CO2 IN 2008
Dr. Brian Kavanagh
Carbon dioxide is a waste gas produced by metabolism. As well as permitting intake of
oxygen, a major function of the respiratory system is to eliminate carbon dioxide. This
has been known and well understood for a very long time and constitutes a major
indication for assisted mechanical ventilation.
Starting with neonatology (Dr. Wung and colleagues in New York) and then
adapted by adult practitioners in the care of ventilated asthmatic patients and thereafter
ventilated patients with ARDS, there has been a paradigm shift in management of CO2 in
ventilated patients. The notion that extremely aggressive attempts should be made to
clear CO2 from the body (normalize the PaCO2) has gradually been abandoned. Instead,
clinicians have adopted approaches that they believe cause less injury to the lung, and
recognize that such approaches involve accumulation of CO2. This new vogue, called
permissive hypercapnia, means that clinicians recognize that physical stretch of the lungs
causes injury in many cases, whether in neonates, infants or adults. Further, it’s clear that
the sicker a patient is, the more difficult is the ventilation in many cases, and thus the
more extreme efforts (and physical damage – barotrauma, volotrauma) will be needed to
clear CO2. Thus, permissive hypercapnia is really nothing to do with carbon dioxide per
se but a recognition that the lungs must be ventilated gently and that when the lungs are
ventilated gently, a degree of hypercapnia (passive, bystander) will almost certainly
Several trials have confirmed that modest degrees of permissive hypercapnia, i.e.
protective lung ventilation, are beneficial. This is a complicated issue because the control
group for many of these studies had a perhaps tenuous relationship with usual care and in
any case usual care is something that changes over time. The second complicating issue
is that elevated levels of CO2 may cause harm that may be independent of how the
ventilator is set. For example, in patients with elevated intracranial pressure or pulmonary
hypertension, acute hypercapnic acidosis can be lethal or extremely harmful. Thus, at the
bedside the clinician has to weigh, based on very poor data, how he or she would manage
a patient, trading off the efforts (and inherent harm) associated with lowering the PaCO2
vs. the costs to the patient of allowing it to rise.
There is an additional layer of complexity. Over the last decade it has become
apparent that CO2 is not only a waste gas with a toxic potential -it is certainly that– but
there are also potential benefits associated with high levels of CO2 or at least with
hypercapnic acidosis. Extensive study from several laboratories has demonstrated that
reperfusion injury as well as ventilator induced lung injury may be attenuated by
hypercapnic acidosis. This means that independent of the amount of lung stretch, adding
CO2 to a patient’s respiratory apparatus could be protective. This was quite a
revolutionary concept and naturally attracted many cynics. It is a concept that is very
difficult to test clinically for a variety of reasons. First, most people have a degree of
unease with high levels of CO2 particularly when it is being added as opposed to being a
bystander resulting from lower levels of ventilation. Second, patients who are critically
ill and are undergoing perioperative care are highly complex and it is very difficult to
imagine that the investigator would understand all aspects of a patient’s illness (at a
molecular and cellular level) and thus be able to weigh accurately whether elevated CO2
would help or harm this particular patient. This point is extremely important because
recent evidence has shown that while CO2 may be helpful, it can also be harmful at a
molecular and cellular level. Hypercapnic acidosis can increase the formation, for
example, of toxic metabolites of nitric oxide synthase as well as altering several other
cellular processes. This talk will review the rationale for permissive hypercapnia, the
metabolism for CO2, the distinction between permissive (i.e. bystander) and “therapeutic”
(i.e. deliberate) hypercapnia, and will examine the physiologic, cellular and biochemical
sequelae of hypercapnia (as well as hypocapnia). The talk will conclude with a
discussion about how the clinician should weigh CO2 management in the critically ill
K Shibata, N Cregg, D Engelberts, A Takeuchi, L Fedorko, BP Kavanagh. Hypercapnic
acidosis may attenuate acute lung injury by inhibition of endogenous xanthine
oxidase. American Journal of Respiratory and Critical Care Medicine 158: 1578-
J Laffey, BP Kavanagh. Carbon dioxide and the critically ill – too little of a good thing?
(Review) The Lancet 354: 1283-1286, 1999.
JG Laffey, BP Kavanagh. Biologic effects of carbon dioxide (Review). Intensive Care
Medicine 26: 133-138, 2000.
J Laffey, D Engelberts, BP Kavanagh. Buffering acidosis abolishes the protective effects
of hypercapnia in acute lung injury. American Journal of Respiratory and Critical
Care Medicine 161: 141-146, 2000.
JG Laffey, M Tanaka, D Engelberts, X Luo, S Yuan, AK Tanswell, M Post, T Lindsay,
BP Kavanagh. Therapeutic Hypercapnia Reduces Pulmonary and Systemic Injury
in an in vivo model. American Journal of Respiratory and Critical Care Medicine
162: 2287-2294, 2000
JG Laffey, BP Kavanagh. Mechanisms of Disease. Hypocapnia (Review). New England
Journal of Medicine 347: 43-53, 2002.
JG Laffey, RP Jankow, D Engelberts, AK Tanswell, M Post, T Lindsay, JB Mullen, A
Romaschin, BP Kavanagh. Systemic vs. pulmonary protection with hypercapnia
following mesenteric reperfusion. American Journal of Respiratory and Critical
Care Medicine 168: 1383-1390, 2003.
BP Kavanagh. Therapeutic Hypercapnia - careful science, better trials (Editorial).
American Journal of Respiratory and Critical Care Medicine, 171:96-97, 2005