Evaluation of the Risk of Hyperoxia-induced Hypercapnia in Obese Patients in a Cardiac Surgery Postoperative Setting
Phase: NA
Conditions: Obesity, Hyperoxia, Hypercapnia
Sponsor: Laval University

Evaluation of the risk of hyperoxia –induced hypercapnia in obese cardiac surgery 
patients 
A crossover comparison of two different oxygen saturation targets achieved by manual 
versus automatic titration 
 
PROTOCOL 
Registration number: NCT02917668 
 
Authors :  
 
Denault, Marie-Hélène, MD 
Ruel, Carolanne, MD 
Bouchard, Pierre-Alexandre, research asst. and respiratory therapist 
Simon, Mathieu, MD 
Lellouche, François, MD, PhD 
 
 
Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec.  
2725, chemin St-Foy, Québec, QC, Canada, GIV 4G5 
Tél.: 418-656-8711 
Fax: 418-656-4762 
marie-helene.denault.1@ulaval.ca 
 
Authors’ contributions:  
MHD designed the protocol, recruited patients, collected data, coordinated the study and will 
write the manuscript. CR and PAB recruited patients and collected data. MS helped with 
protocol design. FL supervised the whole process and will review the manuscript. 
 
Amendments: sample size enlargement from 15 to 30 patients (July 2017) 
Support:  
No financial support was obtained for this study. 
July 13th 2017 
 

1. INTRODUCTION 
 
1.1 Rationale 
 
Oxygen is one of the most widely used drugs in acute care settings, with 34 % and 
13,8 % of patients receiving some in ambulances and in hospitals, respectively [1, 2]. 
It is used to correct hypoxemia (35 %), and to relieve chest pain (35%) and dyspnea 
(40%)[3], even if numerous studies demonstrate that oxygen has no use in treating 
respiratory distress in normoxic patients [3-5]. Interestingly, a prescription is found 
for oxygen therapy in only 55 % of cases, with a saturation target specified in barely 
52 % of those[2].   
While hypoxemia seems to be a daily preoccupation for health care professionals, 
oxygen therapy carries some risks, which have been known for more than 60 
years[6]. It is the pulmonary consequences of hyperoxia that have been studied the 
most. Of note, airway inflammation and cellular lung damage through reactive 
oxygen species production have been related to hyperoxia. In COPD patients, the risk 
of hyperoxia-induced hypercapnia has led international guidelines to recommend a 
target peripheral oxygen saturation of 88-92 % in these patients[5, 7, 8], but they are 
still receiving too much oxygen.  
Obese people are also at risk for hyperoxia-induced hypercapnia[5, 7], but literature 
is sparse. Obesity is defined by WHO as a body mass index (BMI) superior to 30 
kg/m2, affecting more than 600 million adults in 2014, a number that had doubled 
since 1980 and corresponded to 13 % of world population [9]. In Canada, 28,7 % of 
women and 26,8 % of men were obese, percentages as high as 34,8 % and 33,6 % 
respectively in the United States [10]. Obesity-hypoventilation syndrome (OHS), 
originally named Pickwickian syndrome, is defined by the combination of obesity and 
daytime hypercapnia (PaCO2 > 45 mmHg) after exclusion of other causes [11, 12]. It is 
found in 10 to 20 % of obese patients treated in sleep disorders clinics and in 50% of 
hospitalized obese patients having a BMI higher than 50 kg/m2 [11, 13, 14]. Several 
pathophysiologic mechanisms belonging to respiratory centers, ventilator mechanics 
and sleep-disordered breathing have been proposed. Kaw and al. Have recently 

shown that obese patients with obstructive sleep apnea syndrome (OSA) meeting the 
criteria for OHS were at increased risk for postoperative complications-respiratory or 
heart failure, intubation, ICU transfer, prolonged hospital stay- than those with 
isolated OSA [15]. Now, concerning the effect of hyperoxia, Wijesinghe and al. have 
shown that, in stable OHS patients, breathing a FiO2 of 100 % for 20 minutes leaded 
to an elevation in PtCO2 of 5 mmHg compared to ambient air. Moreover, 43,5 % of 
patients had majored their PtCO2 of more than 4 mmHg while breathing a FiO2 of 
100% and the study had to stop in 3 patients because of a worrisome rise of more 
than 10 mmHg [16] . Hollier and al. have compared the effects of FiO2 of 28% and 50 
% on a 20 minutes time lapse, but observed a smaller pCO2 difference [17]. Recent 
international practice guidelines recommend a SpO2 target of 88-92 % in morbidly 
obese patients (BMI > 40 kg/m2), but do not address this matter for obese patients 
with a lower BMI [5, 7]. In light of contemporary available evidence, many questions 
remain unanswered. What is the effect of hyperoxia on obese patients in an acute 
setting? Is there, in obese patients not previously known for OHS, a risk of hyperoxia-
induced hypercapnia in this clinical context? 
 
1.2 Objectives and hypotheses 
This study aimed to evaluate the risk of hyperoxia-induced hypercapnia in obese 
patients after coronary artery bypass grafting, by comparing a SpO2 target  95 % 
achieved by manual titration (usual care) and a more conservative target of 90 % 
achieved by automatic titration in the post-extubation period. 
 
 
2. METHODS 
 
15 obese patients will be recruited at Quebec’s heart and lung Institute. Informed 
written consent will be obtained from each included patient. The protocol will be 
submitted to the establishment's ethics committee for approval. 
 

 
2.1 Inclusion criteria 
• Age ≥ 18 years 
• BMI   30 kg / m2 
• Procedure: coronary artery bypass grafting (CABG) only 
• SpO2  95% before extubation 
 
2.2 Exclusion criteria 
• Comorbidities: 
 Chronic obstructive pulmonary disease 
 Cystic fibrosis 
 Restrictive syndrome other than that associated with obesity (interstitial lung 
disease, neuromuscular disease, etc.) 
 OSA requiring CPAP therapy 
• No FreeO2 device available at the time of the study 
• Patient enrolled in another study that does not allow co-enrollment 
 
2.3 Sample size 
Since there are few data in the literature regarding the effect of hyperoxia in the 
obese population, and these data are for patients known to have hypoventilation 
syndrome and in the stable state, it is difficult for us to estimate the magnitude of 
the possibly observable change in PaCO2. Based on previous studies on stable OHS 
patients[16, 17], empirical sample size will be set at 15 patients to detect a PaCO2 
difference of 5 mmHg between groups. 
 
2.4 Study process 
We will compare the effect of two modes of oxygenation on capnia in post-CABG 
obese patients , immediately after extubation: 
 

A. FreeO2 mode : oxygen via nasal cannulas or mask (if O2 flow rate> 5l / min for 
more than 5 minutes), automatically titrated by FreeO2 for a SpO2 of 90  2% 
B. Control mode : oxygen via ventimask, manually adjusted by nurses for SpO2  95% 
(routine care according to the local protocol in which extubation is done with a FiO2 
equal to FiO2 before extubation + 10%). 
 
Patients meeting all inclusion criteria will be randomized postoperatively. After being 
extubated, they will be oxygenated for 30 minutes according to FreeO2 or control 
mode, in a randomized order. They will then be oxygenated according to the second 
mode of administration for 30 minutes. Each patient will act as his own control 
(crossover design)(see figure 1). 
 
Figure 1 Study process 
 
 
The study will last 1h for each patient, and should begin within 30 minutes after 
extubation. A resource person will be at the bedside for the duration of data 

collection to ensure protocol compliance and integrity. We expect to be able to 
complete the data collection within a 12-month period. 
 
2.5 Parameters collected 
The usual demographic data (age, sex, weight, height, BMI, waist size) will be 
collected during the recruitment of patients as well as the type of surgery (number of 
grafts, extracorporeal circulation duration), intraoperative and postoperative narcotic 
doses, left ventricular function and preoperative renal function. Continuous 
monitoring of oxygen flow, peripheral oxygen saturation and heart rate by FreeO2 will 
be achieved throughout both periods. During the control period, FreeO2 will collect 
data, but will not deliver oxygen. The respiratory rate will also be measured manually 
and on the monitor. When patients are oxygenated with FreeO2, they will record the 
flow of oxygen delivered; with the usual mode, we will note the FiO2 used. At the end 
of each period, hemodynamic measurements will be taken: heart rate, systemic 
arterial pressure, pulmonary artery pressure, vasopressor dosage. A total of four 
blood gases will be collected for each patient : a capillary blood gas the day before 
surgery (baseline), and arterial blood gases before extubation, after the first period 
and after the second period. 
 
2.6 Outcomes 
The primary endpoint will be end-of-period PaCO2. Secondary endpoints will include 
end-of-period pH and PaO2 and percentage of time spent in hypoxemia (SpO2 
<88%), in severe hypoxemia (SpO2 <85%) and in hyperoxemia (SpO2> 96% ). We will 
compare the respiratory rate data with 2 measurements (manual and monitor). We 
will also compare the hemodynamic data. 
 
2.7 Statistics 
Mean differences will be used for all of the outcomes since they are continuous, 
taking into account the crossover design (analyses with four groups). Univariate and 

multivariate analyses will be used to identify factors of response and nonresponse. 
Analyses to assess period, time and carryover effects will be done. 
 
3. AMENDMENT 
 
Analysis of the primary outcome after inclusion of 15 patients showed a trend 
towards a higher end-of-period PaCO2 in control mode, but the study lacked 
statistical power. We thus decided, following the recommendation of our 
statistician, to make an amendment to the protocol in order to enlarge sample size 
to 30 patients. This amendment was accepted by our institution’s board on July 13th, 
2017. 
 
 
 

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