Reducing Reintubation Risk in High-Risk Cardiac Surgery Patients With High-Flow Nasal Cannula
Phase: NA
Conditions: Intubation, Cardiovascular Surgical Procedure
Sponsor: Vanderbilt University Medical Center

 
 
Reducing Reintubation Risk in High-Risk Cardiac Surgery  
Patients with High-Flow Nasal Cannula 
 
Protocol version:  Jan 6, 2026 
IRB approved Jan 26, 2026 
 
 
NCT Number 04782817 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Reducing Reintubation Risk in High-Risk Cardiac Surgery  
Patients with High-Flow Nasal Cannula 
 
Protocol version:  Jan 6, 2026 
 
 
Principal Investigator:  
Robert E. Freundlich, MD, MS, MSCI 
 
 
 
Co-investigators: 
Jonathan Wanderer 
Pratik Pandharipande 
Ashish Shah 
Benjamin French 
Ryan Moore 
 
 

 
 
Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Risks of Investigational Agents/Devices (side effects) 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
9.0 
Statistical Considerations 
10.0 
Privacy/Confidentiality Issues 
11.0 
Follow-up and Record Retention 
 

 
 
1.0 
Background 
 
The iCAN trial is a pragmatic randomized controlled trial that aims to test the hypothesis 
that HFNC versus usual care oxygenation strategies applied immediately after initial 
extubation after cardiac surgery decreases the all-cause 48-hour reintubation rate 
(extubation failure within 48 hours of initial extubation). 
 
2.0 
Rationale and Specific Aims 
 
HFNC may be employed as a strategy to facilitate early extubation and prevent 
reintubation of patients following cardiac surgery. HFNC is routinely employed by 
providers in the cardiovascular intensive care unit and is selectively employed in patients 
who are judged by the provider to be high-risk, along with other therapies: bi-level 
positive airway pressure, non-rebreather masks, among others. 
 
To guide a future, larger, multicenter randomized controlled pragmatic clinical trial, we 
will perform a study in a single, high-volume cardiovascular intensive care unit. We will 
perform a prospective, randomized, pragmatic clinical trial of HFNC compared to 
provider choice of usual care in these patients to test the hypothesis that HFNC versus 
usual care oxygenation strategies applied immediately after initial extubation after 
cardiac surgery decreases the all-cause 48-hour reintubation rate (extubation failure 
within 48 hours of initial extubation). 
 
We will then plan to use data from this study to conduct secondary analyses to better 
understand features of HFNC responders, including within predicted risk strata, 
compared to non-responders, and work to better understand optimal time of extubation 
retrospectively, with the hopes of generating data that could be used by providers to 
facilitate early extubation. 
 
3.0 
Animal Studies and Previous Human Studies 
 
HFNC has been shown to be non-inferior to bi-level positive airway pressure in 
preventing reintubation following cardiac surgery. It may be effective at preventing 
reintubation in high-risk patients but, to date, this has not been specifically studied. 
 
4.0 
Inclusion/Exclusion Criteria 
 
Study Population 
The trial will enroll adult patients undergoing cardiac surgery, defined as surgery on the 
heart or thoracic aorta, excluding percutaneous procedures, at VUMC who fulfill the 
following inclusion and exclusion criteria: 
 
Inclusion Criteria 
• Age ≥18 years 

 
 
• Undergoing cardiac surgery, defined as a documented surgical service of “cardiac 
surgery” in the EHR, performed in the main operating rooms at Vanderbilt 
University Medical Center 
• Admitted to the cardiovascular intensive care unit postoperatively with an 
endotracheal tube in place and mechanically ventilated 
• Surgery duration (documented time between “Anesthesia start” and “Anesthesia 
stop” in the EHR) of at least 180 minutes 
• Received an order to be extubated by a treating provider 
o Patients who meet all other criteria but do not receive an order to extubate 
will be randomized but not enrolled 
Exclusion Criteria 
• None 
 
 
5.0 
Enrollment/Randomization 
 
HFNC is widely used by providers to treat high-risk patients following cardiac 
surgery and is an accepted treatment to prevent reintubation. This study uses therapies 
that are accepted treatments routinely used by providers; therefore, we are requesting a 
waiver of the requirement for informed consent. 
Screening, enrollment, and randomization will be performed using tools 
embedded within the EHR. Among patients that meet inclusion criteria, randomization 
will be performed at the documentation of “anesthesia stop” (at the conclusion of the 
surgical procedure), using a random number that will be generated and associated with 
the patient’s hospital admission medical record. Randomization will not be visible to 
clinicians or investigators and will not be stratified. 
 
Enrollment is performed using an order set in the EHR. At the time an order is 
placed to extubate the patient after surgery, an order set will be automatically placed 
based on the previously generated random number. According to hospital policy, patients 
may not be extubated without an extubation order. The order will assign treatment (usual 
care or HFNC following extubation), based on the randomization allocation. 
 
 
6.0 
Study Procedures 
 
• This study is a prospective, pragmatic, randomized controlled trial. Blinding to 
treatment assignment will be maintained throughout surgery and the early 
postoperative period until an order is placed to extubate the patient in the EHR. 
• Patients will be randomized 1:1 at the time of extubation to either 1] usual care 
(treatment at the discretion of the treating provider) or 2] HFNC, per the existing 
intensive care unit protocol. Respiratory therapists will be instructed to target 24 
hours of HFNC, if clinically appropriate in the judgement of the patient care team, 

 
 
with an absolute minimum of 1 hour of therapy. Respiratory therapists may use 
any HFNC device, at their discretion, with initial settings and titration at the 
discretion of the clinical team. Escalation of care beyond HFNC and transition to 
alternative means of oxygenation will be at the discretion of the patient care team. 
Similarly, usual care is at the discretion of the patient care team and may include 
HFNC. Typical treatment modalities in usual care include, but are not limited to, 
nasal cannula, face mask, HFNC, and bilevel positive airway pressure. All 
concomitant care and interventions will be permitted to continue to ensure 
pragmatism. The decision to reintubate a patient will be at the sole discretion of 
the patient care team; there are no protocolized criteria for reintubation. 
• Blinding to the treatment assignment will be maintained throughout surgery and 
the early postoperative period, until an order is placed to extubate the patient in 
the EHR. The clinical care team will not be blinded to treatment arm following 
enrollment, as blinding cannot be practically performed once patients are 
extubated. Some patients may be randomized but not enrolled if they do not 
receive an extubation order. Most commonly this is due to self-extubation or 
patient death prior to planned extubation 
. 
 
 
7.0 
Risks 
 
Reintubation and respiratory failure are risks in the post cardiac surgery population. It is 
not known if this risk will be lower in one group or the other. HFNC is widely employed 
in the study population, in addition to other adjunct therapies, such as bilevel positive 
airway pressure, but its use is not standardized. It is an accepted treatment, routinely used 
by providers, particularly in high-risk patients. Previous studies have demonstrated that 
HFNC is non-inferior to bilevel positive airway pressure therapy in cardiac surgery 
patients. 
 
Currently, no high-quality clinical data exist to demonstrate that HFNC may decrease the 
risk of reintubation in this critically ill adult population. The trial is felt to pose minimal 
risk as 1) exposure to the intervention occurs only in patients deemed ready for 
extubation by the treating clinician 2) the intervention is already commonly employed in 
routine practice in the study environment 3) no definitive prior data exist to show clinical 
outcomes are better with HFNC; the largest study to date did, however, demonstrate non-
inferiority to bilevel positive airway pressure 4) We will perform an intention to treat 
analysis and, ultimately, the choice of therapy will be left to the treating clinician 5) 
Providers will be blinded to the predicted risk of reintubation and will rely exclusively on 
their clinical judgement, which is considered usual care in routine clinical practice. 
 
Given this minimal risk, the focus of the study on adjunct post-extubation therapy in the 
ICU, and the impracticability of consenting each patient undergoing cardiac surgery, a 
waiver of documentation and alteration of informed consent process are requested. 

 
 
 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
 
Any unanticipated, serious, study related adverse events will be reported per IRB policies 
and procedures. 
 
9.0 
Statistical Considerations 
 
Sample size calculations were based on data from a prior study of reintubation 
after cardiac surgery performed at VUMC (PI: Freundlich, Ann Thorac Surg 2022, PMID 
34329600). Assuming a 3.2% reintubation rate among the control arm and a 1:1 ratio of 
intervention patients to control patients, with at least 1435 patients in each group, a 
two-sample test of binomial proportions achieves 80% power to detect a relative 
decrease of 50% in the 48-hour reintubation rate among the HFNC arm (i.e. from 3.2% 
to 1.6%) at a type 1 error rate of 5%. Accounting for at least 15% crossover between 
groups, we will require at least 1688 patients in each arm of the study using the N/(1-R) 
crossover methodology. The intervention and primary outcome are in hospital; as such, 
we do not anticipate any drop out. Total enrollment will be about 3800. 
The primary endpoint is all-cause unadjusted reintubation at 48 hours after initial 
extubation following cardiac surgery (that is, extubation failure within 48 hours). We will 
not attempt to determine causality of the reintubation as this is frequently multifactorial 
and would introduce subjective bias into the analysis. 
Analysis of the primary endpoint will compare rates of reintubation within 48 
hours of initial extubation after cardiac surgery between the HRNC intervention and 
control arms, based on intention to treat, in which patients are included in the group to 
which they were randomized regardless of the treatment received. 
 
Data generated in the study will be used for secondary analyses to better 
understand treatment response and failure in patients treated with HFNC across strata 
defined by predicted reintubation risk, as well as to better understand optimal time of 
extubation.  
 
Prespecified secondary endpoints are listed below 
• Reintubation within 72 hours of extubation 
• Reintubation at any time after extubation 
• All-cause 30-day mortality 
• Hospital length of stay 
• Intensive care unit length of stay 
• Ventilator-free days 
• In-hospital mortality 
• Adjusted reintubation rate, if needed based on clinically relevant imbalance in 
baseline characteristics between groups 
All data analyzed, including demographic and outcome data, will be limited to data 
generated by clinicians in routine clinical care and captured via query of existing 
databases available within the EHR. In previous work, we have demonstrated that we are 

 
 
able to obtain these data without any missingness, based on our extensive experience 
querying the EHR, as well as by limiting our analysis to those data elements that are 
readily available (PI: Freundlich, Ann Thorac Surg 2022, PMID 34329600). We have 
shown that this may be generalizable (PI: Freundlich, J Clin Anesth 2024, PMID 
37883900). We will analyze data on a modified intention-to-treat basis that includes all 
randomized and enrolled participants grouped according to the treatment assigned at 
randomization as described below. 
• Some patients may be randomized but not enrolled if they do not receive an 
extubation order. Most commonly this is due to self-extubation or patient death 
prior to planned extubation. We will report demographic and outcome data on 
patients who were randomized but not enrolled in a separate analysis to help 
ensure that post-randomization exclusions do not introduce significant bias. 
• A proportion of lung transplants are scheduled as being performed by “cardiac 
surgery” and will be enrolled. Upon the recommendation of the DSMB, these 
patients will be analyzed in the primary intention-to-treat analysis, but we will 
perform a prespecified subgroup analysis excluding these patients. 
 
10.0 
Privacy/Confidentiality Issues 
 
Participant records will be assigned a code and the key to the code will be accessible only 
by Key Study Personnel (KSP). Data will be stored on password protected servers 
accessible only by KSP.  
 
11.0 
Follow-up and Record Retention 
 
Data will be stored on password protected VUMC servers indefinitely.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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