Accepted Manuscript

Capnography During Critical Illness

Boulos S. Nassar, MD, Gregory A. Schmidt, MD, FCCP
PII:

S0012-3692(15)00048-3

DOI:

10.1378/chest.15-1369

Reference:

CHEST 47

To appear in:

CHEST

Received Date: 5 June 2015

Revised Date:

15 September 2015

Accepted Date: 16 September 2015

Please cite this article as: Nassar BS, Schmidt GA, Capnography During Critical Illness, CHEST (2015),
doi: 10.1378/chest.15-1369.
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Capnography During Critical Illness

And

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Boulos S. Nassar MD

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Gregory A. Schmidt, MD, FCCP

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Corresponding Address:
Gregory A. Schmidt, MD
Division of Pulmonary Diseases, Critical Care, and Occupational Medicine
Department of Internal Medicine: C33-GH
University of Iowa
200 Hawkins Drive
Iowa City, IA 52242
Gregory-a-schmidt@uiowa.edu

The authors have no conflicts to disclose with regards to the content of this manuscript.

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Abstract

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Capnography has made steady inroads in the ICU, being increasingly used for all mechanically ventilated
patients. There is growing recognition that capnography is rich in information about lung and circulatory
physiology, providing insight into many diseases and treatments. These include conditions of impaired
matching of ventilation and perfusion, such as pulmonary embolism and obstructive lung diseases;
circulatory questions such as the adequacy of chest compressions during cardiac arrest or fluidresponsiveness in patients in shock; and the safety of procedural sedation. In this review, we emphasize
analysis of the entire capnographic waveform as a way to glean additional useful information. At the
same time, we discuss important limitations of capnography, especially when it is considered as a
surrogate for the PaCO2.

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Volume- and Time-Capnography

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Capnography refers to the measurement and display of carbon dioxide (CO2) concentrations in
respiratory gases. By the 1990s capnography was widely available for critically ill patients and quickly
became part of routine monitoring. There is broad appreciation of its value for assuring that
endotracheal tubes are placed properly in the trachea1; it is also being used to guide tidal volume and
rate settings during mechanical ventilation, focusing on the end-tidal value. Yet the full capnogram is
much richer in information than generally appreciated, finding application to gauge the degree of
ventilation (V)-perfusion (Q) mismatch; measure dead space and quantify airflow obstruction in asthma
and chronic obstructive pulmonary disease (COPD); diagnose pulmonary embolism (PE) and distinguish
it from exacerbations of chronic obstructive pulmonary disease; judge the adequacy of chest
compressions in cardiac arrest and detect return of spontaneous circulation (ROSC); estimate changes in
cardiac output; predict fluid responsiveness; and assist in metabolic assessment and nutritional needs2.
A full appreciation of capnography is founded on the physiology of CO2 exchange in the lung.
Accordingly, this review defines volume-capnography versus time-capnography; describes the phases of
the capnogram; explores the determinants of the CO2 concentration in a single alveolus and in expired
gas; addresses the correlation between arterial and end-tidal CO2 (ET-CO2) values in ventilated patients;
and reviews several key clinical applications relevant to the critically ill.

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Capnography refers to the measurement of CO2 at the airway opening, generally displayed as a partial
pressure (PCO2). Colorimetric, qualitative capnometers can be placed directly in the airway to confirm
endotracheal tube placement, but will not be discussed here further.3,4 Quantitative capnography in the
intensive care unit (ICU) typically relies on infrared absorption, placing the sensor directly in the
ventilator circuit (mainstream capnography) or continuously drawing a sample from the airway and
directing it through fine-bore tubing to an off-line sensor (sidestream capnography). Sidestream
capnography can also be sampled through a nasal cannula in spontaneously breathing patients, while
mainstream capnography is acquired only from an endotracheal or tracheostomy tube. The measured
PCO2 can be displayed as a function of time or of expired volume (time- and volume-capnography,
respectively, Figs 1 A and B). Because it relates CO2 to expired volume, volume-capnography more
intuitively links anatomy to PCO2 and allows calculation of dead space and CO2 production, but requires
measuring flow instantaneously5. This entails higher cost, a mainstream sensor, and more complexity,
precluding its wide application for routine ICU monitoring currently, although it is available in some
commercial ventilators and as standalone monitors. On the other hand, time capnography is readily
available in most ICUs but does not take expiratory flows into account. In this brief review we focus on
standard ICU capnography displaying the time-capnogram, as shown in Figure 1A.
Phases of the Time-Capnogram
The capnogram is divided into four phases (fig 1A). In phase I the PCO2 is effectively zero, representing
the portion of inspiration during which fresh, CO2-free gas enters the airway, and early expiration while
dead space gas (also CO2-free) is exhaled. PCO2 should always be zero unless there is rebreathing of CO2laden expired gas6. Phase II is more interesting, mixing the vestiges of anatomic dead space with alveolar
gas, coming from both alveolar dead space and ventilated alveoli. In addition, phase II includes some gas

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that truly belongs to phases I and III due to turbulent mixing and diffusion at the interface of dead
space and alveolar gas. For these reasons, phase II rises abruptly when V and Q are well-matched, but
more gradually when some high V/Q alveoli (having low PCO2) contribute to the expired gas stream.
Thus many diffuse lung and pulmonary vascular diseases are associated with slowly rising phase II.

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Phase III represents the alveolar plateau, displaying PCO2 values largely from alveoli. In a single alveolus
at steady state, CO2 concentration represents the balance between ventilation, which tends to lower it,
and perfusion, which tends to raise it. In the ideal lung (where ventilation and perfusion are matched
and all alveoli are identical), mean alveolar partial pressure for CO2 (PACO2) is equal to the arterial partial
pressure for CO2 (PaCO2). Breathing is phasic, however, so that the instantaneous PACO2 varies, falling as
fresh gas enters the alveolar compartment and rising again throughout expiration7,8 (Figure 2). The
maximal PACO2 approaches the venous (not arterial) PCO2 level, a value roughly 7 mmHg higher than
arterial. In theory, steady-state ET-CO2 can range from as high as the venous PCO2 (when the lung is
healthy and expiratory time is sufficiently long) to very, very low values (when overall ventilation is high
in comparison to VCO2; in the presence of alveolar dead space; and when expiratory time is short).
These are some of the many reasons that ET-CO2 may correlate very poorly with PaCO2 (Figure 3;
discussed further below), especially in the critically ill.

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Although the normal phase III appears relatively flat, the PCO2 rises progressively, in part reflecting the
fact that alveolar PCO2 rises during expiration as pulmonary blood flow continues to offload CO2 during
expiration into an ever-decreasing alveolar volume, but also for many other reasons in both health and
disease (Table 1). Phase III also rises more quickly when CO2 production is high, as shown elegantly by
DuBois and colleagues who measured their own capnograms during exercise nearly 70 years ago.7
Cardiac output only perturbs the phase III rise or affects the end-tidal value when changing, as following
a fluid bolus or when spontaneous circulation is restored during resuscitation. The most clinically
important contributor to the phase III slope is V/Q heterogeneity related to lung disease. Finally, phase
IV, like phase I, is trivial, plunging rapidly to zero shortly after the onset of inspiration.

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The volume capnogram presents CO2 concentration in relation to expired volume and is divided into 3
similar phases (lacking a phase IV since inspiration is not plotted; figure 1B). Phase I refers to the
emptying of the anatomic dead space. Phase II reflects the transition from airway dead space to
proximal alveoli, while phase III refers to alveolar emptying. The significance of the shapes of these
three phases is similar to those of time-capnography, but the slope of phase III is steeper because
expiratory flow falls exponentially throughout expiration.

Clinical Applications

Correlation between ET-CO2 and PaCO2 during mechanical ventilation

For adjusting mechanical ventilation settings, time capnography offers an attractive alternative to
arterial blood gas analysis, being continuous and non-invasive. Yet while ET-CO2 correlates well with
PaCO2 in health, large discrepancies are common in disease, often related to the factors shown in Table

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1.9,10,11,12 ET-CO2 values may exceed PaCO2 or be very much lower13. When ventilator settings are
adjusted, even the changes in ET-CO2 and PaCO2 are poorly related, even moving in opposing
directions14 (Figure 3). Further, trends over time show a poor correlation between changes in ET-CO2
and PaCO2.15,16 Perhaps this should not be surprising when all the determinants of ET-CO2 are
considered. For example, augmenting ventilator rate or tidal volume should tend to lower both ET-CO2
(because it tends to raise the ratio of alveolar ventilation to CO2 production) and PaCO2 but, if dead
space fraction rises, ET-CO2 may fall while PaCO2 rises. Because PEEP affects alveolar dead space, its
value impacts the capnogram: moreover, these effects have been used to guide PEEP levels in ARDS. 17 18
19 20
These data show that relying on ET-CO2 as a surrogate for PaCO2 is prone to serious error.
Nevertheless, while ventilator waveforms offer similar monitoring, capnography remains important
during mechanical ventilation to ensure airway patency and detect dislodgement or disconnection of
the endotracheal tube.21 It probably plays a bigger role during patient transport when the risk of
endotracheal tube migration is even higher.

Pulmonary embolus

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Pulmonary embolism (PE) remains a diagnostic challenge in the ICU. While computed tomographic
angiography (CTA) is reasonably sensitive and specific, critically ill patients present difficulties in safe
transport, often have many alternative reasons for new cardiopulmonary events, and are at risk of acute
kidney injury, making CTA a cumbersome screening test. PE compromises perfusion of the affected
alveoli, with much less impact on their ventilation, suggesting that capnography could be diagnostically
useful. Based on the physiology described above, one would expect PE to a) raise the alveolar dead
space (thus the physiologic and alveolar dead space fractions); b) lower the expired CO2 value
throughout phase III and widen any gradient between PaCO2 and ET-CO2 (since gas expired from high
V/Q alveoli has little CO2); and c) not raise the phase III slope (perhaps allowing distinction from COPD
and other airway diseases with marked V/Q heterogeneity; Figure 4).

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Volume capnography, as opposed to time capnography, links expired CO2 values more closely to lung
volumes and allows calculation of physiologic dead space fractions (by using the modified Bohr equation
and a simultaneous arterial blood gas). In testing the diagnostic value in patients with suspected PE,
most studies have employed volume capnography, but similar principles underlie the changes seen with
time capnography.22 In one of the earliest studies, PE was shown to raise physiologic dead space fraction
and the arterial-end-tidal CO2 difference.23 These findings have been confirmed in subsequent studies.24
25
In addition, the alveolar dead-space fraction correlates with the lung perfusion defect on lung
scintigraphy and the pulmonary artery pressure at angiography.25 Any difference between arterial and
ET-CO2 depends on tidal volume, leading several investigators to standardize the point of measurement
by extrapolating phase III to a tidal volume equal to 15% of predicted total lung capacity. The difference
between the expired CO2 value and PaCO2 at this extrapolated volume lends itself to calculation of the
late dead-space fraction. When it exceeds 12-15%, this value, even more than overall dead-space
fraction or ET-CO2 to PaCO2 gradient, may best separate those with and without PE. 26 27 28 29 30 Others

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have combined the late dead-space fraction or ET-CO2:PaCO2 gradient with a negative D-dimer value to
reduce the post-test probability of PE sufficiently to obviate further diagnostic testing.25

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Differences in PaCO2 and ET-CO2 are common in critical illness yet only occasionally is this caused by PE.
Most alternative causes consist of lung diseases with great V/Q heterogeneity, having abnormally steep
rises during phase III for the reasons cited above. In contrast, PE should not steepen phase III (in fact, it
flattens the slope for complex reasons related to redistribution of blood flow) 31; and thrombolysis has
been shown to increase the slope.32 In a series of patients presenting to the emergency department with
suspected PE, the slope of phase III was significantly flatter in those with confirmed PE.26

Obstructive Lung Diseases:

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In a pooled analysis of 14 trials and 2291 subjects, the sensitivity of capnography for the diagnosis of PE
was 0.80 while the specificity was 0.49.33 The diagnostic use of capnography for suspected PE has
several limitations. First, most clinical data pertain to volume capnography: time capnography does not
allow calculation of the late dead-space fraction at a standardized tidal volume. A second issue regards
steady-state -- PE may perturb the circulation, causing changes in CO2 delivery to the lung that invalidate
the assumption of steady-state. Moreover, most studies have been conducted on clinically stable
patients in the emergency department, rather than those mechanically ventilated in an ICU. Finally,
since changes in ventilator settings or patient-ventilator interaction can change the capnographic
waveform, care must be taken that artifacts of care are not confused with signals of pathology.
Nevertheless, in the right clinical setting, the capnogram may provide clues to raise or lower suspicion
for PE, especially if joined to a negative D-dimer value.

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Obstructive lung diseases are characterized by widely varying V/Q ratios, producing typical capnographic
signatures (Fig 4).34 The phase II transition from anatomic dead space to alveolar gas is blurred by the
early contribution from high V/Q units (having low PACO2), tending to reduce the steepness of its rise.
During phase III, units with varying V/Q ratios continue to empty in desynchronized fashion (with higher
V/Q regions - having lower PACO2 - contributing more earlier, while lower V/Q regions having higher
PACO2 dominating later), amplifying the rise of the plateau phase. This combination causes the alpha
angle between phases II and III to increase35. In severe obstructive diseases, the capnogram assumes a
sharks fin appearance (Figure 5a). The steeper phase III also causes the end-tidal value to depend
more strongly on expiratory time. This feature, combined with the anatomic dead space inherent in
emphysema, causes marked discrepancies between end-tidal and arterial PCO2 values.
These qualitative features of obstructive diseases on time-capnography correspond to quantitative
aspects on volume-capnography. An increased phase III slope has been demonstrated in most diseases
with airflow obstruction (COPD, asthma and bronchiectasis) 36, 37. The degree of slope correlates with the
severity of airflow obstruction measured by spirometry36,37,38,39,40,41 and the degree of emphysema seen
on chest CT 42. Automated analysis of multiple capnographic indices may increase the sensitivity and
specificity for diagnosing obstructive lung disease. Combining exhalation duration, ET-CO2, endexhalation slope, and time spent at ET-CO2, succeeds in distinguishing patients with COPD from those

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with congestive heart failure.43 Capnography may be even more sensitive than spirometry for detecting
early, small airway changes, as has also been demonstrated for the similar technique of single-breath
nitrogen washout.44,45

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ET-CO2 may differ markedly from the simultaneous PaCO2, especially in obstructed patients, and this is
true when patients are stable or having an exacerbation.46,47 A slow, forced, maximal expiration can
produce a much better correlation between ET-CO2 and PaCO246, but this is not practical in the critically
ill. In some ventilated patients with COPD the difference between ET-CO2 and PaCO2 can exceed
40mmHg, emphasizing the serious errors that can be made in drawing inferences about the adequacy of
ventilation based on ET-CO2 values.

Capnography and cardiac output:

It is commonly recognized that ET-CO2 values change with the return of spontaneous circulation (ROSC)
; when passive leg raising (PLR) augments cardiac output51, 52, 53; and in many shock states54, 55.
These findings give rise to the incorrect idea that cardiac output directly influences ET-CO2. In steady
state, however, the volume of CO2 exhaled through the lungs must equal that produced in the tissues
metabolically, regardless of cardiac output56. Cardiac output largely affects ET-CO2 only in dynamic
situations, not when the circulation is stable.

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48,49, 50

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The appearance of a direct relationship between cardiac output and ET-CO2 relates to non-steady state
conditions combined with the fact that the body can store large amounts of CO2.55 57 58For example, if
cardiac output is reduced through hemorrhagic shock, ET-CO2 falls transiently as less CO2 returns to the
lungs. At the lower cardiac output, tissue and venous PCO2 rise, ultimately restoring the total volume of
CO2 reaching the lungs, balancing metabolic production with excretion. Because so much CO2 can be
stored in the body as tissue CO2 rises, equilibrium will not be reached quickly. In addition, many
interventions to change cardiac output also change dead space (for example, by raising or lowering left
atrial pressure).59 60 Thus short-term experiments may give the appearance of a direct relationship of
cardiac output and time-capnography.

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There is a more subtle effect of cardiac output on alveolar and ET-CO2 related to the Fick Principle.
Recalling that alveolar CO2 tends to approximate the venous value at end-expiration, it should be clear
that low cardiac output states will produce larger (but still modest) swings in alveolar and ET-CO 2. The
tendency, then, is for low cardiac output to produce higher (not lower) ET-CO2 in steady-state and when
all other variables are kept constant. Although ET-CO2 does not directly reflect cardiac output, by
signaling changes, it has great value during resuscitation and when judging fluid-responsiveness.
Cardiopulmonary resuscitation (CPR): During CPR of cardiac arrest, capnography signifies increasing
pulmonary blood flow, thus the adequacy of chest compressions.61 62 An ET-CO2 value of <10 mm Hg
after 20 minutes of CPR is associated with a very high mortality.63 64 65 Similarly, If ET-CO2 is persistently
low, the patient is unlikely to have ROSC.50 66 This could assist the rescuer in deciding whether
resuscitative efforts should continue or be terminated. A drop in ET-CO2 can be an indicator of rescuer

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fatigue or inappropriate chest compression rate or depth.66 Providing feedback on the resuscitative
effort is essential, since even the highest quality CPR generates only a fraction of normal cardiac output.

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CPR is frequently interrupted to examine the patient for return of pulse and to analyze the rhythm. Such
interruptions are known to be detrimental as they dissipate the coronary perfusion pressure that is key
to successful resuscitation.67 With capnography, interruptions can be eliminated since ROSC and a rise in
cardiac output will be signaled by a sharp rise in ET-CO2 (figure 5b).48, 49, 50 With time-capnography now
being available on most defibrillators and in the ICU, this is prime time to integrate our understanding of
capnographic physiology into the realm of resuscitation.

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Predicting fluid-responsiveness: There is increasing recognition that many patients in shock fail to
respond to a fluid bolus68,69. Since empirical fluid administration may be harmful, current practice
emphasizes prediction of fluid-responsiveness in order to guide therapy. PLR is a highly sensitive and
specific indicator of subsequent fluid-response51, but depends on some measure of effect, typically realtime echocardiography. ET-CO2 has been shown to provide a technically simpler alternative in
mechanically ventilated patients without respiratory effort. In fluid-responsive patients, ET-CO2 rises by
at least 5% with PLR, outperforming changes in arterial pulse pressure as a clinically useful predictor. 51,
52, 53

Procedural sedation:

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Sedation and analgesia are increasingly administered by non-anesthesiologists for endoscopy,

bronchoscopy, and other procedures. Moderate sedation frequently progresses inadvertently to deeper
sedation 70 and can lead to hypoventilation or apnea, airway obstruction or laryngospasm, and
hypoxemia, especially in the obese or in patients with sleep apnea. Sedatives and analgesics can
precipitate those complications, all of which have distinct capnographic findings. While bradypnea
decreases the patients respiratory rate and increases the ETCO2, hypopnea decreases the tidal volume;
creating low VQ areas and decreasing the ET-CO2. 71 Oximetry only detects alveolar hypoventilation
when it is significant enough to cause hypoxemia, a late manifestation, whereas capnography allows
early warning of respiratory depression. Several studies show that capnography is more sensitive than
clinical monitoring, oximetry, or visual assessment in detecting respiratory depression in patients
receiving moderate procedural sedation. 72,73,74,75,76 By revealing hypoventilation 1-2 minutes before the
onset of hypoxemia, capnography gives the provider crucial time to adjust sedation or manipulate the
airway, reducing the incidence of oxygen desaturation. 73, 77

Conclusion
Capnography has made steady inroads in the ICU, probably enhancing the safety of mechanical
ventilation and procedural sedation. Yet there are many opportunities to glean additional useful
information by looking beyond the simple end-tidal CO2 value and taking the entire waveform into

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consideration. At the same time, capnography has important limitations, especially when it is considered
as a surrogate for the PaCO2.

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Table 1: Determinants of the phase III rise and ET-CO2 values

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Alveolar ventilation:VCO2 ratio

Magnitude of alveolar dead space
V/Q heterogeneity due to lung disease
Rate of CO2 production
Ventilator expiratory time
Breathing pattern
Level of positive end-expiratory pressure (PEEP)
Changes in cardiac output
Differences in mixed venous and arterial PCO2 (by the Fick Principle)
Out-of-phase emptying of parallel lung regions
Stratified inhomogeneity (longitudinal concentration gradients in the airways related to
convection, airway geometry, and other factors) 78

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Figure Legends
Figure 1: Time-capnogram (1A) and volume-capnogram (1B).

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I, II, III and IV represent the different phases of the capnogram; SII=slope of phase II; SIII=slope of phase
III; PACO2 = alveolar partial pressure for CO2; ETCO2= end tidal CO2; =angle between phases II and III.

Figure 2: Alveolar PCO2 vs time

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The PACO2 varies phasically throughout the respiratory cycle. At the onset of inspiration, PACO2
continues to rise as CO2 diffuses from pulmonary capillaries because gas entering the alveolus comes
from dead space. Thereafter, PACO2 falls rapidly, despite ongoing diffusion of CO2, because of the
dominant effect of fresh gas entry. During expiration, the concentration rises again as the venous blood
steadily delivers CO2 to an ever-smaller alveolar volume. Modified from reference 7.

Figure 3: Graph of the relationship of PaCO2 and ET-CO214

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The correlation between changes in PaCO2 and ET-CO2 in mechanically ventilated patients is shown.
Although there is a modest correlation, there are many discrepant points, sometimes with values
changing in opposing directions. Modified from reference 14.

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Figure 4: The impact of V/Q matching on PACO2 and the time-capnograms in health, COPD, and PE. The
central alveolus, having matched ventilation and perfusion, will exhale a PCO2 near the average arterial
value (PCO2 = 40). If all alveoli were similar, the capnogram labeled A would result. The left-most
alveolus, with low V/Q due to obstruction, has a PACO2 closer to the venous value (PvCO2 = 47). When
combined with relatively normal alveolar units as well as high V/Q units as seen in COPD, capnogram B
may result, with a sharks fin appearance. Since some gas from the most obstructed alveoli, having
especially high PACO2, will only appear near the end of expiration, the end-tidal value may exceed PaCO2.
Finally, the right-most alveolus symbolizes non-perfused units (alveolar dead space) which contribute
gas with a very low (PCO2 = 0) to the expiratory stream, producing a capnogram having a value lower
than the arterial value even at end-expiration (labeled C). PACO2 = alveolar partial pressure for CO2;
PvCO2 = mixed venous PCO2; PaCO2 = arterial PCO2.
Figure 5:

5a: Time capnogram of a patient with airflow obstruction, illustrating a sharks fin appearance

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5b: Time capnogram of a patient in cardiac arrest undergoing chest compressions. A more efficient
rescuer generates a higher cardiac output, and hence a higher PCO2 (thin arrow). ROSC is signaled by a
brisk and sustained rise in PCO2 (thick arrow).

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5c: Cardiogenic oscillation: an artifact seen when expiratory time is sufficiently long that expiratory flow
ceases. Cardiac contraction causes airway gas to oscillate, producing mixing of fresh and alveolar gas at
the ventilator wye. This mixing interface is drawn past the sensor by cardiac oscillation, causing the
capnographic value to fall gradually as more fresh gas dilutes the small volume of CO2-rich gas. This is
purely an artifact of gas mixing and does not reflect the true end-tidal value.

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