American Journal of Emergency Medicine 32 (2014) 643-644

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American Journal of Emergency Medicine

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Hypocarbia, therapeutic hypothermia, and mortality: the Kreb cycle is key

Gary M. Idelchik, MD^a, Joseph Varon, MD^b,c,?

^a Department of Critical Care Services and Department of Cardiology, University General Hospital, Houston, TX

^b Department of Critical Care Services, University General Hospital, Houston, TX

^c The University of Texas Medical Branch, Houston, TX

The availability of Surrogate markers to help determine both mortality and neurologic outcomes in postcardiac arrest patients in whom return of spontaneous circulation (ROSC) is achieved and subsequent treatment with Therapeutic hypothermia is performed is currently lacking. In this issue of the American Journal of Emergency Medicine, Lee et al [1] assess the correlation of mean PaO2 and mean PaCO2 values, derived from 8 different arterial blood gases obtained between ROSC and completion of TH, on subsequent neurologic and mortality outcomes in survivors of cardiac arrest treated with TH.

Mean PaO2, which was evaluated by the authors in quartiles, was not associated with in-hospital mortality but was related to increased risk of Poor neurologic outcome in patients with a mean PaO2 values less than or greater than the second quartile, which was defined as a mean PaO2 of 116.9 to 134.9 mm Hg, and present in 54 postcardiac arrest patients. Patients in the first, third, and fourth quartiles all had significantly worse neurologic outcomes than patients in the second quartile (odds ratio [OR], 4.373; 95% confidence interval [CI], 1.187- 16.109; P = .027; OR, 4.229; 95% CI, 1.227-14.585; P = .022; and OR,

6.466; 95% CI, 1.678-24.910; P = .007, respectively). Prior studies assessing PaO2, specifically hyperoxia and mortality in patients following cardiac arrest, have been mixed, with most studies suggesting no association between elevated PaO2 and survival [2-4]. Theoretically, hyperoxia would exacerbate the production of oxygen free radicals in patients following cardiac arrest, thereby worsening reperfusion injury of all hypoperfused organs and resulting in irreversible multisystem organ failure and ultimately death [2-6]. However, an association between elevated PaO2 and worse neurologic outcome has been demonstrated, with suggested mechanisms including direct oxidation and injury of the neuronal extracellular membrane, disruption of axon-oligodendrocyte integrity in the subcortical white mater, and potentiation of necrosis in ischemic areas of the brain in animal models [4-8]. The current study by Lee et al further supports the negative effects of hyperoxia on Neurologic recovery following cardiac arrest, focusing the general hypothesis of increased oxygen free radical formation worsening reperfusion injury to only the brain.

What is more interesting about this article is that hypocarbia, defined by the authors as a mean PaCO2 less than 35 mm Hg and present in 21% of studied patients, was associated with a significant increase in in-hospital mortality (OR, 2.522; 95% CI, 1.184-5.372; P = .016), with

* Corresponding author. 2219 Dorrington St, Houston, TX 77030, USA. Tel.: + 1 713

669 1670; fax: +1 713 669 1671.

E-mail address: [email protected] (J. Varon).

survivors having as statistically significant higher PaCO2 than nonsurvi- vors (39.0 vs 37.6 mm Hg, P = .033). Moreover, the mean PaCO2 level was not associated with extent of neurologic recovery following ROSC despite previous reports demonstrating decreased cerebral perfusion and oxygenation with TH and hypocarbia [9-11]. The association of hypocarbia and mortality demonstrated in the present study is further supported by Schneider et al [12], who assessed mortality and likelihood of discharge in cardiac arrest patients from the Australian New Zealand Intensive Care Society Adult-Patient-Database. Patients from the Australian New Zealand Intensive Care Society Adult-Patient-Database with a PaCO2 less than 35 mm Hg during the first 24 hours of intensive care admission had a statistically significant increase in both mortality and the composite of death as well as not being discharged home, as compared with normocarbic and hypercarbic patients.

Clinically, the association of hypocarbia and mortality in cardiac arrest patients following ROSC demonstrated by Lee et al is profound and suggests a subset of patients with severe multiorgan insult leading to a gross loss of mitochondrial-dependent oxidative respiration globally. The production of CO₂ by the cell arises from the metabolism of pyruvate through a series of chemical reactions classically called the Kreb cycle (or the tricarboxylic acid cycle), resulting in the formation of adenosine triphosphate and nicotin- amide adenine dinucleotide plus hydrogen [13]. The loss of anaerobic respiration by previously hypoperfused tissues would, in turn, both exacerbate necrosis as well as prevent anabolic metabolism of injured cells leading to apoptosis, thereby resulting in continued or worsening multisystem organ failure. The evaluation of both initial PaCO2 following ROSC and the mean PaCO₂ during TH may allow for identification of patients with high mortality secondary to poor baseline reserve before arrest or profound ischemic organ injury before ROSC, in whom heroic measures are not warranted after cardiac arrest. Further studies prospectively evaluating both initial PaCO2 and mean PaCO2 following ROSC and during TH as well as the effect of mean PaO2 specifically on neurologic outcomes are needed.

References

1. Lee BK, Jeung KW, Lee HY, et al. Association between mean arterial blood gas tension and outcome in cardiac arrest patients treated with therapeutic hypothermia. Am J Emerg Med 2014;32:55-60.
2. Kligannon JH, Jones AE, Shapiro NI, et al. Association between arterial hypoxia following resuscitation from cardiac arrest and in-hospital mortality. JAMA 2010;303:2165-71.
3. Bellomo R, Bailey M, Eastwood GM, et al. Arterial hyperoxia and in-hospital mortality after resuscitation from cardiac arrest. Crit Care 2011;15:R90.

   http://dx.doi.org/10.1016/j.ajem.2013.12.006

   0735-6757/(C) 2014

   644 G.M. Idelchik, J. Varon / American Journal of Emergency Medicine 32 (2014) 643-644

   Kligannon JH, Jones AE, Parillo JE, et al. Relationship between supranormal oxygen tension and outcome after resuscitation from cardiac arrest. Circulation 2011;123: 2717-22.

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