Clinical trial NCT02918877
Conditions: Inflammatory Lung Injury Ischemia-Reperfusion Lung Injury Postoperative Pulmonary Complications
Keywords: Volatile Anesthetics Intravenous Anesthetics Inflammatory Lung Injury Postoperative Pulmonary Complications Cardiac Surgery Cardiopulmonary Bypass
Sponsor: Beth Israel Deaconess Medical Center
Start date: 2017-06-09; Completion date: 2021-02-01
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate whether the use of inhaled anesthetics, compared to intravenous anesthetics, can affect the amount of lung inflammation and postoperative respiratory complications seen after cardiac surgery.

Detailed description:
Randomized, controlled trial involving 45 adult patients undergoing cardiac surgery with cardiopulmonary bypass. Patients will be randomized to receive either inhaled anesthesia with sevoflurane or total intravenous anesthesia (TIVA) with propofol for the maintenance phase of their cardiac anesthetic. Assessment of lung inflammation will take place using fiberoptic bronchoscopic sampling of lung fluid as well as serum collection before and after exposure to cardiopulmonary bypass, and the incidence of compositive postoperative pulmonary complications will take place in the postoperative period.

Arms: arm 1: Patients in the inhaled anesthesia arm will be given sevoflurane anesthesia maintenance for the duration of the procedure including cardiopulmonary bypass. arm 2: Patients in the intravenous anesthesia arm will be given total intravenous anesthesia with propofol for the duration of the procedure including cardiopulmonary bypass.
Interventions: intervention 1: Sevoflurane intervention 2: Propofol
Intervention descriptions: intervention 1: Volatile Anesthetic intervention 2: Intravenous Anesthetic

Protocol documents:
Prot_SAP_001.pdf: 
(CCI) Committee on Clinical Investigations 
Page 1 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 08/27/2018 
 
PART B 
STUDY DESCRIPTION 
 
TITLE OF PROTOCOL 
Anesthetics to Prevent Lung Injury in Cardiac Surgery 
Principal Investigator 
Brian O’Gara MD 
 
 
B1. 
PURPOSE OF PROTOCOL 
Hypothesis: 
Volatile anesthetics provide anti-inflammatory protection against pulmonary ischemia-reperfusion 
injury observed during cardiopulmonary bypass   
 
Specific Aims: 
 
1) To determine the feasibility and protocol adherence of a prospective trial investigating the 
potential lung protective effects of volatile anesthetics 
2) To investigate whether the use of volatile anesthetics during cardiac surgery can result in a 
reduction in inflammatory lung injury as defined by key biomarkers found in bronchoalveolar 
lavage fluid and serum 
3) To investigate whether the use of volatile anesthetics during cardiac surgery can result in a 
reduction in the composite outcome of perioperative pulmonary complications 
  
 
B2. 
SIGNIFICANCE AND BACKGROUND FOR THE STUDY 
Background: 
Of the more than 400,000 patients undergoing cardiac surgery with cardiopulmonary bypass per year 
in the United States, an estimated 25% of them will experience respiratory dysfunction for up to one 
week (Taggart).  Furthermore, respiratory failure requiring prolonged endotracheal intubation and 
mechanical ventilation occurs in nearly 10% of patients, who then suffer over a 6 times higher in-
hospital mortality rate than patients without respiratory failure (Filsoufi).  The acute respiratory 
distress syndrome (ARDS), a severe form of inflammatory lung injury, has been found to occur in only 
as many as 3% of such patients, but the mortality rate for those with this condition is between 40-
50%, a figure in stark contrast to a 1-1.5% overall mortality rate for the cardiac surgical population 
(Milot, Kogan).  Although the etiology of postoperative pulmonary complications amongst cardiac 
surgical patients is multifactorial, a substantial body of evidence exists suggesting that the pulmonary 
ischemia-reperfusion injury known to occur during CPB is a major contributor.   
 
During cardiopulmonary bypass, the lungs are dependent on a very limited blood supply, receiving 
less than 1% of the blood flow observed under normal conditions (Apostolakis 2010).  When CPB is 
weaned, fully oxygenated blood flow is restored to the lung tissue resulting in a massive inflammatory 
response with release of inflammatory mediators and complement activation.  This ultimately leads to 
diffuse pulmonary capillary leak and accumulation of fluid, protein, and cellular debris within the 
alveolar space, ultimately resulting in impaired oxygenation and ventilation (Hall 1997).  Evidence is 
available that suggests that patients who experience an exaggerated release of pro-inflammatory 
cytokines during CPB have increased rates of postoperative hypoxia and prolonged dependence on 
mechanical ventilation (Tomasdottir 2003, Grunenfelder 2004).  Thus it seems logical that 
interventions to reduce the amount of lung inflammation known to occur during CPB may potentially 
lead to improved outcomes for many thousands of cardiac surgical patients. 
 
The volatile anesthetic sevoflurane has been shown to both prevent and minimize the extent of 
inflammatory lung injury in multiple preclinical models of ARDS, ventilator induced lung injury (VILI), 


(CCI) Committee on Clinical Investigations 
Page 2 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 08/27/2018 
 
endotoxin exposure, and pulmonary ischemia-reperfusion injury (Ferrando, Strosing, Fortis, 
Casanova).  Proposed mechanisms for this observed effect include a reduction in the release of 
inflammatory mediators from pulmonary neutrophils and macrophages and preservation of 
alveolar/endothelial integrity. The result of these effects is reduced migration of pulmonary 
neutrophils, fluid, and protein into the alveolar space in the injured state.  Data supporting the anti-
inflammatory effect of sevoflurane on human lungs comes from the thoracic anesthesia field, where 
reductions in inflammatory markers have been shown when sevoflurane use is compared to propofol 
(Sugasawa 2011/2012, Potocnik 2014, Schilling 2011, Ertuk 2014).  Furthermore, sevoflurane use as 
compared to propofol in such patients has been found to be associated with a reduction in 
postoperative pulmonary complications including pneumonia, reintubation, and ARDS (DeConno).  
Surprisingly, despite the knowledge of the high risk of inflammatory lung injury for patients undergoing 
CPB and the evidence suggesting the potential for sevoflurane to mitigate this risk, this concept has 
not been formally investigated.   
 
Significance: 
The finding that sevoflurane use can result in a reduction of inflammatory lung injury and 
postoperative pulmonary complications in cardiac surgical patients could have a major impact on 
perioperative anesthetic management.  The simple intervention of anesthetic selection represents an 
attainable practice change for cardiac anesthesiologists looking to provide the ideal anesthetic for the 
more than 400,000 patients a year under their care.  Furthermore, the knowledge gained from this 
trial could potentially be expanded to potentially reduce morbidity for other patient groups at risk for 
lung injury in the operating room and beyond.      
 
Rationale: 
Clinical equipoise exists as to the superiority of a volatile anesthetic regimen versus an intravenous 
based regimen for patients undergoing cardiac surgery.  Volatile anesthetics may provide protection 
from pulmonary ischemia-reperfusion injury known to occur during cardiopulmonary bypass.  This 
protection from injury may result in improved pulmonary outcomes for patients anesthetized with the 
volatile agents.      
 
 
B3. 
DESCRIPTION OF RESEARCH PROTOCOL 
A. 
Study Design – Overview, Methods, Procedures 
 
Research Question: 
Does the use of inhaled anesthetics during cardiac surgery with cardiopulmonary bypass reduce 
inflammatory lung injury and pulmonary complications compared to the use of total intravenous anesthesia 
(TIVA)? 
 
Study Overview: 
Prospective, randomized, feasibility trial at a single institution.  Enrolled patients will be randomized into one 
of two groups: one receiving inhaled anesthetics only for anesthetic maintenance (IA group) or a group 
receiving total intravenous anesthesia (TIVA group).  Subjects will undergo a protocolized anesthetic 
regimen based on their group assignment.  Study investigators will evaluate for any difference between 
groups in the presence of indicators of inflammatory lung injury in bronchoalveolar lavage fluid (BALF) 
obtained before and after exposure to cardiopulmonary bypass, a known precipitant of ischemia-reperfusion 
lung injury.  To investigate whether or not a presumed reduction in lung inflammation can lead to 
differences in clinical outcomes, we will observe patients in the perioperative period for the occurrence of 
pulmonary adverse events.  Additionally, the investigators will assess for any potential differences between 
groups with respect to evidence of lung and myocardial injury as well as systemic inflammation found in 
patient serum.  Lastly, the investigators will determine the feasibility of performing this study and adherence 
to protocol so that future studies into this concept can be adequately designed. 


(CCI) Committee on Clinical Investigations 
Page 3 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 08/27/2018 
 
 
Trial Design: 
Prospective, randomized, feasibility study at a single institution.    
 
As the feasibility of performing a study investigating the occurrence of inflammatory lung injury in BIDMC 
cardiac surgical patients is unknown, a study involving a convenience sample of 45 patients (20 in each 
group, allowing for potential dropout of 5 patients) will be conducted investigating the effect of volatile 
versus intravenous anesthesia with regards to pulmonary inflammation and injury.    
 
Patients will be screened for recruitment according to inclusion/exclusion criteria utilizing hospital 
scheduling systems and medical record review.  Informed consent will be obtained in all subjects.  Once 
enrolled, patients will be randomly assigned 1:1 prior to surgery into one of two groups: maintenance of 
anesthesia with volatile anesthesia or maintenance of anesthesia with intravenous anesthesia.  
 
Collection of serum and bronchoalveolar lavage fluid (BALF) will occur at 2 time points.  The first set of 
samples will be obtained after induction of general anesthesia and before surgical stimulus begins.  The 
second set will be obtained approximately 2-4 hours after the removal of the aortic cross clamp.  
Depending on the completion time of the operation, the second collection of serum and BALF samples 
may take place in the OR or the ICU.  We will collect 10cc of serum and approximately 10-20cc lavage 
specimen at each of the 2 time points. In addition, clinical data such as vital signs, lab results, radiology 
results, ventilator settings, medications administered, and incidence of postoperative pulmonary 
complications will be collected before, during, and after surgery. 
 
Conduct of the assigned anesthetic will take place according to a pre-defined protocols constructed in 
collaboration with the cardiac anesthesia service.  These protocols are provided below.  Cardiac surgery 
will take place according to current hospital standards.    
 
Please refer to the following figure for a flow diagram of patient group assignment and timing of patient 
laboratory samples:  
 
 
 
 


(CCI) Committee on Clinical Investigations 
Page 4 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 08/27/2018 
 
Intervention: 
Inhaled anesthetic with sevoflurane versus total intravenous anesthesia (TIVA) for maintenance of 
anesthesia throughout the operative course including cardiopulmonary bypass.  
 
Inhaled anesthetic protocol: 
Induction of anesthesia will take place according to the discretion of the anesthesiologist.  Inhaled 
anesthetic maintenance will be accomplished thereafter using a range of 0.7-1.5 MAC Sevoflurane.  This 
dosing range was selected based on doses previously described as effective in preventing lung injury in 
animal and human studies (Sugasawa 2011/2012, Potocnik 2014, Schilling 2011).  To allow for changes 
in this dose to be made by the anesthesiologist who may need to respond to a rapid change in clinical 
status, we ask that this range be accomplished as an average MAC dose per hour of anesthetic.  
Sevoflurane was chosen as the anesthetic to be used in this study based on background evidence of its 
efficacy and its prevalent use by our anesthesia team.      
 
To reduce the potential confounding influence of known inflammatory or anti-inflammatory exposures, 
the anesthesia team will be asked to refrain from the use of systemic steroids, nitrous oxide, or 
cisatracurium throughout the course of anesthesia in the OR.  Use of alternative, similar acting 
medications is permissible.         
 
Intravenous anesthetic protocol: 
Maintenance of intravenous anesthesia will be accomplished with the use of a continuous infusion of 
propofol (50 – 200mcg/kg/min).  Dosing of these infusions will be within these prescribed ranges but will 
ultimately be at the discretion of the anesthesiologist and will be selected based on achievement of 
adequate plane of anesthesia, satisfactory surgical conditions and safe hemodynamic profile.  Although 
most clinicians will use a BIS monitor to monitor the depth of anesthesia for such patients it is not a 
requirement for this study.  As with patients in the inhaled anesthesia group, we will ask the 
anesthesiologist to refrain from administering systemic steroids, nitrous oxide, or cisatracurium 
throughout the course of anesthesia in the OR.  Use of alternative, similar acting medications is 
permissible.         
       
Mechanical ventilation protocol (intra-op): 
As mechanical ventilation can potentially induce confounding inflammatory lung injury through 
barotrauma and volutrauma and high fraction of inspired oxygen (FiO2) concentrations can potentially 
contribute to worse outcomes from reperfusion injury, we will restrict the mechanical ventilation and 
oxygenation of the study patients according to the following guidelines: 
 
Tidal volume – 6-8cc/kg of ideal body weight 
PEEP – 2-12 cm H2O 
FiO2 equal to or less than 50% 
• 
Titrate to target SpO2 > 92% 
• 
Brief exposure (<20 min) to 100% FiO2 for hypoxia or immediate post CPB allowed  
Peak airway pressure < 40 cm H2O 
Plateau pressure < 35 cm H2O 
PaCO2 > 20, <60 mmHg 
PaO2 > 60, < 200 mmHg   
 
Protocol adherence will be monitored by a member of the study team in real time by direct conversation 
with the anesthesiologist and review of the anesthetic record.  If a deviation from protocol is found, a 
conversation with the anesthesia team will take place so that corrective measures can be taken.   
 


(CCI) Committee on Clinical Investigations 
Page 5 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 08/27/2018 
 
Bronchoalveolar Lavage Protocol: 
All bronchoalveolar lavage samples will be obtained by a member of the study team with the appropriate 
training in the performance of bronchoalveolar lavage according to current BIDMC policy and procedure 
for BAL collection #RC-4.08.16.  Direct vision bronchoscopy will be utilized for this purpose to minimize 
the risk of trauma from unintentional misplacement of a catheter.  A flexible bronchoscope will be passed 
through the endotracheal tube and gently wedged into the right lower lobe bronchus.  60cc of a sterile 
saline solution will then be used to lavage the cavity.  Gentle continuous suction will then be used to 
obtain the residual lavage specimen (usually 10-20cc) for laboratory analysis of the markers indicated 
below.  
 
Blood and lung fluid specimens: 
Blood and BAL specimens will be centrifuged.  The plasma and buffy coat will be separated from red 
blood cells, aliquoted into small samples, labeled and frozen at -80ºC for future use.  The BAL specimen 
will also be aliquoted into small samples, labeled and frozen at -80ºC for future use.  All samples will be 
stored in a freezer in a locked laboratory at BIDMC.  They will be labeled with a unique coded ID and will 
not contain any patient identifiers.  These specimens may be sent to an outside lab for analysis of 
markers of inflammation and injury or they may be analyzed in a lab at BIDMC.  No specimens will be sent 
outside BIDMC without a fully executed DTA from OSP.  No PHI will be sent to the lab. 
 
The study investigators will be establishing a specimen repository under a separate IRB protocol number.  
Any specimens left after testing from this protocol will be saved to the repository for future investigations.   
 
Subjects may be co-enrolled in this study and 2016-P-000144 and/or 2008-P-000151.  Since specimens 
are collected in the OR for all 3 studies, if a subject is co-enrolled, specimens may be collected in tandem 
to increase the risk-benefit ratio.  For all 3 studies, informed consent will be obtained only by co-
investigators who are listed on the Research Staffing Form for each individual study.  
 
Primary Outcome: 
Measures of trial feasibility including recruitment, enrollment, and adherence to protocol in order to form 
the basis for a potential larger clinical trial. 
 
Secondary Outcomes: 
1) Incidence of inflammatory lung injury 
 
Incidence of inflammatory lung injury will be defined as an increase in key lung specific markers                 
of inflammation and injury, identified in bronchoalveolar lavage (BAL) and serum.     
 
2) Incidence of postoperative pulmonary complications 
 
Incidence of postoperative pulmonary complications will be defined according to a composite outcome of 
clinically relevant adverse pulmonary complications including: 
- 
prolonged intubation (greater than 48 hours) 
- 
failed extubation (reintubation within 24 hours of extubation) 
- 
reintubation (any time after 24 hours post extubation) 
- 
hypoxia (defined as PaO2:FiO2 ratio of less than 300) 
- 
respiratory acidosis (defined as serum PCO2 > 45) 
- 
ARDS according to the Berlin criteria: 
- acute onset 
- bilateral infiltrates on CXR 
- p:f ratio less than 300 
- not explained solely by cardiac failure 
 


(CCI) Committee on Clinical Investigations 
Page 6 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 08/27/2018 
 
 
 
- 
chest x-ray findings of pulmonary edema, pleural effusion, atelectasis or infiltrate 
- 
pneumonia 
- 
pneumothorax  
- 
bronchospasm 
- 
exacerbation of chronic lung disease 
 
Collection of complications data will occur throughout the hospital stay, until time of discharge.   
 
Additionally, to track other important intraoperative and postoperative factors related to overall patient 
outcome and protocol adherence we will record other clinical data including: 
• 
Vital Signs 
• 
Medications administered 
• 
Ventilator settings 
• 
Urine output 
• 
End tidal carbon dioxide concentration 
• 
Dead space ventilation  
• 
Alveolar-Arterial oxygen gradient 
• 
Pre/post ejection fraction from transesophageal echocardiography 
• 
Blood transfusion history 
• 
Length of operation 
• 
Length of aortic cross clamp time 
• 
Type of operation 
 
Adverse Event Reporting:    
This patient population is undergoing high risk surgery and it is expected that they may have a number 
of unrelated adverse health events during their hospital course.  Patients in this study are being 
randomized to anesthetic protocols that are both considered within the standard of care.  Therefore, we 
will limit the scope of AE monitoring and reporting to the following: 
 
• 
All Serious Adverse Events, including unexpected death, believed to be related to the study   
• 
All non-serious Adverse Events believed to be related to the study procedures or unexpected 
based on the patient’s clinical condition 
 
We will assess for adverse events during the intraoperative period, as well as for the first 48 hours post-
surgery. 
B. 
Statistical Considerations 
a. Sample Size Justification:   
The ability to perform a study investigating the occurrence of lung injury on cardiac surgical 
patients is unknown.  Because of this we plan to conduct a feasibility study of 45 patients (20 
in each group) investigating the effect of inhaled versus intravenous anesthesia with regards 
to pulmonary inflammation.  A sample size of 20 patients per group will allow us to assess our 
feasibility, adherence/compliance and recruitment aims.  Encouragingly, previous data has 
suggested that only 16 subjects per group are necessary to detect a difference of more than 
40% in alveolar cytokine concentrations with an alpha level of 0.05 and 80% power (Schilling 
2011).  This suggests that even in a small feasibility study, and allowing for some potential 
dropout, we may be able to identify significant differences in our secondary outcomes, namely 
changes in alveolar TNF alpha and IL-8 concentrations.   
We estimate that 65 patients will be enrolled (consented) in order to achieve this sample size. 


(CCI) Committee on Clinical Investigations 
Page 7 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 08/27/2018 
 
This increase in sample size is required because it is possible that patients can be withdrawn 
before randomization (i.e. cancelled surgery) as well as after randomization, but before 
receiving either of the pre- and post-bypass bronchoscopies. Enrollment will be stopped once 
we have complete data for 45 patients. However, patients who were enrolled prior to the 
completion of 45th subject will be followed and go through the study procedures. 
 
b. Data Analysis:   
The primary outcome of this feasibility trial will be recruitment, enrollment, and adherence to 
protocol in order to form the basis for a potential larger clinical trial.  We will calculate 
recruitment by considering all those cardiac patients who meet the inclusion and exclusion 
criteria and are asked to be part of the study.  The total number of eligible participants who 
agree to take part in the study will be divided by the total number of individuals who meet 
eligibility criteria without any exclusions, regardless of participation.  The proportion of patients 
in each group who receive their assigned study intervention will also be reported.   
 
Because this trial will serve as a feasibility trial for a larger prospective randomized trial, this trial 
will not be powered to assess for differences in secondary outcomes, however analyses will give 
insight into effect estimates for the larger trial. We plan to assess the following clinical and 
biomarker outcomes, as well as safety parameters: 
 
- 
Difference in markers of inflammation and lung injury found in BALF: IL1B, IL6, IL8, 
TNFa, MCP1, protein, neutrophil count, sRAGE, angiopoietin 1 and 2, surfactant protein 
D, sICAM1  
- 
Difference in serum markers of lung injury: sRAGE, surfactant protein D, sICAM1, e 
selectin, VWF 
- 
Incidence of perioperative hypoxia (defined as PaO2:FiO2 ratio of less than 300) 
- 
Incidence of perioperative respiratory acidosis (defined as serum PCO2 > 45) 
- 
Time to extubation 
- 
Incidence of failed extubation/need for reintubation 
- 
Incidence of pulmonary edema, effusion, atelectasis or infiltrate on postoperative CXR 
- 
Incidence of pneumothorax seen on post op CXR 
- 
Blood transfusion data 
 
Descriptive statistics of the data will be performed and presented, including baseline 
demographics, intraoperative data and inflammatory markers.  Categorical data will be reported 
as frequencies or proportions and assessed with chi-square (or Fisher’s Exact test as 
appropriate). Continuous data will be represented using mean (± SD) or median (IQR) for 
variables not normally distributed and compared using parametric or non-parametric tests as 
appropriate.  Both linear and logistic regression will be used in order to test our secondary 
hypotheses.  Changes in inflammatory markers over time will also be assessed.  All p-values < 
0.05 will be considered statistically significant.  SAS 9.3 or later (SAS Institute, Cary, NC) will be 
used for all analyses.     
 
C. 
Subject Selection 
Inclusion Criteria: 
• 
Adult patients (age 18+)  
• 
Undergoing cardiac surgery with cardiopulmonary bypass 
 


(CCI) Committee on Clinical Investigations 
Page 8 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 08/27/2018 
 
Exclusion Criteria: 
• 
Emergency surgery 
• 
History of severe COPD, emphysema, or ILD 
• 
Recent (<2wk) or current use of systemic glucocorticoids 
• 
Prior history of pneumothorax 
• 
Allergy/contraindication to intravenous anesthetics (egg white or soybean allergy) 
• 
Personal or family history of malignant hyperthermia or high risk for malignant hyperthermia 
 
Drop Out Criteria: 
• 
Inability to safely provide adequate anesthetic maintenance with prescribed regimen for the 
duration of the case (at the discretion of the cardiac anesthesiologist).   
 
• 
Inability to safely perform a bronchoscopy secondary to: 
- 
severe hypoxia defined as a p:f ratio of less than 100 or SpO2 < 90% 
- 
> 15 cm H2O PEEP or > 80% FiO2 requirement to maintain SpO2 > 90%   
 
Women of childbearing potential: 
Women of childbearing potential will be eligible for enrollment in this study.  Preoperative pregnancy 
testing will take place according to the current BIDMC cardiac surgery and anesthesia guidelines.   
 
Gender and Racial Distribution of Subjects: 
We anticipate that our study population will reflect the normal distribution of race and gender currently 
seen in the BIDMC cardiac surgical population.   
  
B4. 
POSSIBLE BENEFITS 
As this is a feasibility study, it is not possible to predict whether there will be direct benefit to the 
individual subject.  However, based on the data we have reviewed regarding this topic, it is possible that 
the use of volatile anesthetics in our subjects will result in a lower incidence or severity of inflammatory 
lung injury.  It is also possible that potential differences in the levels of biomarkers could translate to a 
benefit to the patient in the form of a reduction in pulmonary complications.  We hope to use the 
information we learn from this study to design a larger randomized, controlled trial that would be more 
adequately powered to detect a potential difference in patient-specific outcomes.   
 
B5. 
POSSIBLE RISKS AND ANALYSIS OF RISK/BENEFIT RATIO 
The following includes descriptions of reasonably foreseeable risks or discomforts associated with 
participation in this study: 
 
Risks associated with serum collection 
It is anticipated that serum collection will be done using existing indwelling catheters, thereby reducing 
the risks and discomforts to the patient. It is possible that, in some circumstances, venipuncture could be 
required to collect the specimen. The primary risks of phlebotomy include local discomfort, occasional 
bleeding or bruising of the skin at the site of needle puncture, and rarely hematoma, infection, or fainting.   
 
Risks associated with bronchoalveolar lavage 
Bronchoalveolar lavage (BAL) is a safe, easily performed, and well-tolerated procedure.  This will be 
performed on patients who are already intubated and sedated, and done by experienced clinicians 
following standard clinical operating procedures to obtain BAL fluids with minimal risk and discomfort to 
patients. We will not perform the BAL procedure on patients who are suffering from hypoxia (defined in 
the drop out criteria above) to minimize the risk of even transiently worsening this condition secondary to 
the study procedure. 


(CCI) Committee on Clinical Investigations 
Page 9 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 08/27/2018 
 
 
The most commonly reported complication of the procedure is transient hypoxia, with a rate reported of 
around 5% (Hertz 1991, Prebil 2014).  Other rare (<1% incidence) complications such as bleeding and 
pneumothorax are made even more rare when BAL is performed without an accompanying biopsy, as it 
will be in this study.  We will utilize trained personnel to perform specimen collection in a manner 
consistent with local clinical practice, observing all standard safety measures including hemodynamic 
monitoring, patient positioning and suction pressure. 
 
In the event a subject experiences any of the risks above, or any unanticipated problems, the Principal 
Investigator will be available to coordinate care and counsel, as necessary. 
 
Risks attributable to the anesthetic agents: 
The two agents being used in this study, Propofol and Sevoflurane, have a long track record of 
widespread use worldwide and an excellent safety record.  They are both considered standard of care 
anesthetics.  Therefore we do not anticipate any additional risk to the study population given either of 
these anesthetic agents.   
 
Both agents come with the principal risk of hypotension through vasodilation, common to any of the 
inhaled or intravenous anesthetic maintenance agents.   
 
Sevoflurane, along with all other halogenated inhaled anesthetics, is associated with an incredibly rare 
risk of Malignant Hyperthermia (MH).  MH is a condition characterized by accelerated muscle 
metabolism in patients with a mutation in the ryanodine muscle receptor (www.mhaus.org).  Due to its 
rarity (less than 1/200,000 anesthetics) and the presence of the antidote Dantrolene, the inhaled 
anesthetics including Sevoflurane are the most widely used anesthetic agents despite this risk.  Patients 
at risk for MH or with a personal or family history of MH will be excluded from our study to further reduce 
this risk.  Sevoflurane use has been linked to a concern for nephrotoxicity when used in low flow states in 
anesthetics given to rats (gas flows less than 4L/min).  This concept has not been proven in humans.   
 
Propofol carries a risk of an allergic reaction in patients with egg or soybean allergies.  Patients with such 
allergies will be excluded from our study to mitigate this risk. 
 
Analysis of Risk/Benefit Ratio: 
Although there is substantial evidence supporting the potential lung protective effect of the volatile agents 
in preclinical trials, the human data is lacking.  We believe that further research including the proposed 
study is necessary in order to provide more meaningful insight into the potential impact the 
anesthesiologist’s choice of anesthetic regimen can have on a safe outcome for the cardiac surgery 
patient.  Detailed knowledge of this impact and the potential mechanisms of effect could guide future 
study into how volatile anesthetics may benefit patients suffering from or at risk for other types of 
inflammatory lung injury.  We believe that these potential benefits justify the moderate risk associated 
with limited serum and BAL sample collection.   
  
 
B6. 
RECRUITMENT AND CONSENT PROCEDURES 
Recruitment 
Members of the study team will screen operating room schedules and patient medical records for the 
presence of inclusion or exclusion criteria to determine eligibility for enrollment.  A secure screening and 
enrollment log will be kept.  If a patient is deemed a potential candidate, they will be approached for 
informed consent. 
 
Consent 
Once a patient is found eligible, he or she will be approached by a physician co-investigator for 


(CCI) Committee on Clinical Investigations 
Page 10 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 08/27/2018 
 
informed consent.  Non-physician study team members may initiate the discussion about potential study 
participation and answer questions.  This may occur in the cath lab holding area, PAT clinic, cardiac 
surgery clinic, or in the preoperative holding area.  All subjects will be consented with curtains drawn or 
the door closed, assuring patient privacy.  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 surgery and any research procedures.  Copies of the signed consent will be provided to the 
patient and filed in the medical record.    
 
The study team undergoes standardized, rigorous training regarding the informed consent process for 
research. Within the Center for Anesthesia Research Excellence (CARE) at BIDMC, this training is 
personally overseen by the Clinical Research Administrator and 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.   All CARE members, including non-physicians, undergo this training. 
 
Subject Protection 
Although patients of co-investigators may be approached for inclusion in this study, it will be clearly 
stated that the subjects’ decision to participate or refrain from participation in the research study will 
not affect the performance or outcome of their upcoming surgery.   
 
B7. 
STUDY LOCATION 
Privacy  
All study interactions will take place in private settings with curtains/doors closed so as to provide 
privacy and comfort for the subject.  For patients being approached for informed consent, if they are 
uncomfortable answering questions regarding their medical history with someone other than a 
medical provider, an approved MD participating in the study will be contacted to conduct that portion.  
 
Physical Setting 
Enrollment will take place at BIDMC.  Study procedures (blood and BALF specimen collection) will 
take place in the OR and/or ICU.  Data collected will be housed on password-protected BIDMC 
network servers and/or locked filed cabinets/offices.   
 
B8. 
DATA SECURITY 
All electronic files containing PHI will be stored on a secure research server behind the BIDMC 
firewall on password protected computers; paper files will be stored in locked cabinets/offices at 
BIDMC.  Limited information will be retained on patients who are prescreened and do not qualify, or 
who are approached and declined, for the purposes of generating a CONSORT diagram at the 
conclusion of the trial.  Blood and BAL specimens will be stored in a freezer in a locked laboratory at 
BIDMC. These specimens will be labeled only with a unique coded ID and will not contain any patient 
identifiers. 
 
B9 
Multi-Site Studies 
Is the BIDMC the coordinating site?       
 Yes    
 No  
Is the BIDMC PI the lead investigator of the multi-site study?     
 Yes    
 No  
 


(CCI) Committee on Clinical Investigations 
Page 11 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 08/27/2018 
 
B10 
Dissemination of Research Results 
Patients will be thanked for their time throughout the study. There is no plan to share the data at the 
conclusion of the trial. Because study results are likely to be published a few years after a given 
subject’s participation, it is not feasible to send subjects follow-up with the published results. The 
study investigators are concerned that mailing the published manuscript and an additional thank-you 
note years after participation risks violating subject privacy, as mailing addresses are increasingly 
likely to change with passing time. It is out of the scope of this study to continue tracking mailing 
addresses after completion of enrollment since this is not a longitudinal study.