The Goldilocks Principle, Carbon Dioxide, and Acute Respiratory Distress Syndrome: Too Much, Too Little, or Just Right?

Anesthesiology, V 124 • No 3 532 March 2016 O N the face of it, we have blown hot, then cold when it comes to carbon dioxide. We have tolerated it (permissive hypercapnia), considered adding it (therapeutic hypercapnia), and even at times deliberately or inadvertently decreased it.1 Advances in extracorporeal therapies, as reported in this month’s ANesthesiology,2 mean that if we wish, we can just remove it. should we? Careful science, rather than caprice, has guided our understanding of the biology of carbon dioxide and the fundamental role it plays in normal physiology, adaptation to, and modulation of disease. Carbon dioxide is essentially a “waste product” of aerobic cellular respiration. Arterial carbon dioxide tension (PaCo2) represents the balance between carbon dioxide produced and eliminated. hypercapnia has been an unavoidable component of lung protection strategies in several key clinical studies over the past four decades. hickling et al.3,4 first described the concept of “permissive hypercapnia” in two case series, wherein low tidal volume, pressure-limited mechanical ventilation in patients with acute respiratory distress syndrome (ARDs) led to substantial elevations in PaCo2 and a mortality that was significantly lower than that predicted by Apache ii scores. Comparable findings had been reported a decade before, whereby lowering tidal volumes in status asthmaticus5 and in neonatal pulmonary hypertension6 was associated with improved survival. eventually, two pivotal large randomized controlled trials indicated that low tidal volume mechanical ventilation improves survival in patients with ARDs.7,8 in all these studies, the relative contribution of lung-protective ventilation or an increase in PaCo2 could not be ascertained, although a post hoc analysis of one revealed an association between hypercapnia and improved survival.9 in parallel with this clinical evolution, several laboratory studies attested to the clear benefit of induced hypercapnia in some circumstances, distinct from tidal volume reduction. in models of lung injury, sepsis and ischemia– reperfusion, hypercapnia has beneficial anti-inflammatory and organ-protective effects.10 Buffering of hypercapnic acidosis diminishes this benefit,11 whereas hypocapnia worsens organ injury.12 Arising from these observations, laffey and Kavanagh13 introduced the term “therapeutic hypercapnia,” proposing the intentional use of hypercapnic acidosis in select patient populations. however, just as a pinch of salt can bring out the flavor in food where a fistful will ruin it, excess carbon dioxide has the potential for harm: hypercapnic acidosis has important off-target deleterious effects that limit its use in selected patients (i.e., raised intracranial pressure and pulmonary hypertension), for prolonged periods (increased risk of infection) and at high dose (mitochondrial effects).14 so there are two sides to the hypercapnia story with the potential for benefit and the risk of harm. Key questions remain around the correct means to achieve hypercapnia to optimize benefit/minimize harm and around dosing and duration. And although the answers to these questions are not straightforward, evidence is emerging that even lower tidal volumes and plateau pressures beyond those investigated heretofore may have incremental survival benefit.15 extracorporeal carbon dioxide removal (eCCo2R) is necessary to consistently achieve such low tidal volumes and prevent prolonged and potentially deleterious elevations in carbon dioxide. eCCo2R has an appealing rationale in ARDs and in other causes of acute respiratory failure: in addition to ultraprotective The Goldilocks Principle, Carbon Dioxide, and Acute Respiratory Distress Syndrome