The CO2 GAP Project – CO2 GAP as a Prognostic Tool in
Emergency Departments
Amith Shetty* , Kevin Lai , Karen Byth
Westmead Hospital, Emergency Department, Sydney, NSW
ABSTRACT
Background:
Capnography has been recommended for monitoring severity of pulmonary disease and
evaluating response to therapy, especially therapy intended to improve the ratio of dead
space to tidal volume (VD/VT) and the matching of ventilation to perfusion (V/Q), and
possibly, to increase coronary blood flow. CO2 GAP [(arterial- end tidal)PCO2] is known
to be a marker for dead space and V/Q mismatching and responds to changes in cardiac
output.
Objective:
Prospective Observational study to determine if CO2 GAP can be used as a prognostic
tool to predict need for assisted ventilation in patients presenting with shortness of breath
(SOB) to emergency department (ED).
Methods:
412 patients underwent concurrent Arterial blood gas and ETCO2 measurements in
emergency department as part of management of shortness of breath. CO2 GAP and
Arterial –alveolar PO2 gradient results were derived from these readings and matched to
1
assisted ventilation outcomes and admission to High Dependency Unit/ Intensive Care
Unit or death in Emergency Department.
Results:
27.2% of patients required assisted ventilation and 35.2% were either admitted to High
Dependency Unit/ Intensive Care Unit or died in the training set of cohort. Analysis of
the Receiver Operator Characteristics curves revealed the CO2 GAP performed
significantly better than the A-a gradient in predicting worse outcomes (Area under curve
0.950 vs. 0.726). A CO2 GAP > 10.5 predicted need for assisted ventilation outcomes
when applied to the validation test set with 100% sensitivity.
Conclusions:
The CO2 GAP [(arterial – end tidal) PCO2] may have a prognostic role in predicting
need for assisted ventilation outcomes in emergency departments in patients presenting
with shortness of breath.
Glossary of Abbreviations:
CO2 GAP – [(a-ET)PCO2], SOB – shortness of breath, ED – Emergency department,
ABG – Arterial blood gas measurement, HDU – High dependency unit, ICU – Intensive
care unit, AUC – area under curve, ETCO2 – end-tidal CO2, AAG - Arterial – alveolar
Oxygen Gradient, VT – tidal volume, VD – dead space volume, ROC - Receiving operator
characteristic.
2
INTRODUCTION:
Capnography is used commonly for verification of endotracheal intubation, ventilator
weaning, monitoring during procedural sedation and during cardiopulmonary
resuscitation (CPR)1. Arterial blood gas data and derived values e.g. Arterial – alveolar
oxygen gradient (AAG) are used widely in clinical practice.
ETCO2 monitoring provides an insight into the three main systemic functions:
metabolism, circulation and ventilation. If two of these parameters are held constant,
changes in ETCO2 reflect a variation in the third2. Measurements of ETCO2 constitute a
useful non-invasive tool to monitor PaCO2 and hence the ventilatory status of patients
during anaesthesia or in the Intensive care unit, when the cardiovascular and pulmonary
parameters are stable. In normal individuals, the (a-ET) PCO2 (CO2 GAP) may vary from
2-5 mmHg3,4,5,6,7,8.
The CO2 GAP is due to V/Q mismatch in the lungs as a result of temporal, spatial and
alveolar mixing defects9. The (a-ET) PCO2/PCO2 (VD/VT) fraction is a measure of
alveolar dead space, and changes in alveolar dead space correlate well with changes in
CO2 GAP10. Reductions in cardiac output and pulmonary blood flow cause a decrease in
PETCO2 and conversely increases in cardiac output cause an increase in PETCO2 due to
better perfusion of upper segments of the lung11. These changes may also be reflected as
changes in the CO2 GAP.
3
ETCO2 monitoring has potential as a non-invasive indicator of cardiac output during
resuscitation and a prognostic indicator for effective resuscitation12,13. Studies in critically
ill patients after ventilator resetting have shown that ETCO2 correlates poorly with
PaCO214. The ETCO2 is shown to be affected during changes in posture due to its effects
on cardiac output, tidal volume and functional residual capacity15.The CO2 GAP has been
shown to increase significantly with an increase in anatomic dead space and has been
suggested as a serial measurement tool in critically ill patients16. CO2 GAP has been
suggested as a possible monitoring tool for efficacy of thrombolysis for pulmonary
embolism17.
The gradient between arterial CO2 (Pa-ET)CO2 and end-tidal CO2 (CO2 GAP)has been
identified as a predictor of mortality in patients undergoing emergency trauma surgery18.
A CO2 GAP > 10 was associated with higher mortality even when blood pressure had
normalized in trauma patients19.
The CO2 GAP project aimed to determine the relevance of P(a-ET)CO2 in patients
presenting to emergency departments with shortness of breath. It also aimed to determine
whether CO2 GAP can be used as a prognostic tool (change in value of CO2 GAP with
worsening clinical disease) to predict worse outcomes in patients presenting to ED with
SOB. No studies to date have been conducted in any subset of patients to determine the
validity of CO2 GAP as a prognostic tool.
4
METHODS
Patient selection:
CO2 GAP project was a prospective observational study conducted at an adult ED of a
tertiary referral hospital with an annual census of approximately 59000. Human Research
Ethics Committee approval was obtained. Statistical Power analysis revealed the need for
conducting the study with 300 patient training set and a 100 patient validation test set, to
predict with 90% CI for a change in management with at least 5% change in CO2 GAP.
Patients presenting to ED with SOB undergoing arterial blood gas analysis (ABG) as a
part of their clinical work up were included in the study. To avoid selection bias, all
patients undergoing ABG during their stay in ED irrespective of cause were enrolled into
the data collection. Patients underwent ABG measurement when indicated clinically and
with no prior intention for inclusion into the study. The clinical notes and CO2 GAP
datasheet were reviewed to determine the reason for ABG. Only patients investigated for
SOB were included in the study. Data was collected prospectively during a pilot study
period in June 2008 and over a six month main study period from November 2008 to
April 2009.
Training:
The nursing staff in emergency department underwent intensive training prior to the pilot
study and the main study period to identify major issues involved in the measurement of
ETCO2. Emphasis was placed upon recognition of mouth breathers and use of combined
5
oral-nasal sidestream microstream ETCO2 adapters in this set of patients. Nurses were
also trained to await the stabilisation of the ETCO2 reading and sensor warming period.
To avoid extraneous gas flow related ETCO2 measurement error, patients did not receive
supplemental oxygen through the ETCO2 sampling devices. Only initial ABG
measurements undertaken on patients during their stay in ED were included in the study.
In case the patient was intubated on arrival to ED, Only the initial immediate ABG and
ETCO2 measurements were included in the study. Patients already intubated prior to
arrival to ED were not included in the study.
All doctors were advised to inform the nursing staff when planning to conduct an ABG.
Where possible the ETCO2 measurement was conducted as close as possible to the ABG
collection. The ABG analysis results were entered into a standard CO2 GAP project data
entry form by the doctor and the nursing staff entered the ETCO2 measurement results.
The data collection form was reviewed by the scientific advisory committee of the area
health service prior to initiation of study.
Equipment:
ABG was analysed using a radiometer ABL gas analyser or the I-STAT ABG analyser,
both available within ED. ETCO2 was measured using either mainstream infrared
analyser or sidestream microstream analyser using Phillips Intellivue X2 patient monitors
installed in each acute care bed in the department. The ETCO2 was measured using
Philips NIV CO2 nasal cannula or combined oral-nasal cannula in conscious patients.
Studies have proven reliability of microstream infrared CO2 analysis in measuring
6
ETCO2 in non-intubated patients20. Patient management was unaltered and carried out as
per department guidelines.
Outcomes Measured:
Datasheets were reviewed at the end of each week during the study period. Patients’
clinical notes were reviewed to determine outcomes – assisted ventilation use (invasive
and non-invasive), admission to medical High Dependency Unit (HDU) (including
coronary care unit/ respiratory HDU) or Intensive Care Unit (ICU), and death during stay
in ED.
CO2 Derived variables:
For purpose of our study, following CO2 derived variables were calculated:
CO2 GAP in mm Hg = PaCO2 – ETCO2
CO2 gradient % =
VD/VT =
CO2 GAP
ETCO2
X 100
CO2 GAP
PaCO2
7
Arterial – alveolar Oxygen Gradient:
A-a gradient was calculated from the datasheets for all patients using the standard
formula:
A-a Gradient = [(FiO2) x (Atmospheric Pressure - H2O Pressure) - (PaCO2/0.8)] - PaO2
The hospital is situated at sea level and atmospheric pressure used for this calculation was
760mmHg. FiO2 values were filled in by staff conducting the ABG according to a
standardised FiO2 table available in the department.
Statistical methods:
SPSS for Windows, version 17 software was used for the statistical analysis. The 412
patients in the cohort were randomly assigned to either a training set of 312 patients and
onto a validation test set of 100 patients. The area under the curve (AUC) of the receiver
operating characteristic (ROC) curve was used to quantify the overall predictive value of
each variable of interest. Cut-points achieving maximal specificity and at least 90%
sensitivity were identified for each variable using the training set data. The performance
of these prognostic ‘rules’ was then assessed in the independent test set of 100 patients.
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RESULTS
A total of 759 patients underwent recorded ABG measurement during the study period. In
275 patients, ETCO2 measurements were not completed or recorded and thus could not
be included in the study (Figure 1). 72 patients were excluded from the study as ABG
was conducted for causes other than SOB (Table 1). The 275 patients also included
patients who were intubated prior to arrival in ED and patients whose ABG measurement
was conducted late during their course of treatment and also repeat ABG measurements
conducted in the same patient during their stay in ED.
Demographics:
A total of 412 patients’ data was analysed. There were 210 male patients in the cohort.
The mean age for the whole group was 63.79 ± 18.7 with mean age for males being 63.8
± 17.8 and mean age of females being 63.7 ± 19.7. The overall mortality was 17 (4.1%)
during their stay in the ED. 126 of patients from the cohort received ventilatory support
(invasive and non-invasive) (30.5%). 134 of patients were admitted to high acuity beds
(HDU/ICU) (32.5%).
In the training set, 85 patients received assisted ventilation (invasive and non-invasive)
(27.2%) and 110 patients were either admitted to HDU/ICU or died (35.2%).
In the validation test set 33 patients received assisted ventilation (invasive and noninvasive) (33%) and 39 patients were admitted to HDU/ICU or died in ED (39%). The
training and validation test sets were comparable with respect to demographics and
outcomes.
9
Patients undergoing ABG
measurements during study period
n= 759
Incomplete data forms/ ETCO2
measurement not conducted
n = 275
Patients excluded from study ABG
for reasons other than SOB
n = 72
Patients included in CO2 GAP
project
n= 412
Fig. 1 CONSORT flow diagram of Patients included in CO2 GAP Project
Reasons for Exclusion
Reduced level of consciousness from CNS causes e.g.
CVA, meningitis, status epilepticus
Number
18
Drug overdose - assessment of acidosis
14
Abdominal pain – assessment of acidosis
8
Pancreatitis – no SOB
5
Severe trauma
7
Diabetic ketoacidosis
10
Non-respiratory causes of Sepsis
9
Neck swelling
1
Total exclusions
72
Table 1 - Excluded patients and Reasons for exclusion.
10
Diagnoses
Number
Chronic Airway Limitation
86
Pneumonia
89
Congestive Cardiac failure
75
Investigation of Chest pain to rule out Pulmonary embolism
51
Cardiac or respiratory arrest
27
Asthma
16
Smoke Inhalation
5
Bronchiectasis
2
Sepsis with respiratory cause/compromise
6
Pleural effusion/pneumothorax
8
Carcinoma lung
2
Pulmonary Hypertension
2
Anemia
1
Shortness of breath (unknown cause/ mixed cause)
42
Total inclusions
412
Table 2. Diagnoses of patients included in study.
11
All data was analysed for two outcomes:
 Need for assisted ventilation in ED (invasive or non-invasive)
 Need for admission to HDU/ICU or death during stay in ED
Receiving Operating Characteristic (ROC) curves:
ROC curves were used to quantify the overall predictive value of each variable of
interest. The curves associated with the training and test sets for each outcome are
illustrated in figure 1. The AUC and their associated standard errors (SE) are given in
Table 1. The AUC analysis revealed a significantly better performance of CO2 GAP, CO2
Gradient and VD/VT over A-a gradient in predicting each outcome of interest.
The cut-points achieving maximal specificity with at least 90% sensitivity in the training
set for each outcome are shown in table 2 along with the actual sensitivity and specificity
achieved by each ‘value’ in the independent test set.
A CO2 GAP of >10 was associated with assisted ventilation in the validation test set
(sensitivity of 100% and specificity of 70%). A VD/VT ratio of >0.31 was associated
with assisted ventilation (sensitivity 88% and specificity 85.7%).
12
Figure 2. Receiving Operating Characteristic (ROC) curves
Assisted ventilation
Training set n=312
Test set n=100
Admission to HDU/ICU or Death
Training set n=312
Test set n=100
13
DISCUSSION
ETCO2 measurement has been increasingly used in emergency departments. It is a cheap
and non-invasive measurement with wide array of applications. The CO2 GAP is an
easily measureable entity in patients undergoing ABG and ETCO2 measurements.
Capnography has been recommended for monitoring severity of pulmonary disease and
evaluating response to therapy, especially therapy intended to improve the ratio of dead
space to tidal volume (VD/VT) and the matching of ventilation to perfusion (V/Q), and
possibly, to increase coronary blood flow. It has also been recommended for evaluation
of efficiency of mechanical ventilatory support by determination of the CO2 GAP and
monitoring adequacy of pulmonary, systemic, and coronary blood flow21.
Recent advances in infrared microstream gas analysis have increased the reliability of
ETCO2 measurements in non-intubated patients20. Improvements in infrared gas
measurement techniques have reduced the errors caused in the past due to adjacent
absorption spectra of oxygen, nitrous oxide and carbon dioxide.
Another major source of error during ETCO2 measurements is gas flow related reduction
in ETCO2 reading. In our study, we tried to eliminate this by avoiding concomitant
oxygen administration to patients undergoing the measurement when possible. The CO2
sampling cannula was used solely for the ETCO2 measurement.
14
Retrospective and prospective studies involving CO2 derived variables and outcomes in
trauma surgery have shown significant differences between survivors and nonsurvivors22. No studies to date have investigated the value of CO2 GAP measurements as
a prognostic tool in patients presenting to ED.
ABG measurements are frequently carried out in patients presenting with SOB to ED.
Currently measured data such as PCO2, pH, PO2 and HCO3- and calculated data such as
A-a gradient are used to make clinical decisions about patient management. We aimed to
determine if the changes in CO2 GAP correlated with outcomes.
The CO2 GAP data was significantly different in patients requiring assisted ventilation
and HDU/ICU admission (p<0.001). The calculation of CO2 gradient (CO2 GAP/ETCO2)
did not offer any advantage over CO2 GAP in predicting these outcomes as was evident
from the AUC (area under curve) analysis from the ROC curves(fig. 2 and 3). The CO2
GAP performed significantly better than A-a gradient in both predicting assisted
ventilation (AUC 0.905 vs. 0.724) and predicting HDU/ICU/Death outcomes (AUC
0.891 vs. 0.713).
The receiver operator characteristic curves demonstrated a CO2 GAP of 10.5 as a
significant threshold value for need for intervention. This value is similar to the result
obtained by the prospective study in trauma surgical patients in the past by Tyburski JG
et al20.
15
When correctly measured the CO2 GAP thus provides a sensitive additional tool in
prognosticating patients presenting with SOB to ED. An increased CO2 GAP may thus
signal the need for assisted ventilation, more aggressive resuscitation and closer
monitoring in this subset of patients.
Future Implications:
Further study needs to be conducted to verify the role of CO2 GAP as a monitoring tool.
Serial measurements of ABG and ETCO2 undergoing non-invasive ventilation may help
verify this role.
The role for quantitative capnography needs to be further investigated, but the complexity
of this method makes it less attractive for use in ED setting.
Limitations of the study:
The CO2 GAP study was conducted in a busy ED of a tertiary adult hospital. Though the
Human Research Ethics Committee approval was gained for this study, it was not
possible to make ETCO2 readings compulsory for all patients undergoing ABG
measurements due to clinical constraints. It is very likely that of the 225 patients who did
not get ETCO2 measurements conducted, a significant proportion would have been in the
assisted ventilation group.
The study was conducted in both intubated and non-intubated patients, though intubation
does not fully obviate the CO2 GAP, ventilator settings may have affected some of the
16
readings. Where possible the measurements were conducted prior to initiation of assisted
ventilation, but in keeping with the nature of emergency departments; this was not the
case in all instances. Since no other study has ever been done in the past to observe the
CO2 GAP, we had not initially foreseen this limitation and 27 intubated patients who had
immediate ABG measurements after intubation were included in the analysis. The CO2
GAP in patients either intubated or subsequently intubated, was significantly higher than
patients who did not need invasive ventilation. Time to intervention from time of
conduction of ABG and ETCO2 were not recorded during the study.
The calculation of A-a gradient requires the accurate recording of FiO2. Since patients in
the department received oxygen via nasal prongs, masks or venturi masks; calculations of
FiO2 may not have been entirely accurate in some instances. This may be a reason for the
wide variation in values of A-a gradient in this study.
The CO2 GAP study was a single centre prospective study and involved extensive
training of nursing staff in understanding the concepts and methods of ETCO2
measurements. ETCO2 measurements in unstable non-intubated patients are prone to
many errors, which will need to be addressed in future studies as well.
Further studies need to be conducted in non-intubated patients to observe the trend of
CO2 GAP and confirm its relevance to prognosis. This study may be considered as pilot
study for further investigation into this subject.
17
Conclusion:
The CO2 GAP is consistently higher in patients with shortness of breath requiring noninvasive or invasive ventilation when compared to patients not requiring the same. This is
in keeping with the knowledge of CO2 GAP as a surrogate marker for pulmonary dead
space and also cardiovascular insufficiency. The CO2 GAP [(a-ET) PCO2] may have a
prognostic role in predicting need for assisted ventilation outcomes in emergency
departments in patients presenting with shortness of breath. Though decisions regarding
need for ventilator assistance are largely clinically based, we believe the CO2 GAP may
add as an additional easily derivable tool to the clinician’s aid.
Acknowledgements:
We thank the Director, the medical and nursing staff at Westmead Hospital for their help
and support; Emma Clarke for the data collection work; Jim Skidmore for technical
assistance and all the ancillary staff at Westmead hospital Emergency department.
18
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20
Table 1.
Outcome
Training set (n=312)
Sensitivity Specificity
Test set (n=100)
Sensitivity Specificity
Required assisted
ventilation
CO2 gap
CO2 gradient
AAG
Vd/Vt
>=10
>=27.3
>=18
>=0.27
91%
91%
91%
93%
70%
71%
16%
67%
100%
91%
85%
94%
70%
78%
18%
74%
CO2 gap
CO2 gradient
AAG
Vd/Vt
>=9.2
>=26.5
>=17.9
>=0.27
93%
94%
91%
93%
63%
67
15%
67%
100%
94%
85%
94%
61%
73%
13%
74%
>=9.2
>=26.5
>=17.9
>=0.27
90%
92%
90%
93%
68%
73%
15%
74%
92%
90%
90%
90%
64%
79%
18%
79%
>=10
>=27.3
>=18
>=0.27
86%
87%
89%
93%
75%
76%
15%
74%
92%
87%
90%
90%
72%
82%
21%
79%
Admitted ICU/Death
CO2 gap
CO2 gradient
AAG
Vd/Vt
CO2 gap
CO2 gradient
AAG
Vd/Vt
Cut-points achieving maximal specificity
and at least 90% sensitivity for Assisted
ventilation
Cut-points achieving maximal specificity
and at least 90% sensitivity for
ICU/Death
Cut-points achieving maximal specificity
and at least 90% sensitivity for
ICU/Death
Cut-points achieving maximal specificity
and at least 90% sensitivity for Assisted
ventilation
21
22