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The PaCO2-ETCO2 Gradient

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Our previous post introduced you to the normal and abnormal capnogram and the end-tidal carbon dioxide (ETCO2). In this post, we will dive deeper into the ETCO2 and explore how this relates to the clinically significant arterial partial pressure of carbon dioxide (PaCO2). Current guidance encourages using the ETCO2 as a stand-in for the PaCO2. However, the ETCO2 and PaCO2 do not always match, and the relationship between the two may not be as predictable as previously thought.

How about a quick physiology primer?

Before exploring the differences between PaCO2 and ETCO2, it is important to recap some of the basics of ventilation and perfusion.

The lung can be split into three zones based on the relationship between the pressure of the air in the alveoli and the perfusion pressure from the arteries and veins. These zones are called West’s Zones (although apparently, West wasn’t the first person to describe the concept!).

West's zones of the lung

In Zone 1, the alveolar pressure (air pressure) is highest. Still, the arterial and venous pressure is lowest, partly because of gravity and the increasing distance that the blood travels. This means that the alveoli in Zone 1 are comparatively less perfused than the other lung zones, and gas exchange is less efficient. In contrast, in Zone 3, the arterial and venous pressure is higher (leading to greater blood flow), and the alveolar pressure is lower compared to Zone 1.

The fraction of the tidal volume (the amount of air that moves in and out of the lungs with a normal breath) that does not participate in gas exchange is called dead space. Dead space can be split into apparatus, anatomical, and alveolar.

The apparatus, anatomical and alveolar dead space

Changes in the cardiac output alter the blood flow to the lungs and perfusion of the alveoli. Increased cardiac output will result in better perfusion of the lungs, increased gas exchange, and a higher ETCO2. In contrast, decreases in cardiac output will reduce the flow of blood to the lungs, decrease alveolar perfusion, increase the alveolar dead space, and result in a reduced ETCO2 (even though the PaCO2 might be high).

What is the PaCO2-ETCO2 gradient?

The PaCO2-ETCO2 gradient is the difference between arterial and end-tidal carbon dioxide. This difference is due to the alveolar dead space, which is small in healthy children and young people. Alveoli which are ventilated but not perfused have a gas mixture which is almost the same as that which is inspired. This dilutes the expired carbon dioxide and decreases the ETCO2 resulting in the ETCO2 being slightly lower than the PaCO2. Under normal physiological conditions, this gradient is approximately 0.5 kPa (3.8 mmHg).

What can increase the PaCO2-ETCO2 gradient?

The gradient can increase with changes in the perfusion of the lungs. Local perfusion changes may occur due to pulmonary embolism, infarct or contusion. More globally, reduced perfusion may occur due to hypovolaemia, hypotension, cardiac failure, pulmonary hypertension, or cardiac arrest.  All these changes to perfusion can increase the gradient. Since the publication of the ARDSnet trial in 2000, which demonstrated improved outcomes with lower tidal volume ventilation of 6 ml/kg, it is likely that we have observed a greater PaCO2-ETCO2 gradient owing to an increase in the ratio of physiological dead space and tidal volume. However, this has not been confirmed in a clinical study.

Can the ETCO2 be higher than the PaCO2?

Although seen much less frequently, it is possible to have an ETCO2 higher than the PaCO2.

This tends to occur if there are significant changes in the alveolar CO2 over the course of a breath, when there is a high tidal volume and low respiratory rate, low functional residual capacity, or lung compliance, or if there is rebreathing of expired CO2 (which is particularly relevant for our anaesthetic colleagues). This has previously been described most commonly in pregnancy, obesity and infants.

Can the PaCO2- ETCO2 gradient be predicted?

Current guidance recommends an ETCO2 of 4.0–4.5 kPa (30.0–33.8 mmHg) as a stand-in for a low-normal PaCO2 with an expected difference of 0.5 kPa (3.8 mmHg). These guidelines are based upon evidence which has been extrapolated from healthy individuals, often in the controlled setting of an operating theatre. However, in the presence of ventilation-perfusion mismatch, acid-base disturbance, and haemodynamic instability, this difference may increase.

More recent studies have demonstrated the gradient in unstable patients exceeds the expected difference of 0.5 kPa (3.8 mmHg). This has been observed to result in patients with high or low CO2 being misclassified as having normal CO2. Moreover, a correlation has only been moderate, meaning there is variation between the levels, making it difficult to predict the difference in the gradient.

Given that in unstable patients, the gradient is more significant than previously thought and that there is a lack of a predictable relationship, the ETCO2 is not a suitable stand-in for the PaCO2 where pH or PaCO2 requires precise control. This is particularly relevant for traumatic brain injury, where high carbon dioxide can lead to raised intracranial pressure, whilst low carbon dioxide can lead to cerebral ischaemia. In such situations, arterial measurement may be more appropriate.

Take-Home Points:

In healthy patients the normal PaCO2-ETCO2 gradient is approximately 0.5 kPa (3.8 mmHg).

The gradient increases in unstable patients

Changes in the gradient may not be predictable

In critically ill patients where careful control of arterial carbon dioxide is required, arterial samples should be taken when practical

References

Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-1308. doi:10.1056/NEJM200005043421801

Hibberd O, Hazlerigg A, Cocker PJ, et al. The PaCO2-ETCO2 gradient in pre-hospital intubations of all aetiologies from a single UK helicopter emergency medicine service 2015–2018. Journal of the Intensive Care Society. 2022;23(1):11-19. doi:10.1177/1751143720970356

Kodali BS. Capnography. 2022. Accessed online at https://www.capnography.com

Price J, Sandbach DD, Ercole A, et al. End-tidal and arterial carbon dioxide gradient in serious traumatic brain injury after prehospital emergency anaesthesia: a retrospective observational study. Emerg Med J. 2020;37(11):674-679. doi:10.1136/emermed-2019-209077

West JB. Respiratory physiology: the essentials. 9th ed. Baltimore, MD, USA: Lippincott Williams & Wilkins, 2012.

Yang JT, Erickson SL, Killien EY, et al. Agreement Between Arterial Carbon Dioxide Levels With End-Tidal Carbon Dioxide Levels and Associated Factors in Children Hospitalized With Traumatic Brain Injury. JAMA Netw Open. 2019;2(8):e199448. doi:10.1001/jamanetworkopen.2019.9448

Yarstev A. The Respiratory System. 2022. Accessed online at https://derangedphysiology.com/main/cicm-primary-exam/required-reading/respiratory-system

Authors

  • Owen Hibberd is an Emergency Medicine Trainee in Cambridge, currently studying on the QMUL PEM MSc. Interested in Paediatric Emergency Medicine, Pre-Hospital Emergency Medicine and Medical Education. He/him.

  • Ed Barnard is an EM/PHEM consultant who proudly holds the Diploma in Child Health. His ethos is delivering high-quality EM regardless of the patient’s location: as a clinician, an educator, and through scholarly activity. He/him.

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