and are 
free to decline participation at any time. Written informed consent will be obtained prior 
to any research procedures.  Copies of the signed consent will be provided to the 
subject and filed in the medical record while the original is retained by the study 
personnel to be filed in the patient9s study folder kept at a secure location.   
  
The research staff undergoes a rigorous consent training process. Within the Center for 
Anesthesia Research Excellence (CARE) at BIDMC, this training includes: didactic 
sessions, mandated attendance at CCI/HSPO seminars related to the informed consent 
process, shadowing of informed consent in a variety of contexts, trainee-led informed 
consent conversations with the aid of consenting checklists and accompanied by senior 
staff member and/or PI, robust feedback sessions, and clear communication when the 
team member is skilled enough to engage in informed consent discussions without 
direct supervision.  
  
A BIDMC approved eConsent platform can be used.  When used, this process will 
follow the exact wording as the currently approved ICF, and that ICF will be placed in a 
HIPAA compliant platform that creates a secure link. A phone script to assess subjects9 
interest will be used, and, if subjects are interested, they will receive a secure link to 
eConsent through email.  Once the eConsent is signed, a copy will be attached to the 
patient9s medical record.  
  
  
Stanford Hospital and Clinics:  
  
Informed consent will be requested after confirmation of eligibility of inclusion and 
exclusion criteria of each potential participant. All questions and concerns will be 
addressed prior to obtaining Informed consent either in-person or through 
videoconference.  Consent will be obtained in person in a private room by one of the 
licensed physician investigators listed on the protocol. Study coordinator may assist in 
the consent process by explaining the study to potential participants and answering any 
questions. All subjects will be given the opportunity to speak to a doctor during the 
consent process. Participants in this study must fulfill study criteria and be able to follow 
instructions of incentive spirometry and ambulation, and thus subjects whose cognitive 
status makes them unable to cooperate will not be eligible to participate. One copy of 
the informed consent will be provided to the patient and other will remain as part of 
patient9s medical record. The original signed informed consent form will be kept locked 
in a secure location in the PI9s or research coordinator9s office. A Stanford University 
approved eConsent platform can be used.  When used, this process will follow the exact 
wording as the currently approved ICF, and that ICF will be placed in a HIPAA 
compliant platform that creates a secure link. A phone script to assess subjects9 interest 

 
36  
  
will be used, and, if subjects are interested, they will receive a secure link to eConsent 
through email.  Once the eConsent is signed, a copy will be attached to the patient9s 
medical record.  
  
  
UCSF Medical Center at Mission Bay:  
  
Informed consent will be requested after confirmation of eligibility of inclusion and 
exclusion criteria of each potential participant. All questions and concerns will be 
addressed prior to obtaining Informed consent either in-person or through 
videoconference.  Consent will be obtained in person in a private room by one of the 
licensed physician investigators listed on the protocol. Study nurses, coordinators, or 
other study staff may assist in the consent process by explaining the study to potential 
participants and answering  any questions. All subjects will be given the opportunity to 
speak to a doctor during the consent process. Participants in this study must fulfill study 
criteria and be able to follow instructions of incentive spirometry and ambulation, and 
thus subjects whose cognitive status makes them unable to cooperate will not be 
eligible to participate. A copy of the informed consent will be provided to the patient. The 
original signed informed consent form will be kept locked in a secure location in the PI9s 
or research coordinator9s office. A UCSF approved eConsent platform can be used.  
When used, this process will follow the exact wording as the currently approved ICF, 
and that ICF will be placed in a HIPAA compliant platform that creates a secure link. A 
phone script to assess subjects9 interest will be used, and, if subjects are interested, 
they will receive a secure link to eConsent through email.  Once the eConsent is signed, 
a  copy will be attached to the patient9s medical record.  
  
  
University of Rochester Medical Center:    
  
Informed consent will be requested after confirmation of eligibility of inclusion and 
exclusion criteria of each potential participant either in-person or through 
videoconference. All questions and concerns will be addressed prior to obtaining 
Informed consent.  Consent will be obtained in person in a private room by one of the 
research staff members certified to consent participants and listed on the study staff log 
for this protocol.  
  
Study nurses or other study staff may assist in the consent process by explaining the 
study to potential participants and answering any questions. All subjects will be given 
the opportunity to speak to a study staff member during the consent process or to take 
the consent form home to review prior to signing consent. A copy of the signed informed 
consent will be provided to the patient. The original signed informed consent form will 
be kept locked in a secure location in the Anesthesia Clinical Research Center office. A 
URMC approved eConsent platform can be used.  When used, this process will follow 
the exact wording as the currently approved ICF, and that ICF will be placed in a HIPAA 
compliant platform that creates a secure link. A phone script to assess subjects9 interest 

 
37  
  
will be used, and, if subjects are interested, they will receive a secure link to eConsent 
through email.  Once the eConsent is signed, a  copy will be attached to the patient9s 
medical record.  
 
Mayo Clinic Rochester: 
 
Informed consent will be requested after confirmation of eligibility of inclusion and 
exclusion criteria of each potential participant. Informed consent will take place in 
person in a private room of a medical center, or by phone conversation if the participant 
agrees to it. Consent will be obtained by one of the study team members listed on the 
protocol. Study nurses, coordinators, or other study staff may assist in the consent 
process by explaining the study to potential participants and answering questions. 
Participants to this study must fulfill study criteria and be able to follow instructions of 
incentive spirometry and ambulation, and thus subjects whose cognitive status makes 
them unable to cooperate will not be eligible to participate in this study. A copy of the 
informed consent will be provided to the patient. The original signed informed consent 
form will be kept locked in a secure location in the Mayo Clinic Rochester9s Anesthesia 
Clinical Research Unit office. The study team members who will meet with the 
prospective subject and obtain informed consent must be sufficiently trained, 
knowledgeable about the research project in order to answer questions posed by the 
subject and must have IRB approval to obtain consent. 
 
Memorial Sloan Kettering Cancer Center: 
 
Informed consent will be requested after confirmation of eligibility of inclusion and 
exclusion criteria of each potential participant. All questions and concerns will be 
addressed prior to obtaining Informed consent.  Consent will be obtained in person in a 
private room by one of the investigators listed on the protocol. Research nurses, 
coordinators, or other research staff may assist in the consent process by explaining the 
study to potential participants and answering any questions. All subjects will be given 
the opportunity to speak to a doctor during the consent process. Participants in this 
study must fulfill study criteria and be able to follow instructions of incentive spirometry 
and ambulation, and thus subjects whose cognitive status makes them unable to 
cooperate will not be eligible to participate. A copy of the informed consent will be 
provided to the patient. The original signed informed consent form will be kept locked in 
a secure location in the PI9s or research coordinator9s office and a copy will be scanned 
to the patient9s electronic medical record. 
 
 
University of Massachusetts Medical School- Hospital System:  
 
Informed consent will be requested after confirmation of eligibility of inclusion and 
exclusion criteria of each potential participant. All questions and concerns will be 

 
38  
  
addressed prior to obtaining Informed consent.  Consent will be obtained in person or 
virtually in a private room by one of the members of the study staff. Study nurses, 
coordinators, or other study staff may assist in the consent process by explaining the 
study to potential participants and answering any questions. All subjects will be given 
the opportunity to speak to a doctor during the consent process. Participants in this 
study must fulfill study criteria and be able to follow instructions of incentive spirometry 
and ambulation, and thus subjects whose cognitive status makes them unable to 
cooperate will not be eligible to participate. A copy of the informed consent will be 
provided to the patient. The original signed informed consent form will be kept locked in 
a secure location in the PI9s or research coordinator9s office/laboratory. 
 
Columbia University Irving Medical Center:  
 
Informed consent will be requested after confirmation of eligibility of inclusion and 
exclusion criteria of each potential participant. Informed consent will take place in 
person at the medical center, or by phone conversation if the participant agrees to it. 
Consent will be obtained by one of the study team members listed on the protocol. 
Study nurses, coordinators, or other study staff may assist in the consent process by 
explaining the study to potential participants and answering questions. Participants to 
this study must fulfill study criteria and be able to follow instructions of incentive 
spirometry and ambulation, and thus subjects whose cognitive status makes them 
unable to cooperate will not be eligible to participate in this study. A copy of the 
informed consent will be provided to the patient. The original signed informed consent 
form will be kept locked in a secure location in the Columbia University Irving Medical 
Center9s Anesthesia Clinical Research Unit office. 
 
Cleveland Clinic Foundation:  
 
We are requesting approval for virtual consent for this study as well as approval of a 
phone script to use in the consenting process. 
Please see below for a summary of the remote consent process: 
The main way we plan to consent will be remotely via DocuSign and this process is 
described here. There will be a focus on obtaining patient consent remotely. We are 
proposing to use the new DocuSign (Part 11 Compliant) platform that will allow a patient 
to provide consent remotely via electronic signature. The process of obtaining consent 
will be as follows: 
 
- Once the patient has been determined as potentially eligible, they will be contacted via 
remote platform (telephone or video platform) for a discussion regarding this study using 
an IRB approved phone script. A member of the study team will verify the patient's 
identity, present the consent via email with IRB approved cover letter language (with the 
patients approval to receive e-mail and verifying their email address) along with 
instructions for using DocuSign and answer any initial questions the patient may have. 

 
39  
  
The patient will be given sufficient time to review the consent. After the patient has 
reviewed and has expressed interest in the trial, one of the clinical team members will 
again review the consent via remote platform (telephone or video platform), answer any 
remaining questions, and ensure the patient9s understanding. That clinical team 
member will then provide instructions on how the patient will sign the consent via the 
DocuSign platform. The patient will sign the consent electronically. The clinical team 
member will then provide their signature as the person obtaining consent electronically. 
The clinical team member will document the entire process, including whether the 
patient consented to the trial, in the patient9s electronic medical record. The patient will 
be provided a copy of the signed informed consent form. 
 
Any patient not signing consent via DocuSign will follow this procedure for in-person 
consenting: 
- Once a patient has been determined to be potentially eligible for this study, a member 
of the study team will present the study as a potential treatment option to the patient 
during an in-person visit in a private room and answer any initial questions the patient 
may have. After the patient has had sufficient time to review the informed consent, the 
clinical research coordinator will again review the study with the patient, ensure the 
patient9s understanding of the study and answer all of the patient9s questions. 
 
The study team member will then witness the patient signing the informed consent and 
will also sign the informed consent. The patient will be given a copy of the signed 
consent. The study team member will document the entire interview process per IRB 
Policy, including whether the patient consented to the trial, in the patient9s electronic 
medical record. 
 
Protections Against Risk  
The study design implies a high degree of individual attention to each patient during the 
performance of the study. Consequently, safety is evaluated in a continuous basis 
during execution of the study. At least one physician or research coordinator of the 
study team will be available throughout the entire study.   
As an overarching principle, the primary clinical team caring for the patients along the 
study (anesthesiologists, surgeons, and nurses) can intervene at any time if it is 
believed that patients are at risk.   
The planned strategies for protecting participants from identified potential risks related 
to this study include:  
I. 
Hemodynamic instability: The recruitment maneuver and PEEP adjustment will 
be interrupted if the patient becomes bradycardic or tachycardic, develops a new 
arrhythmia, or becomes severely hypotensive (systolic blood pressure < 80 
mmHg or mean blood pressure <50 mmHg). The patient will be managed by the 
primary anesthesia team if any hemodynamic changes occur during the 
recruitment maneuver or decremental PEEP titration. PEEP levels will be 
decreased for any urgent clinical reasons at the discretion of the managing 
anesthesia team. In the absence of an emergency need for change, the 

 
40  
  
anesthesia team caring for the patient will consider addressing any reasons of 
hemodynamic changes with intravenous fluids, vasoactive medications, and/or a 
stepwise adjustment of PEEP consisting of reducing PEEP by 2-5 cmH2O. The 
anesthesia team will reassess repeating the recruitment maneuvers and  
PEEP optimization once the patient is stable (heart rate <100 beats/minute, 
SBP>100 mmHg). Anesthesiologists are experienced at reducing or responding 
to these events during usual care for surgery.   
II. Respiratory deterioration: It is at the primary anesthesiologist9s discretion to 
change the protocol ventilator settings if any emergent respiratory deterioration is 
observed. In the absence of an emergency need for change, a new PEEP 
optimization will be performed. If it fails to improve SpO2, FIO2 will be increased 
by 0.1-0.2 until a SpO2 96% is obtained. If plateau pressures are beyond 30 
cmH2O, we will follow the guidelines provided by the ARDSnet to maintain 
plateau pressures below this threshold17: if Pplat >30 cmH2O: decrease VT by 
1mL/kg PBW steps (minimum = 4 mL/kg PBW); if later Pplat <25 cmH2O and VT 
<6 mL/kg PBW, increase VT by 1 mL/kg PBW until Pplat >25 cmH2O or VT=6 
mL/kg PBW; if Pplat <30 cmH2O and breath stacking or dyssynchrony occurs, VT 
may be increased in 1mL/kg PBW increments to 7 or 8 mL/kg PBW as long as 
Pplat remains f30 cmH2O.  
III. Pneumothorax: Before and during any recruitment maneuver, signs of excessive 
airway pressure will be searched for to prevent barotrauma and pneumothorax. 
During recruitment maneuvers, sufficient depth of anesthesia will be ensured to 
minimize the risk of barotrauma caused by patients9 gasping or opposing 
ventilation. Also, as mentioned before, plateau pressure f30 cmH2O during 
ongoing ventilation will always be targeted. Anesthesiologists are experienced at 
reducing or responding to these events during usual care for surgery.  
IV. Amongst the potential adverse effects, development of hemodynamic instability 
or worsened oxygenation to increases in PEEP to values g10 cmH2O during 2 
separate attempts will lead to discontinuation of intervention until susceptibility 
factors are corrected. Continuation will only be pursued if approved by the 
primary clinical care team. PEEP can be modified at any time at the primary 
anesthesiologist's discretion if considered clinically needed for any reason, 
including but not limited to: (i) Systolic arterial pressure lower than 90 mmHg for 
more than 3 min not responding to fluids and/or vasoactive drugs; (ii) New 
arrhythmias not responding to the treatment suggested by the Advanced Cardiac 
Life Support Guidelines; (iii) Need for a dosage of vasoactive drugs at the highest 
level tolerated, upon the attending physician9s evaluation; (iv) Need of massive 
transfusion to maintain hematocrit > 21% (hemoglobin > 7 mg/dl); (v) Life-
threatening surgical complication. The welfare of the patient will always be 
prioritized over their participation in the study. In such circumstances, the 
interventions will be stopped as appropriate.   
V. Risk of muscle weakness due to inadequate muscle paralysis management. Our 
intervention bundle has been designed to reduce residual muscle weakness after 
surgery by protocolizing muscle paralysis administration and reversal. Thus, our 

 
41  
  
intervention patients should have a lower risk of muscle weakness than patients 
receiving standard of care. Muscle weakness can contribute to atelectasis, poor 
oxygenation, swallowing problems, aspiration of saliva or gastric contents, 
coughing, and pneumonia. If during our study visits we suspect this problem in 
any study patient, we will record it and notify the patient9s primary care team. 
Anesthesiologists are experienced at reducing or responding to these risks that 
sometimes occur during usual care for surgery.  
VI. Risk of pain and lightheadedness from incentive spirometry and early ambulation 
after surgery: Pain will be assessed before starting incentive spirometry 
exercises and/or ambulation, and these interventions may be delayed until pain 
is better controlled. Should a participant complain about pain during these 
postoperative interventions to the research coordinator, the interventions will be 
interrupted, and the research coordinator will instruct the participant to inform his 
/her care team about the pain and inability to perform incentive spirometry and/or 
ambulation. Pain management through oral, intravenous or epidural anesthesia 
composes the standard of care in these cases as are orders for additional doses 
as needed in case of discomfort.  If incentive spirometry is done repeatedly too 
fast, or if standing up is performed too quickly, they can cause a slight temporary 
lightheadedness. The research coordinator will instruct the patient to do the 
incentive spirometry and ambulation more slowly and/or pause until the 
lightheadedness resolves. These two interventions are considered standard of 
care, as are the precautions to minimize their risks. In any case, patient safety 
will be prioritized. The alternative of not performing or delaying those 
interventions can contribute to insufficient lung expansion, low oxygenation, and 
increased risk of pneumonia after surgery.   
VII. Discomfort and hematoma due to blood sampling: In order to minimize patient 
discomfort, we will attempt to synchronize routine blood test samples for clinical 
care with the collection of blood samples for the study whenever possible. Local 
pressure will be applied to minimize the risk of hematoma. Only experienced 
personnel in venipuncture will attempt to obtain these blood samples.  
VIII. Risk to patient privacy: Patient information will be de-identified and assigned a 
study ID that will be used for all data records and blood samples. A list linking 
patient names to their study ID will be kept separate from the data in secure 
storage. Deidentified data, after review by the NHLBI BioLINCC data repository 
staff, will be available through the NHLBI BioLINCC biorepository.  The plan to 
redact or convert all PHI data (e.g. date of hospitalization will be converted to 
days after randomization; rare events will be grouped to minimize the risk of 
participant identification; site will not be identifiable from published or internal 
data) will be reviewed and approved by the NHLBI BioLINCC prior to being 
implemented. Patients will be allowed to opt-out the biorepository of blood 
samples if they do not desire to participate in the availability of their blood 
samples for future research on pulmonary conditions or other research. All 
individually identifiable information (signed consent forms, data collection sheets) 
will be stored in a secure, locked, location in the site PI's office. 

 
42  
  
Passwordprotected computer databases will be used with limited access to the 
study data. An electronic data capture (EDC) system at the SDCC will be used to 
store all study data. Participants will be identified only by study ID also in this 
data system.  This system, which is both HIPAA and 21CFR11 compliant, is 
secured from unauthorized use within the Partners IT infrastructure used to 
project the Massachusetts General Hospital's own hospital data.   
IX. Risk of anxiety: We will minimize the risk of anxiety by assuring patients that: the 
study is based on sound medical reasoning and data, the study is entirely 
voluntary, they may withdraw and have usual care at any time, their doctors have 
the last say in the manner their care will be provided, and that their decision of 
whether or not to participate will in no way affect their care.   
X. Risk of distress: We will minimize the risk of distress by reminding participants 
that they may skip any question if they would prefer not to answer.  
If any incidental findings are discovered from participants9 interactions with the 
research team, they will be communicated to the patient9s primary medical team as 
appropriate for further handling.   
  
VIII. POTENTIAL BENEFITS  
  
In this study, we will determine whether an anesthesia-centered bundle involving 
individualization of PEEP level during abdominal surgery, optimized neuromuscular 
blockade administration and reversal, and supervision of incentive spirometry/early 
mobilization after surgery after preoperative patient education will reduce the 
occurrence of pulmonary complications after surgery. Each one of these interventions 
have been suggested in our pilot studies and in previous publications to reduce the 
likelihood of postoperative pulmonary complications. Accordingly, we presume that 
patients receiving the intervention could benefit from it by having a reduced incidence 
and severity of postoperative pulmonary complications.  
Because patients with a large range of intraoperative surgical requirements and 
characteristics related to restriction of lung expansion as well as anthropometric 
characteristics undergo abdominal surgery, use of fixed PEEP values is not likely to be 
an optimal strategy to achieve a protective ventilatory strategy in clinical practice. For 
instance, the PEEP level for optimal lung recruitment in a thin small female patient is 
expected to be substantially different from that required in a large muscular male 
patient. Use of a fixed large PEEP in a higher PEEP interventional arm could lead to 
lung overexpansion in some cases, and insufficient expansion in others, ultimately 
increasing the risk for ventilator associated lung injury. Similarly, in the same patient the 
respiratory conditions change rapidly during surgery, and the optimum PEEP during 
periods with the surgical retractors constraining the lung expansion, for example, will 
likely be very different than periods without them. Accordingly, we presume that enrolled 
subjects who receive individualization of PEEP settings to achieve optimal individual 
ventilation would have optimal intraoperative mechanical ventilation during abdominal 
surgery and their risk of experiencing pulmonary complications after their surgery may 

 
43  
  
be lower compared to the usual care group. This rationale is also true for other efforts in 
our bundle to optimize lung expansion during and after surgery, including by avoiding 
muscle weakness after surgery and encouraging early mobilization and incentive 
spirometry exercises. The risks to subjects related to our intervention bundle include 
episodes of lower blood pressure that may happen during recruitment maneuvers and 
PEEP management. This potential risk, and others, is also present during usual care 
with mechanical ventilation for surgery, and anesthesiologists are particularly 
experienced at reducing and managing intraoperative low blood pressure and other 
possible complications. We have established specific processes to minimize these 
otherwise standard risks for any patient undergoing surgery and, thus, we believe our 
study-specific risks are reasonable in relation to the anticipated benefits to research 
participants and others.  
The benefit to future patients and the health care system can also be important. Indeed, 
PPCs affect more than a million patients every year in the US, with 46,200 additional 
deaths, and 4.8 million additional days of hospitalization. Abdominal surgery is 
associated with the largest absolute number of PPCs. Respiratory complications have 
been reported as the costliest major postoperative complication. US estimates suggest 
that PPCs add $717 to the average cost of each elective surgery, 92,200 additional 
intensive care unit (ICU) admissions, 584,300 additional ICU days, and $3.42 billion in 
additional costs18. There is a remarkable paucity of high-level data in this field. If we 
establish that our bundle is relevant to postoperative pulmonary complications, this 
would provide evidence to modify clinical practice towards use of specific protective 
methods for intraoperative ventilatory settings, neuromuscular blockade administration 
and reversal, and early mobilization and incentive spirometry after abdominal surgery. 
Future patients would benefit from significant risk reduction in postoperative pulmonary 
complications and related morbidity and mortality. The health care system could also 
benefit substantially with reduction in costs of postoperative care.  
  
IX. MONITORING AND QUALITY ASSURANCE   
  
This study is implemented with a Data Safety Monitoring Board established by the 
NIH/NHLBI and a Medical Monitor. The SDCC will perform checks on accuracy and 
completeness of case report forms in StudyTRAX and other electronic data capture 
systems.   
 
The SDCC will generate performance reports for individual sites monthly. The CCC will 
approach sites with performance issues to resolve them in a timely manner.  
  
Because no new medication, new medical interventions, or new device is used in this 
study, except for the risks under the standard medical procedures, no additional 
adverse events are expected. The study design implies a high degree of individual 
attention to each patient during the performance of the study. Consequently, safety is 
evaluated in a continuous basis during execution of the study. The principal investigator 

 
44  
  
will be responsible to review safety information, communicate with the IRB and other 
members of the research team, and alter or stop the study.   
  
The DSMB has been convened by the NIH-NHLBI for oversight of this trial. The 
principal investigator is responsible for submitting all communications received from the 
DSMB to the IRB. 
  
At least one physician investigator will be immediately available throughout the entire 
study. Adverse events will be discussed with all research staff.   
  
We will comply with all policies and requirements for data safety and monitoring 
specified by the Partners single IRB (sIRB), the DSMB, or NHLBI. Consistent with 
NHLBI reporting guidelines, PRIME-AIR investigators will notify the SDCC as soon as 
possible, but no later than seven calendar days after becoming aware of all SAEs, and 
within 15 calendar days of becoming aware of all other AEs. In addition, we propose 
that specific events (listed below) occurring during surgery that might be related to study 
procedures be reported as soon as possible, but not later than seven calendar days 
after the investigator becomes aware of their occurrence, whether serious or not.  
  
AE reporting: There is a high complication rate after major abdominal surgery. Virtually 
any complication could increase duration of hospitalization and, thus, be defined as a 
SAE. For this reason, we propose to follow the approach defined on Table 7 to define 
the subset of AEs that needs to be reported with AE forms, AEs that will be reported as 
outcomes in the daily/discharge forms, or both. A subset of AEs will have expedited 
reporting to the sIRB and DSMB within 24 hours or 7 days of receipt by the SDCC, and 
these are described in detail below. 
 
Table 7: AE Reporting – PRIME-AIR Study 
AE Reporting Criteria 
Actions 
Serious 
File AE Form 
Unexpected 
File AE Form 
Targeted AE* 
File AE Form 
Report as clinical outcome in the corresponding 
clinical report forms 
Other PRIME-AIR clinical 
outcomes not included 
above. 
Report as clinical outcome in the corresponding 
clinical report forms 
AE not included above and 
expected, not serious, or not 
a clinical outcome 
Not reported 

 
45  
  
 
*Targeted AEs:  
Acute myocardial ischemia or infarction 
Cardiogenic pulmonary edema 
Arrhythmia 
Cardiac arrest 
Stroke 
GI bleeding 
Anastomotic Breakdown 
Paralytic ileus 
Acute liver failure 
Acute renal failure 
Systemic inflammatory response syndrome 
Surgical site infection 
Urinary tract infection 
Bacteremia 
Sepsis 
Septic shock 
Infection - source uncertain 
Disseminated intravascular coagulation 
Postoperative hemorrhage 
Thromboembolism 
Pulmonary embolism 
ARDS 
 
AEs with Expedited Reporting: Only a subset of SAEs will have expedited reporting to 
the sIRB and the DSMB. We propose that only the following categories of events have 
expedited reporting (within 7 days of receipt by the SDCC):  
• Any unanticipated problem (defined in the Detailed Protocol);  
• Any AE that is serious, unexpected and suspected of being related (probably or 
possibly related) to the study procedures;   
• Any occurrence of hemodynamic or respiratory instability, or pneumothorax, 
occurring during surgery and potentially arising from participation in the study.  
• All adverse events that are serious, unexpected and occurring intraoperatively 
and immediately postoperatively (Day 0-1).   
  
Definition of severe intraoperative respiratory AEs and hemodynamic instability. We 
define the intraoperative adverse events related to severe respiratory events (severe 
hypoxemia, pneumothorax) or severe hemodynamic instability as follows:  
• Severe hypoxemia: SpO2 f92% or 2% below the participant's preoperative room 
air value (if that value is f92%) for at least 10 minutes; OR increase in FiO2 to 
1.0 preceded by a SpO2 f95% in the previous 5 minutes (excluding in 
preparation for extubation); AND requiring treatment in intensity or duration 

 
46  
  
beyond the usual intraoperative requirements according to the participant9s 
anesthesiologist.  
• Pneumothorax: presence of air in the pleural cavity occurring during surgery and 
requiring intervention  
• Hemodynamic instability: SBP>160 or <80 mmHg, MAP>120 or <50 mmHg, 
HR>140 or <50 bpm, or deviations by more than 20% in any of those 
parameters from patient9s baseline for >3 minutes despite treatment or cardiac 
events (e.g. significant arrhythmias, ST segment changes or cardiac arrest); 
AND requiring treatment in intensity or duration beyond the usual intraoperative 
requirements according to the participant9s anesthesiologist  
  
Relatedness is determined by the site PI, recognizing that the site PI may not be blind 
to the treatment intervention. The reports are also assessed by an independent 
Medical Monitor. 
 
  
Site-PIs will be instructed to report fatal AEs as soon as possible, latest within 24 h after 
becoming aware of the event. The sIRB, NHLBI, DSMB and CCC PIs will be notified as 
soon as the information is confirmed. The report to the DSMB will be blinded.  
  
Events assessed as unrelated to participation in the study (including hemodynamic 
instability, respiratory deterioration, and pneumothorax that occur during surgery 
because of causes unrelated to participation in the study or occur after the end of 
surgery and anesthesia) will be reported within 15 calendar days to the SDCC.  
  
For the expedited events listed above, the SDCC will have reporting procedures to 
notify, the CCC Co-PIs and CCC manager, the sIRB for the study, and NHLBI of the 
events listed above. Specific mechanisms for reporting these events to the sIRB for the 
study and NHLBI will be developed collaboratively with the sIRB and the NHLBI. 
Reports will be filed with the sIRB and NHLBI. All SAEs will be reported by the site PI in 
a blinded fashion and adjudicated by the blinded study PI for expectedness and 
relatedness to the study procedure.  
  
For each expedited report, one of the CCC Co-PIs will contact the site PI and review the  
issue prior to the next weekly Study Management Committee meeting. Unanticipated 
problems and AEs that are serious, unexpected and suspected of being related (or 
possibly related) to the study procedures will be discussed at the next weekly Study 
Management Committee meeting. Any occurrence of hemodynamic instability, 
respiratory deterioration, or pneumothorax occurring during surgery and potentially 
arising from participation in the study will be discussed at the next weekly Study 
Management Committee meeting.  
 
Because of the importance of these events, this topic will be a standing item on the 
meeting agenda after the first patient is enrolled on the study, and the SDCC notifies the 

 
47  
  
CCC and the Medical Monitor about them daily. The occurrence of hemodynamic 
instability, respiratory deterioration, or pneumothorax occurring during the surgery and 
thought to relate to the intervention bundle will lead to site or attending anesthesiologist 
retraining on the intervention bundle if appropriate. All sites will be trained in the 
consistent assessment and reporting of adverse events.  
  
The DSMB letter resulting from its review of AEs and SAEs will be submitted to the sIRB 
within 7 calendar days of receipt.     
  
  
 

 
48  
  
X. REFERENCES   
  
  
1. Lawrence VA, Hilsenbeck SG, Mulrow CD, Dhanda R, Sapp J, Page CP: Incidence 
and hospital stay for cardiac and pulmonary complications after abdominal surgery. 
J Gen Intern Med 1995; 10:671–8  
2. Shander A, Fleisher LA, Barie PS, Bigatello LM, Sladen RN, Watson CB: Clinical 
and economic burden of postoperative pulmonary complications: patient safety 
summit on definition, risk-reducing interventions, and preventive strategies. Crit 
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55  
  
Appendix I – Definitions of Outcomes 
 
 
 
List and definitions of secondary and exploratory outcomes: 
 
− All-cause mortality at 7, 30 and 90 days: mortality for any cause within 7, 30, 
and 90 days after the day of surgery; 
 
− Grade 3 and 4 PPCs at 30 and 90 days: individual grade 3 and 4 PPCs within 
30 and 90 days after the day of surgery; 
 
− Presence of each of the individual components of the list of pulmonary 
complications in the primary endpoint (Table 5) within 7, 30 and 90 days after 
the day of surgery; 
 
− Rate of intraoperative adverse events (hypoxemia, hypotension during lung 
recruitment, need for vasoactive medications and volume replacement, 
muscle weakness.  This will be assessed as TOF<0.9 after extubation, or, in 
the absence of quantitative assessment, clinical assessments such as 
inability to generate a tidal volume above 4ml/kg of predicted body weight, 
PBW,  at time of extubation or to maintain sustained hand grip or 5-s head lift, 
presence of diplopia or ventilatory failure after extubation); 
 
− Rate of major extrapulmonary complications, defined based on existing 
diagnosis in the medical chart following usual accepted definitions61 unless 
otherwise specified: 
 
• Cardiovascular: 
o myocardial ischemia or infarction: Increase in serum cardiac 
biomarker values (preferably cardiac troponin) with at least one 
value above the 99th percentile upper reference limit and at least 
one of the following criteria65: 
- Symptoms of myocardial ischemia; 
- New ischemic ECG changes; 
- Development of pathological Q waves; 
- Imaging evidence of new loss of viable myocardium or new 
regional wall motion abnormality in a pattern consistent 
with an ischemic etiology; 
- Identification of a coronary thrombus by angiography or 
autopsy. 
o cardiogenic pulmonary edema: Cardiogenic pulmonary edema is 
defined as evidence of fluid accumulation in the alveoli due to poor 
cardiac function. 

 
56  
  
o arrhythmia: electrocardiograph (ECG) evidence of cardiac rhythm 
disturbance. 
o cardiac arrest: The International Liaison Committee on 
Resuscitation defines cardiac arrest as the cessation of cardiac 
mechanical activity, as confirmed by the absence of signs of 
circulation68.   
o stroke: defined as an embolic, thrombotic or hemorrhagic cerebral 
event with persistent residual motor, sensory or cognitive 
dysfunction (e.g. hemiplegia, hemiparesis, aphasia, sensory 
deficit, impaired memory).                                                           
 
• Gastrointestinal:  
o bleeding: Gastrointestinal bleed is defined as unambiguous clinical 
or endoscopic evidence of blood in the gastrointestinal tract. 
Upper gastrointestinal bleeding (or hemorrhage) is that originating 
proximal to the ligament of Treitz, in practice from the esophagus, 
stomach and duodenum. Lower gastrointestinal bleeding is that 
originating from the small bowel or colon.  
o anastomotic breakdown: Leak of luminal contents from a surgical 
connection between two hollow viscera. The luminal contents may 
emerge either through the wound or at the drain site, or they may 
collect near the anastomosis, causing fever, abscess, septicemia, 
metabolic disturbance and/or multiple organ failure. The escape of 
luminal contents from the site of the anastomosis into an adjacent 
localized area, detected by imaging, in the absence of clinical 
symptoms and signs should be recorded as a subclinical leak69. 
o paralytic ileus; Failure to tolerate solid food or defecate for three or 
more days after surgery70. 
 
• Liver Disease:  
Liver failure: serum bilirubin level>34 μmol/L with elevation of the 
transaminase and lactic dehydrogenase levels above twice normal 
values. 
 
• Acute renal failure: Stage 1 or higher Kidney Disease Improving Global 
Outcomes (KDIGO) guidelines71  (Table A1). 
 
Table A1 Kidney Disease Improving Global Outcomes Guidelines (KIDGO) 
Stage 
Serum Creatinine 
Urine Output 
1 
1.5–1.9 times baseline value within 7 days  
or  
27mmol/L (0.3 mg/dL) increase within 48 h 
0.5 mL/kg/h for 6–12 h 
2 
2.0–2.9 times baseline value within 7 days  
0.5 mL/kg/h for 12 h 

 
57  
  
3 
3.0 times baseline value within 7 days  
or 
Increase in serum creatinine to 354 mmol/L 
(4.0 mg/dL with an acute rise of >44 
mmol/L (0.5 mg/dL) 
or 
Initiation of renal replacement therapy 
0.3 mL/kg/h for 24 h  
or  
Anuria for 12 h 
 
• Systemic inflammatory response syndrome (SIRS): Defined by the 
presence of two or more of the following60 
o Temperature >38°C or <36°C 
o Heart rate >90/min 
o Respiratory rate >20/min or PaCO2 <32 mmHg (4.3 kPa) 
o White blood cell count >12 000/mm
3 or <4000/mm
3  
 
• Infections  
o Source uncertain: The CDC defines infection, source uncertain as 
one where there is strong clinical suspicion of infection but the 
source has not been confirmed because clinical information 
suggests more than one possible site, meeting two or more of the 
following criteria72 core temperature <36°C or >38°C; white cell 
count >12 x 109/L  or <4 x 109/L; respiratory rate >20 
breaths/minute or PaCO2 <4.7 kPa (35mmHg); pulse rate >90 
beats/minute 
o Bacteremia (bloodstream infection): The CDC defines laboratory 
confirmed bloodstream infection as one which meets at least one 
of the following criteria72 which should not be related to infection at 
another site:  
1) Patient has a recognized pathogen cultured from one or 
more blood cultures and the organism cultured from blood 
is not related to an infection at another site. 
2) Patient has at least one of the following signs or symptoms: 
fever > 38°C, chills or hypotension, and at least one of the 
following: 
a. Common skin contaminant cultured from two or 
more blood cultures drawn on separate occasions 
b. Common skin contaminant cultured from at least one 
blood culture from a patient with an intravascular 
line, and the physician institutes appropriate 
antimicrobial therapy 
c. Positive blood antigen test. 
o Sepsis: defined following the Sepsis-3 criteria60. Sepsis is a life-
threatening organ dysfunction caused by a dysregulated host 
response to infection. Organ dysfunction can be identified as an 
acute change in total SOFA score 2 points consequent to the 

 
58  
  
infection. The baseline SOFA score can be assumed to be zero in 
patients not known to have preexisting organ dysfunction. The 
SOFA score is included in the table below 
 
o Surgical site infection: defined as one which meets the following 
criteria72. 
1) Infection occurs within 30 days after surgery and 
2) Involves skin and subcutaneous tissue of the incision, or 
deep soft tissues (e.g. fascial and muscle layers) of the 
incision, or the infection appears to be related to the 
surgical procedure and involves any part of the body, 
excluding the skin incision, fascia or muscle layers opened 
or manipulated during the operative procedure. 
3) The patient has at least one of the following: 
a. purulent drainage from the superficial/deep incision 
or from a drain that is placed through a stab wound 
into the organ/space 
b. organisms isolated from an aseptically obtained 
culture of fluid or tissue from the superficial incision 
c. at least one of the following symptoms or signs of 
infection:  
i. pain or tenderness, localized swelling, 
redness or heat, and superficial incision is 
deliberately opened by surgeon and is culture 
positive or not cultured. A culture negative 
finding does not meet this criterion. 
ii. a deep incision spontaneously dehisces or is 
deliberately opened by a surgeon and is 
culture-positive or not cultured when the 
patient has at least one of the following 
symptoms or signs: fever (> 38°C), or 

 
59  
  
localized pain or tenderness. A culture-
negative finding does not meet this criterion. 
iii. an abscess or other evidence of infection 
involving the deep incision is found on direct 
examination, during surgery, or by 
histopathological or radiological examination.  
iv. an abscess or other evidence of infection 
involving the organ/space that is found on 
direct examination, during reoperation or by 
histopathological or radiological examination. 
d. diagnosis of a surgical site infection by a surgeon or 
attending physician.  
o Urinary tract infection: A simplified version of the CDC 
recommendations defines a urinary tract infection as follows: a 
positive urine culture of 105 colony forming units per mL with no 
more than two species of micro-organisms, and with at least one 
of the following symptoms or signs: fever (> 38°C), urgency, 
frequency, dysuria, suprapubic tenderness, costovertebral angle 
pain or tenderness with no other recognized cause72.  
 
• Coagulation  
o Disseminated Intravascular Coagulation (DIC): defined following 
the 2001 definition by the International Society on Thrombosis and 
Hemostasis (ISTH): <DIC is an acquired syndrome characterized 
by the intravascular activation of coagulation without a specific 
localization and arising from different causes. It can originate from 
and cause damage to the microvasculature, which if sufficiently 
severe, can produce organ dysfunction=74. It will be diagnosed 
following the modified algorithm currently used and described75: 
 
 

 
60  
  
 
 
 
o Postoperative hemorrhage: defined as blood loss within 72 h after 
the start of surgery which would normally result in transfusion of 
blood. 
o Thromboembolism: A new blood clot or thrombus or embolus 
reducing blood circulation within the venous or arterial systems 
with the exception of the pulmonary venous system. 
o Pulmonary embolism: A new blood clot or thrombus or embolus 
reducing blood circulation within the venous pulmonary system.  
 
• Other (describe): 
 
− Length of stay in the post-anesthesia care unit 
 
− Length of postoperative oxygen therapy/other respiratory support 
 
− Unexpected admission to ICU 
 
− Length of ICU stay 
 
− Length of hospital stay 
 
− Hospital readmission(s) after initial discharge 
 
− Patient-Reported Outcomes Measurements (PROMIS®) short forms 
(Appendix IV) addressing: Dyspnea Characteristics, Severity and Functional 
Limitations; and Fatigue, at days 7, 30 and 90 after the day of surgery, 
compared to before surgery. 
 
− Plasma concentrations (raw and ratios compared to individual9s levels before 
surgery) of selected biomarkers of inflammatory, epithelial and endothelial 
injury. 
 
 
 

 
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Appendix II - Written educational material for the intervention 
group 
 
Patient Education for the PRIME-AIR study  
Our goal with this study is to reduce respiratory complications after abdominal 
surgery. These complications are one of the main reasons why patients like you have a 
slower recovery and stay in the hospital longer. We think that keeping your lungs 8open9 
(well filled with air) may improve the amount of oxygen in your blood, reduce the risk of 
lung infection and other respiratory complications and lower the need for breathing 
treatments.  
What we will do:  
• Before surgery: We will teach you breathing exercises (incentive spirometry).  
• During surgery: We will use the ventilator (the machine that helps you breathe 
during surgery) to keep your lungs well inflated during your surgery. We will also 
make sure that your muscles are not weak at the end of surgery. You will be under 
anesthesia for this part and not aware of it. 
• After surgery: We will work with you so that you do your breathing exercises well 
after surgery. We will also check that you are getting out of bed and starting to walk 
as expected. We will check on you and your medical chart to record your respiratory 
symptoms, complications and treatments. We will do this several times every day 
after your surgery until you leave the hospital or up to 7 days after your surgery. We 
will follow up with you by calling you at home or visiting you at the hospital after 7, 30 
and 90 days have passed after your surgery.  
What we would like you to do: Follow current recommendations for patients 
after surgery like yours. These include breathing exercises (incentive spirometry) 
and ambulation to keep your lungs open after surgery. 
• Keep the head of your bed elevated (higher than 30°), if possible. 
• Do your breathing exercises (incentive spirometry). For these:  
o Keep the incentive spirometer within reach. 
o Sit up as straight as possible and cough to clear your lungs if needed.  
− Support your incision with a pillow or by hugging your belly with your arm 
o Place your lips around the mouthpiece and hold the incentive spirometer upright.  
o Breathe in slowly and as deeply as possible by raising the ball or the 
piston/plate in the chamber of your device to the set target; hold your breath 
for at least 5 seconds once your lungs are full. If your incentive spirometer 
has a floating ball, your goal is to keep that ball in the middle of the chamber 
while you breathe in. 
o Exhale slowly and repeat. 
o Do 10 incentive spirometry breaths every hour while awake for at least 10 hours 
per day. This will add up to at least 100 deep breaths/day. 
• As soon as you can after surgery, get out of bed and walk (ambulation) 
o Check with your nurses and doctors if it is safe to move, and get assistance. 

 
62  
  
o Please ask your nurse or doctor for pain medication if you need it for controlling 
your pain. 
o We hope that you can achieve these goals:  
− Day-of-surgery (Day 0): sit up in a chair with assistance.  
− Day after surgery (Day 1): sit up in a chair 3 times/day for meals; walk in 
room or hallway 2 times/day with assistance.  
− Day 2: get out of bed for all meals and for at least 6 hours during the day; 
walk in hallway more than 15 meters (about 50 feet) or approx. 20 steps) 3 
times/day with assistance.  
− Day 3 and on: increase ambulation, ideally walking beyond 75 m (about 
250 feet or approx. 100 steps) 3–5 times/day. 
Thank you for participating in this study! 
 
 

 
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Appendix III -   Maximal compliance strategy for PEEP titration 
 
Ventilatory 
Settings 
• Volume-controlled ventilation, square flow-waveform  
• VT=7 mL/kgPBW, adjustment to 6-8 ml/kg PBW if required 
• RR=12 bpm titrated to PetCO2=35-45 mmHg  
• FIO2 g0.4 to SpO2g96% 
• I:E  ratio started at 1:2 and adjusted if necessary to the patient9s 
physiology 
• Inspiratory pause 20% 
• Maximum acceptable plateau pressure 30 cmH2O, VT will be reduced if 
needed to achieve that value 
 
Decremental PEEP titration 
When 
• Immediately following intubation;  
• After any intervention potentially associated with lung collapse such as 
application of surgical retractors, pneumoperitoneum 
insufflation/deflation, disconnection of the endotracheal tube, tracheal 
suctioning, Trendelenburg position, or if the static respiratory system 
compliance is reduced by g15%;  
• Otherwise, hourly trials will be done counted from the last trial. 
Recruitment 
maneuver  
• Assure adequate muscle paralysis, volemia and hemodynamics 
• Recruitment maneuver: This will consist of a stepwise incremental 
PEEP maneuver: 
In volume-controlled ventilation, starting from a PEEP=0 cmH2O, 
increase PEEP in steps of 5 cmH20 until Ppl=30-32 cmH2O cmH2O (i.e., 
PEEP= 5, 10, 15 and 20 cmH2O). Remain for at least 30 s at each step. 
If there is any concern for cardiopulmonary instability at the last step, this 
can be reduced to 2-3 cmH2O aiming for the targeted Ppl range.  
Address hemodynamic issues if they occur before advancing to a higher 
PEEP step, and reduce PEEP if needed to prioritize hemodynamic 
management before proceeding. 
Recruitment maneuvers will be performed before the spontaneous 
breathing trial preceding extubation.  
The maneuver will be interrupted if the patient becomes bradycardic or 
tachycardic (< 60 or > 140 beats per minute), develops a new arrhythmia, 
becomes hypotensive (systolic blood pressure < 80 mmHg) or 
hypoxemic (SpO2 < 85%). Incidence of out-of-protocol change of 
ventilatory settings to assure SpO2>90%, Ppl30 cmH2O, or at the 
discretion of the patient9s anesthesia providers will be recorded. 
Decremental 
PEEP 
Titration 
Performed in steps of 45-75 s each until a drop in the static Crs is 
observed. At this point the PEEP is set at the value which reached the 
recruitment range of Pplateau =30-32 cmH2O for 30 sec after which the 
chosen PEEP is set to continue ventilation. If a value lower than 20 
cmH2O was used as the maximal level of recruitment, that will be the 
starting PEEP for the decremental titration. 
 

 
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Appendix IV – PROMIS Forms 
 
 
Short Form Fatigue: 
 
PROMIS Short Form v1.0 - Fatigue - 13a - 20Feb2017 
http://www.healthmeasures.net/index.php?option=com_instruments&view=measure&id=
822&Itemid=992 
 

 
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Short Form Dyspnea Functional Limitations: 
 
PROMIS Short Form v1.0 - Dyspnea Functional Limitations - 10a 02Sept2016 
http://www.healthmeasures.net/index.php?option=com_instruments&view=measure&id=
774&Itemid=992