Supplementary Oxygen in Surgical and Medical Wards in the Capital Region of Denmark Evaluated by 30-day Mortality, a Retrospective Cohort Study
Conditions: Oxygen Toxicity, Oxygen Deficiency
Sponsor: Hannibal Troensegaard

Hannibal Troensegaard 
SUPPLEMENTARY OXYGEN  
25/07-2018 
IN SURGICAL AND MEDICAL WARDS  
 
EVALUATED BY 30-DAY MORTALITY (SOSAM) 
Side 1 af 14 
SUPPLEMENTARY OXYGEN IN SURGICAL AND MEDICAL 
WARDS EVALUATED BY 30-DAY MORTALITY (SOSAM) 
- FULL STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN 
INTRODUCTION 
OBJECTIVE 
The aim of this study is to investigate oxygen treatment and its correlation with morbidity and 
mortality in hospitalized medical and post-operative patients, the primary outcome being 30-day 
mortality.  
Hyperoxia is hypothesized to increase 30-day mortality due to previous research indicating 
elevated arterial oxygenation as a negative predictor for mortality outcomes in various patient 
groups. 
BACKGROUND 
Supplementary oxygen is widely used to both treat and prevent hypoxia in a clinical hospital 
setting. In spite of the widespread use of oxygen, and the well-known malicious effects of hypoxia, 
little is known about the harmful effects of abundant oxygen supply during hospital admission. 
Several methods of action have been proposed for the mechanism of harmful effects of hyperoxia, 
and studies have found hyperoxia to be harmful on a cellular level1,2  
Studies conducted on selected groups of patients have shown a harmful effect of short-term 
exposure of hyperoxia. Patients undergoing abdominal operations have been shown to have an 
increased long term-mortality when exposed to high levels of perioperative inspiratory oxygen3,4 
and patients with ST-elevation-myocardial infarction appear to have an increase in their level of 
myocardial injury after being randomized to high levels of supplementary oxygen.5 It has been 
pointed out, that further research into this topic is of high relevance, seeing the current 
randomized controlled trials have focused mainly on the benefits of oxygen, rather than the 
potiential harmful effects of hyperoxia.6,7  
 
 

Hannibal Troensegaard 
SUPPLEMENTARY OXYGEN  
25/07-2018 
IN SURGICAL AND MEDICAL WARDS  
 
EVALUATED BY 30-DAY MORTALITY (SOSAM) 
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METHODS 
STUDY DESIGN 
This study is designed as an observational retrospective cohort study, using a database consisting 
of data from the National Early Warning Score (EWS) from approximately 170.000 patients during 
hospitalization in the Capital Region of Denmark.  
SETTING 
Regular measurements of NEWS-values on patients admitted to a hospital in the Capital region of 
Denmark has been standard practice since 2013. Data from NEWS-recordings on patients admitted 
to hospital in the period from 1 January 2014 to 31 December 2014 in the Capital Region of 
Denmark have previously been critically assessed and sanitized for unreliable entries.8 These 
sanitized recordings, combined with the primary diagnosis and 30-day mortality linked by the 
Danish CPR-number, are the primary datasets in this study.  
Secondary analyses will be carried out on existing data for blood samples collected during hospital 
admission, and data for readmissions, ICU-admissions and reoperations.  
PARTICIPANTS 
INCLUDED PATIENTS 
Patients are included according to the following criteria: 
 Admission date (medical patients) or end of operation date (surgical patients) between 1st 
of January 2014 to 29th of December 2014.  
 Age: ≥18 
 Unique (first) admission for either: 
Surgical Patients: 
Admitted for: 
 Major operation with significant perforation of the peritoneum (laparotomy) 
 Admission diagnosis (primary diagnosis) of hip fracture (DS720-DS722) combined with a 
surgical procedure code starting with KNF (hip surgery) for the same admission.  
DS720 
Fracture of neck of femur 
DS721 
Pertrochanteric fracture 
DS722 
Subtrochanteric fracture 

Hannibal Troensegaard 
SUPPLEMENTARY OXYGEN  
25/07-2018 
IN SURGICAL AND MEDICAL WARDS  
 
EVALUATED BY 30-DAY MORTALITY (SOSAM) 
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Medical patients: 
Admitted under the primary diagnosis of:  
 COPD with either acute exacerbation (DJ441) or acute lower respiratory infection  (DJ440) 
DJ440 
Chronic obstructive pulmonary disease with acute lower respiratory infection   
DJ441 
Chronic obstructive pulmonary disease with acute exacerbation, unspecified 
 
 Acute myocardial infarction (DI21X) 
DI21 
Acute myocardial infarction 
DI210 
Acute transmural myocardial infarction of anterior wall 
DI210A 
Anterior non-ST-elevation acute transmural myocardial infarction 
DI210B 
Anterior ST-elevation acute transmural myocardial infarction 
DI211 
Acute transmural myocardial infarction of inferior wall 
DI211A 
Inferior non-ST-elevation Acute transmural myocardial infarction 
DI211B 
Inferior ST-elevation Acute transmural myocardial infarction 
DI212 
Acute transmural myocardial infarction of other sites 
DI213 
Acute transmural myocardial infarction of unspecified site 
DI214 
Acute subendocardial myocardial infarction 
DI219 
Acute myocardial infarction, unspecified 

Hannibal Troensegaard 
SUPPLEMENTARY OXYGEN  
25/07-2018 
IN SURGICAL AND MEDICAL WARDS  
 
EVALUATED BY 30-DAY MORTALITY (SOSAM) 
Side 4 af 14 
EXCLUDED PATIENTS 
Patients are excluded according to the following criteria: 
 No data on saturation within 48 hours after 
o Admission (Medical patients) 
o Discharge from the post anaesthesia care unit, PACU (Surgical patients) 
 No data on primary outcome (30-day mortality) 
A patient inclusion diagram will be included in the final manuscript. See below figure for proposed 
illustration.  
PATIENT INCLUSION DIAGRAM 
 
Figure 1 - Overview of patient inclusion 
VARIABLES 
As the majority of patients do not have a regular measurement of 𝑃𝑎𝑂2, the  exposure to 
hyperoxia will be estimated by combining the 𝑂2-saturation (SpO2) as measured by pulse oximetry 
PATIENTS IN EWS DATABASE:  
TOTAL PATIENTS 
Patients included for 
 
Abdominal surgery: 
 
subpopA 
Hip fracture: 
 
 
subpopB 
COPD 
 
 
 
subpopC 
AMI: 
 
 
 
subpopD 
Total: 
 
 
 
TOT 
Included patients: 
 
N 
Hypoxia: 
HYPO 
Normoxia: 
NORM 
Hyperoxia: 
HYPER 
Exclusion of  patients due to 
No data on SAT:   
 
ex1 
No data on primary outcome: 
ex2 
Total:    
 
 
extot 

Hannibal Troensegaard 
SUPPLEMENTARY OXYGEN  
25/07-2018 
IN SURGICAL AND MEDICAL WARDS  
 
EVALUATED BY 30-DAY MORTALITY (SOSAM) 
Side 5 af 14 
and the amount of oxygen administration (measured in litres/min), both values obtained during 
the recording of EWS values.  
Patients will be classified into three groups based on their oxygenation level. Patients will be 
assigned to the group according to which they spend the majority of time during the first 48 hours 
after either hospital admission for medical patients or discharge from the post anaesthesia care 
unit (PACU) for surgical patients. Patients previously diagnosed with COPD have a different 
setpoint for blood oxygenation, these patients are therefore classified according to the 
international guidelines for oxygenation in COPD-patients. Table 1 depicts the detailed 
classification of the three groups.  
 
 
Hypoxia 
Normoxia 
Hyperoxia 
Non-COPD 
SpO2 <94% irrespective of 
supplemental oxygen 
SpO2 94-98% in combination with 
supplemental oxygen 
Or 
SpO2 ≥94% without supplemental oxygen. 
SpO2 >98% in combination with 
supplemental oxygen 
COPD 
SpO2 <88% irrespective of 
supplemental oxygen 
SpO2 88-92% in combination with 
supplemental oxygen 
Or 
SpO2 ≥88% without supplemental oxygen. 
SpO2 >92% in combination with 
supplemental oxygen 
Table 1 – Classification of oxygenation 
 
Due to EWS measurements not being a function of time, a calculation will be done in order to 
estimate the weight of the individual EWS-measurement.  
Based on the frequency of the EWS-measurements one measurement will be given a value 
corresponding to the fraction of time in the 48-hour period it covers, thus making it possible to 
estimate the oxemia status for the entire 48-hour period.  
The normoxia group will serve as reference group for the analysis of the following outcome 
parameters in order to evaluate the effects of hyperoxia (primary analysis) and hypoxia 
(supplemental analysis): 
The primary outcome is 30-day mortality, with secondary analysis of length of hospital stay, as 
well as the 30-day occurrence of admission to the Intensive Care Unit, re-operations and hospital 
readmission.  

Hannibal Troensegaard 
SUPPLEMENTARY OXYGEN  
25/07-2018 
IN SURGICAL AND MEDICAL WARDS  
 
EVALUATED BY 30-DAY MORTALITY (SOSAM) 
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We will also assess associations of hyperoxia to organ-markers of disease severity:  CRP 
(inflammation), creatinine (acute kidney injury) and troponin (myocardial injury), which will be 
analysed by the peak level of each organ marker within 30 days. 
As a supplemental analysis, we will also assess the clinical effects among patients with at least one 
arterial blood gas analysis during the 48 hours observation window, in which we divide patients in 
groups of hypoxia (PaO2 <8 kPa), normoxia (PaO2 8-12 kPa) and hyperoxia (PaO2 ≥12 kPa), 
according to the highest measured  PaO2 . We will also do a sensitivity analysis reassessing the 
effect when patients are reassigned to groups according to exposure to hypoxia ≥8 hours or 
hyperoxia ≥8 hours. 
DATA SOURCES 
This study will be based on data from a National Early Warning Score (EWS) database recorded on 
all patients hospitalized from 1 January 2014 to 31 December 2014 in the Capital Region. Data 
Protection approval and Ethics Committee waiver have been approved for these data. The data 
has been thoroughly validated for accurate entries and consists of data from approximately 
170.000 unique hospital admissions in the Capital Region of Denmark.8 Furthermore, the unique 
CPR registration of all Danish patients, enables the analysis of organ markers within 30-days as 
well as arterial blood gas in the previously defined 48-hour period.  
BIASES 
The measurements of patients EWS-scores have all been manually registered and entered in the 
EWS-database. Previous analyses of the EWS Database show inaccuracies in the entries with a bias 
towards “normalized” values of vital parameters. Furthermore, EWS-measuring in the capital 
region of Denmark was optional on patients at an “end of life pathway”, potentially distorting the 
data by not including the most critically ill patients.  
The classification of patients according to their state of oxygenation was based on SpO2 measured 
on a plethysmograph. Although such measurements correlate with the actual saturation of the 
blood, factors such as peripheral circulation and nutritional status can effect this measurement 
and thus affect the initial data. 
POWER CALCULATION 
MORTALITY 

Hannibal Troensegaard 
SUPPLEMENTARY OXYGEN  
25/07-2018 
IN SURGICAL AND MEDICAL WARDS  
 
EVALUATED BY 30-DAY MORTALITY (SOSAM) 
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The 30 day mortality in each of the four patient groups is estimated in order to calculate the 
power of the proposed study: 
 
A - Acute myocardial infarction: A = 7,5 
Note: Estimated from a Prospective analysis on Danish patients with AMI. 9 
 
B - COPD with exacerbation: B = 10% 
Note: Estimated from a Danish study on COPD patients admitted with exacerbation with or 
without pneumonia (8,3-12,1 %). 10 
 
C - Hip fracture and surgery: C = 10% 
Note: Estimated from a nationwide, population-based cohort study using prospectively collected 
data from the Danish Multidisciplinary Hip Fracture Registry, reporting 7,3 – 10% 30- day mortality 
on all admissions for hip fracture. Due to selection of patients WITH surgery in the proposed study, 
the 30-day mortality is expected to be towards the higher end, maybe higher, than the range 
referenced in the study. 11 
 
D – Major abdominal surgery: D = 3,5% 
Note: 30- day mortality estimated from the 30-day mortality in the PROXI-trial (2,9-4,4%).12 
WEIGHTED AVERAGE OF 30-DAY MORTALITY: 
Preliminary analysis suggests the following population sizes: 
 
A 
B 
C 
D 
TOTAL 
Pop size (𝑁𝑥) 
𝑁𝐴= 2300 
𝑁𝐵= 3100 
𝑁𝐶= 2100 
𝑁𝐷= 4600 
12100 
Mortality (𝑃𝑥) 
𝑃𝐴= 7,5% 
𝑃𝐵= 10% 
𝑃𝐶= 10% 
𝑃𝐷= 3,5% 
 
 
Weighted average 30-day mortality: 
𝑃̅ = 𝑃𝐴∗𝑁𝐴+ 𝑃𝐵∗𝑁𝐵+ 𝑃𝐶∗𝑁𝐶+ 𝑃𝐷∗𝑁𝐷
𝑁𝐴+ 𝑁𝐵+ 𝑁𝐶+ 𝑁𝐷
≈𝟕% 
POWER ON BASIS OF PRESUMED CLINICAL EFFICACY OF OXYGEN-GROUP 

Hannibal Troensegaard 
SUPPLEMENTARY OXYGEN  
25/07-2018 
IN SURGICAL AND MEDICAL WARDS  
 
EVALUATED BY 30-DAY MORTALITY (SOSAM) 
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Values according to Figure 15.2, page 456 in “Practical Statistics for Medical Research”13 See 
appendix 1. 
Presumed difference  in 30-day mortality between 
hyperoxia and normoxia  
(if N1-N2=0) 
P1 −P2 = P  
Standardized difference  
P1 −𝑃2
√𝑃̅(1 −𝑃̅)
 
Power at N=10.000 patients 
(derived from Figure 15.2, 
Appendix 1) 
7,25% - 6,75% = 0,5% 
0,0196 
0,17 
7,50% - 6,50% = 1,0% 
0,0392 
0,42 
7,75% - 6,25% = 1,5% 
0,0588 
0,80 
8,00% - 6,00% = 2,0% 
0,0784 
0,97 
8,25% - 5,75% = 2,5% 
0,0980 
>0,995 
8,50% - 5,50% = 3,0% 
0,1176 
>0,995 
WEAKNESSES OF THIS POWER CALCULATION 
The only patient population corresponding geographically to the currently proposed sample is the 
group from the PROXI trial used in group “D – major abdominal surgery”. The other three 
mortality rates are from comparable but not exact same population base. 
The power of the study was derived from a nomogram (Appendix 1) and not calculated with a 
formula, thus leaving room for reading errors.  
Furthermore, the power calculation assumes the patient count in normoxia and hyperoxia are 
equal. 
CONCLUSION 
With 12000 patients included in this study we have 80% power to detect a statistically significant 
difference in 30-day mortality of absolute risk reduction of 1.5% (relative risk reduction 19%) 
assuming the average 30-day mortality of the study sample is 7%, a distribution of patients 1:1 in 
the two groups and a significance level of 5%.  
 
 

Hannibal Troensegaard 
SUPPLEMENTARY OXYGEN  
25/07-2018 
IN SURGICAL AND MEDICAL WARDS  
 
EVALUATED BY 30-DAY MORTALITY (SOSAM) 
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PLAN FOR STATISTICAL ANALYSIS 
SUGGESTED DESCRIPTIVE DATA 
Descriptive data for the population will be presented in table 1. For each of the three exposure 
groups, the following will be reported to characterise the study population: Age (mean), sex 
(percentage female), admission-hospital distribution and patient inclusion group distribution. The 
average EWS value (adjusted for chronic values) will also be included in the population description 
table.  
 
Hypoxia 
Normoxia 
Hyperoxia 
Age (yr) 
 
 
 
Sex (F%) 
 
 
 
Hospital 
 
 
 
 
RH (%) 
 
 
 
 
BFH (%) 
 
 
 
 
GLO (%) 
 
 
 
 
XX (%) 
 
 
 
Patient Group 
 
 
 
 
MI (%) 
 
 
 
COPD (%) 
 
 
 
HIP (%) 
 
 
 
ABD (%) 
 
 
 
Average EWS Value 
 
 
 
OUTCOME DATA 
Outcome data will be presented in table 2. The table will contain the three exposure groups and 
outcome data as calculated for each of the groups.  
The primary outcome, 30 day mortality, is a binary variable for the individual patient, and will be 
reported as a fraction of positives within the exposure group population.  
Length of stay and highest values for organ markers during the 30-day period will be treated as 
continuous variables with a non-normal distribution, and thus the median, not the mean, will be 
reported for these outcomes.  
30-day admission to ICU, 30-day reoperation and 30-day readmission will be reported as a fraction 
of positives within the exposure group population.  

Hannibal Troensegaard 
SUPPLEMENTARY OXYGEN  
25/07-2018 
IN SURGICAL AND MEDICAL WARDS  
 
EVALUATED BY 30-DAY MORTALITY (SOSAM) 
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GROUP 
Mortality 30 d 
Length of stay 
Adm. ICU 30 d 
Reop. 30 d 
Readm. 30 d 
Blood 30 d 
Hypoxia 
 
 
 
 
 
CRP 
Creatinine 
Troponine 
Normoxia 
 
 
 
 
 
CRP 
Creatinine 
Troponine 
Hyperoxia 
 
 
 
 
 
CRP 
Creatinine 
Troponine 
 
For patients with least one arterial blood gas analysis during the 48 hours observation window, a 
secondary table will be reported, in which patients are divided in groups of hypoxia (PaO2 <8 kPa), 
normoxia (PaO2 8-12 kPa) and hyperoxia (PaO2 ≥12 kPa), according to their highest measured  
PaO2 . 
GROUP 
Mortality 30 d 
Length of 
stay 
Adm. ICU 30 
Reop. 
30 d 
Readm. 
30 d 
Blood 30 d 
Hypoxia PaO2 <8 kPa 
 
 
 
 
 
CRP 
Creatinine 
Troponine 
Normoxia PaO2 8-12 kPa 
 
 
 
 
 
CRP 
Creatinine 
Troponine 
Hyperoxia PaO2 ≥12 kPa 
 
 
 
 
 
CRP 
Creatinine 
Troponine 
ANALYSES: 
All outcome data will be compared in the normoxia vs. hyperoxia groups data and reported as an 
odds ratio in the primary analysis. 95% confidence intervals and the p-value will be reported for 
each outcome parameter. All values, including non-significant values, will be included in the final 
reporting.  

Hannibal Troensegaard 
SUPPLEMENTARY OXYGEN  
25/07-2018 
IN SURGICAL AND MEDICAL WARDS  
 
EVALUATED BY 30-DAY MORTALITY (SOSAM) 
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Normoxia 
Hyperoxia 
Odds Ratio 
(95% CI) 
P value 
Primary Outcome 
 
 
 
 
   30 day mortality  
 
 
 
 
 
Secondary outcomes: 
 
 
 
 
   Adm. ICU 30 d 
 
 
 
 
   Reop. 30 d 
 
 
 
 
   Readm. 30 d 
 
 
 
 
   Blood 30 d 
 
 
 
 
 
CRP 
 
 
 
 
 
Creatinine 
 
 
 
 
 
Troponine 
 
 
 
 
OTHER ANALYSES 
Secondary analyses will be carried out on normoxia vs hypoxia patients with the same outcome 
parameters as the primary analysis.  
 
Hypoxia 
Normoxia 
Odds Ratio 
(95% CI) 
P value 
Primary Outcome 
 
 
 
 
   30 day mortality  
 
 
 
 
 
Secondary outcomes: 
 
 
 
 
   Adm. ICU 30 d 
 
 
 
 
   Reop. 30 d 
 
 
 
 
   Readm. 30 d 
 
 
 
 
   Blood 30 d 
 
 
 
 
 
CRP 
 
 
 
 
 
Creatinine 
 
 
 
 
 
Troponine 
 
 
 
 
 

Hannibal Troensegaard 
SUPPLEMENTARY OXYGEN  
25/07-2018 
IN SURGICAL AND MEDICAL WARDS  
 
EVALUATED BY 30-DAY MORTALITY (SOSAM) 
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In order to assess the feasibility of the exposure groups, a supplementary sensitivity analysis will 
be made, reassessing the effect on outcome parameters when patients are reassigned to groups 
according to exposure to hypoxia ≥8 hours or hyperoxia ≥8 hours. 
OTHER INFORMATION 
FUNDING 
This project has been funded by the internal grand for research projects at Bispebjerg and 
Frederiksberg Hospitals.  
 
 

Hannibal Troensegaard 
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25/07-2018 
IN SURGICAL AND MEDICAL WARDS  
 
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APPENDIX 1 
 
 
 

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SUPPLEMENTARY OXYGEN  
25/07-2018 
IN SURGICAL AND MEDICAL WARDS  
 
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