Hyperoxia post-cardiac arrest – The debate continues, MEDYCYNA, RATOWNICTWO MEDYCZNE, BLS, RKO


Hyperoxia post-cardiac arrest - The debate continues?

Początek formularza

Dół formularza

Anaesthesia and Intensive Care Medicine, Bristol School of Anaesthesia, Severn Deanery, United Kingdom

Received 29 January 2012 published online 10 February 2012. http://www.resuscitationjournal.com/article/S0300-9572(12)00054-8/fulltext

Article Outline

  1. Conflicts of interest statement

  2. References

  3. Copyright

 

Concerns about the use of high concentrations of inspired oxygen have provoked considerable debate. Detrimental effects of hyperoxia are well established in neonatal resuscitation.1 Experimental and conflicting observational data have fuelled discussion in adult post-cardiac arrest practice.2, 3 The safety of exposing non-hypoxaemic patients to high fraction of inspired oxygen (FiO2) in the context of acute myocardial ischaemia and stroke4 has also been questioned and appropriate arterial blood partial pressure of oxygen (PaO2) targets are being reconsidered in numerous settings including traumatic brain injury, acute lung injury and even the general critical care patient population.5, 6, 7

In post cardiac arrest care the debate has been dominated by the publication of two large retrospective database analyses, one using the Project IMPACT database in the United States (US) and the second the Australian and New Zealand Adult Patient Database (ANZ-APD).8, 9 After a multivariate analysis, the US investigators found that post-resuscitation hyperoxaemia was an independent predictor of in-hospital mortality (odds ratio 1.8; 95% CI 1.2-2.2) compared with normoxaemia or hypoxaemia. In a secondary analysis of this data the authors demonstrated a dose-dependent association of hyperoxaemia with mortality and independent status at hospital discharge. For every 1000x01 graphic
mmHg rise in PaO2, mortality increased by 24% (OR 1.24; 95% CI 1.18-1.24).10

The ANZ study considered a larger, more complete data set (5.4% excluded versus 27% in the US study) generated from 12,108 patients across 125 intensive care units (ICUs). It was rigorously conducted with multifaceted assessments, which included adjustment for illness severity. Hyperoxaemia was found to be relatively uncommon. No robust or consistently reproducible relationship with mortality could be demonstrated. The authors cautioned against polices of deliberately reducing FiO2 because of the risks of precipitating the well-established adverse effects of hypoxaemia.

Delivery of higher FiO2 occurs in sicker patients and hyperoxaemia could therefore simply constitute some other marker of illness severity; however, there are several important differences between these two studies that are also worth highlighting. Firstly, the US study used the first blood gas at an unspecified time within 240x01 graphic
h of admission whereas the authors of the ANZ study chose the worst blood gas in the first 240x01 graphic
h. When considering the effect of hyperoxaemia, neither could be considered ideal. Although the ANZ study attempted to correlate the worst blood gas with the mean PaO2 in the first 24-480x01 graphic
h, it remains likely that a significant proportion of patients exposed to hyperoxaemia were not identified in either study. Moreover, duration and timing of exposure, which may be critical, cannot be considered. Secondly, although most baseline characteristics were comparable, a marked difference in lowest median body temperature was noted (ANZ 34.90x01 graphic
°C, US 360x01 graphic
°C). This presumably represents a far higher uptake of therapeutic hypothermia in Australasia and is more representative of current clinical practice. It could also explain the 50% increase in favourable outcome seen in the ANZ study (65% discharged home, 44% in the US). It may however, provide an explanation for the difference in primary outcome. Hypothermia is known to mitigate reperfusion injury and could feasibly reduce the magnitude of effect of hyperoxaemia on mortality. This hypothesis was also suggested by a small randomised controlled pilot trial of 28 patients resuscitated from out-of-hospital cardiac arrest.11Patients were ventilated with either 30% or 100% O2 for 600x01 graphic
min post return of spontaneous circulation (ROSC). The use of 100% O2 was associated with an increase in neuron specific enolase (NSE) at 240x01 graphic
h in a subgroup of patients not treated with therapeutic hypothermia. As NSE is an established marker of neuronal injury, this result also suggests that hypothermic conditions may protect against hyperoxygenation-generated reperfusion injury. This trial was underpowered to make any assessment of outcome or survival.

In the context of this controversy, it is useful to revisit the experimental data on which early concern was based. In this issue of Resuscitation, Pilcher et al. present a timely summary of the available animal studies and their clinical applicability.12 In a meta-analysis of six included studies (n0x01 graphic
=0x01 graphic
95) they report that resuscitation with 100% oxygen resulted in significantly worse neurological deficit score (NDS) than oxygen administered at lower concentrations in a variety of animals following experimental cardiac arrest, by a factor of approximately two-thirds of a standard deviation (standardised mean difference of −0.64; 95% CI −1.06 to −0.22). Interpreting this quantitative meta-analysis must be done with caution given the heterogeneity of the included studies, the different species studied, the differences in FiO2 strategies, the small numbers and methodological weaknesses in the remaining publications. The authors acknowledge the questionable inclusion of the study by Yeh et al., which was primarily designed to consider the effects of oxygenation strategy during CPR, and administered 100% oxygen to all animals after ROSC.13 However, omitting this study in a sensitivity analysis did not significantly affect the results. The Lipinski et al. study also used a very different asphyxial model of cardiac arrest, which may have impacted significantly on the findings.14 This is of particular relevance given that this is the only animal model to date that has failed to demonstrate an adverse affect of hyperoxic resuscitation.

Despite these reservations a magnitude of effect is clearly demonstrated and cannot be ignored. The results were correlated in a number of the studies with increased histological neuronal cell damage and evidence of impaired cerebral metabolic function, in addition to reversal by antioxidant pretreatment.12 These results are supported by additional animal studies excluded from this review because they considered a global cerebral ischaemia model without inducing full cardiac arrest. These studies also consistently demonstrated that early exposure to 100% oxygen increases oxidative stress, worsens neuronal cell death and has a detrimental effect on short-term neurological function.15, 16, 17

How do we interpret these findings? Whilst the consistency of results across a number of species is compelling, the animal models do not accurately replicate the post-cardiac arrest clinical situation. Timing of exposure to hyperoxaemia varies, often from the onset of CPR and in some cases prior to cardiac arrest, with a duration of exposure from 10 to 600x01 graphic
min post reperfusion. None of the studies consider the effect of therapeutic hypothermia, increasingly a standard of care in many ICUs. This may influence significantly the effects of hyperoxaemia. Crude NDS in animals is not a clinically tangible measure when considering advanced cognitive function in humans and effect on NDS was only assessed 1-4 days post ROSC. The animal studies to date have failed to consider or demonstrate a significant effect on longer-term outcome. It must also be emphasized that the experimental data reflect the effect of hyperoxaemic reperfusion on ischaemic brain injury in otherwise healthy animals. Clearly, this is very different to the clinical situation involving typically elderly patients with multiple co-morbidities. Post-cardiac arrest syndrome constitutes not only brain injury but myocardial dysfunction, a systemic ischaemia reperfusion (IR) response and persistent precipitating pathology.18 Hyperoxaemia may well have effects on each of these processes and global end-organ function. As cardiac arrest in adults often occurs in the context of an acute coronary event, the myocardial effects of hyperoxia, including coronary vasoconstriction, reduced coronary blood flow and impaired myocardial mitochondrial function, may all have significance.19, 20

How do we progress from here? Oxygen has a complex biological role. We are only just beginning to understand the mechanisms that have evolved to enable the body to adapt and survive hypoxic insults and the variation in individual, organ-based and disease-related responses to both low and supernormal PO2.21, 22 Without a simple means of monitoring the adequacy of regional tissue perfusion and oxygenation it is difficult to define and prevent harm from both hypoxaemia and hyperoxaemia.

There is clearly a limit to how much further useful information can be provided by animal studies of cardiac arrest. Insight may still be gained by determining the impact of hyperoxaemia beyond the first hour post ROSC, examining effects on long-term survival and considering how therapeutic hypothermia may impact on the effects of hyperoxia. It seems likely, given the cumulative interest in the effects of oxygen exposure in various patient groups, that we will gain valuable clinical insight from additional studies in the setting of acute myocardial infarction, stroke and general ICU patients. The available experimental and clinical data certainly gives cause for concern. However, only well-designed randomised controlled clinical trials will aid understanding of any association between hyperoxaemia and mortality and enable us to evaluate the safety and efficacy of a controlled reoxygenation strategy post-cardiac arrest. In the mean time clinicians must, as ever, weigh up the available evidence and consider the relative risks and benefits in individual patients before turning down the FiO2.

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Conflicts of interest statement 

None.

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References 

  1. Davis PG, Tan A, O'Donnell CPF, Schulze A. Resuscitation of newborn infants with 100% oxygen or air: a systematic review and meta-analysis. Lancet. 2004;364:1329-1333

  • Neumar RW. Optimal oxygenation during and after cardiopulmonary resuscitation. Curr Opin Crit Care. 2011;17:236-240