Introduction
The mortality following a sudden cardiac arrest (CA) is high [
1,
2]. Following return of spontaneous circulation a pathophysiological state named post cardiac arrest syndrome ensues and treatment focuses on stabilising circulation and alleviating the evolving neurological injury [
3]. Factors associated with worsening neurological injury after cardiac arrest includes hyperthermia, hyperglycaemia, and hypercapnia [
4‐
6]. Recently hyperoxia exposure after cardiac arrest has also been suggested to be associated with poor outcome [
7]. Hyperoxia may increase free radical production, triggering cellular injury and apoptosis [
3]. Another study by Bellomo and colleagues did not show any correlation between arterial hyperoxia and outcome following cardiac arrest [
8]. Both these studies did not include important resuscitation data, such as initial rhythm and time to return of spontaneous circulation (ROSC) that may have influenced outcome [
3]. In addition both studies included only oxygen values measured in the intensive care unit (ICU), and this might underestimate the true incidence of hyperoxia exposure following cardiac arrest.
The purpose of this study was to examine the prevalence of hyperoxia in an unselected sample of patients treated in the ICU of a tertiary hospital following either out-of-hospital (OHCA), in-hospital (IHCA) or ICU cardiac arrest (ICUCA). In this single centre trial we aimed to describe the prevalence of hyperoxia exposure and factors correlating with hyperoxia exposure immediately prior to and during the first 24 hour of intensive care.
Discussion
In this single centre study we found that hyperoxia is a common phenomenon during the first 24 hours after cardiac arrest. The incidence was higher than in the two previous registry trials and a recent trial focusing on pediatric cardiac arrest [
7,
8,
12]. Hyperoxia exposure is more common following OHCA, which may be related to differences in arrest aetiology, difficulties with monitoring, the use of higher fractions of oxygen than needed, and lack of protocols for adjusting inspired oxygen concentration. There were differences between patients exposed to hyperoxia and those not exposed concerning time to ROSC. The reason for this in unclear, but this might influence survival and should be controlled for in studies investigating the relationship between hyperoxia exposure and survival.
There are conflicting results in studies about the prevalence of hyperoxia and its effects [
7,
8,
12,
13]. In a multicentre registry study by Kilgannon colleagues of a cohort of 6326 patients who had survived non-traumatic cardiac arrest admitted to the ICU, 18% were exposed to hyperoxia. In a similar study by Bellomo and colleagues, with a much larger cohort (12,108 pts), hyperoxia occurred in only 10.6% of the patients and isolated hypoxia (PaO
2 < 60 mmHg, regardless of FiO
2 level) seemed to be as common as hyperoxia. Janz and colleagues investigated hyperoxia in patients treated with mild therapeutic hypothermia: about 30% of the patients had maximum PaO
2 values over 300 mmHg during the first 24 hours after ROSC [
13]. In a multi-centre study by del Castillo and colleagues, who examined hyperoxia in resuscitated paediatric patients, hyperoxia occurred in only 8.5% of the patients after ROSC [
12]. They also looked at oxygen values measured 24 h after the CA and found that the prevalence of hyperoxia was 1.7%. The ethology of cardiac arrests is nevertheless different in pediatric patients compared to adults and paediatricians are more aware of the risks of hyperoxia from neonatal experience [
14,
15]. The conflicting findings of these studies maybe in the methodology, i.e. Kilgannon and colleagues used the first blood gas measured in the ICU whereas Janz and del Castillo and colleagues used the highest oxygen value measured in the ICU during the first 24 hours after the CA. Bellomo and colleagues on the other hand used the worst oxygen value of the first 24 hours. In our study, in which we used the highest arterial oxygen value measured during the first 24 hours after ROSC, 41.2% were exposed to hyperoxia. This is probably related to the fact that we also included blood gas values obtained prior to ICU admission and thus previous trials may have underestimated the true prevalence of hyperoxia exposure in patients treated in the ICU following cardiac arrest. In the study by Kilgannon and colleagues, 63% of the patients where exposed to hypoxia, and in Bellomo and colleagues study as many as 73.5% [
7,
8]. The rate of hypoxia was only 14% in our study and it differs considerably from the rates in the previous investigations. Hyperoxia may be an unintentional result of strictly avoiding hypoxia and according to the study by Kilgannon and colleagues it is associated with higher mortality than hypoxia [
7].
In this trial 60% of OHCA patients were exposed to oxygen values higher than 300 mmHg. This reflects the use of higher oxygen fractions prehospital and in the emergency department. Mechanically ventilated patients in the ED might receive less attention than those in the ICU and monitoring difficulties might such as the use peripheral oxygen saturation may contribute. It is also possible that the initial ventilation perfusion mismatch in OHCA patients is more rapidly corrected after the arrest and thus maintaining high oxygen fractions results in a higher likelihood of hyperoxia exposure. Therefore diligent reassessment of ventilator setting is of high priority. Interestingly in the present trial delay to ICU admission was associated with hyperoxia exposure. This supports the notion of a more diligent follow-up of mechanical ventilation settings in the ICU than in the ED, with titration of inspired oxygen to lower fractions when a sufficient SpO2 level is reached. This may be of importance since overcrowding of EDs and ICUs is not uncommon.
According to the current resuscitation guidelines by the American Heart Association, 100% oxygen should be used during initial resuscitation, but after ROSC, the inspired oxygen should be titrated to the lowest level required to achieve an arterial oxygen saturation of ≥94% [
10]. The exact SpO
2 goal in critically ill patients is unknown. Recently Smith and colleagues argued that a SpO
2 goal of 94% in ward patients might be too low [
16]. They suggest that that the lower SpO
2-range should be reassessed to 96%, because in their study the majority of the patients had SpO
2-values >96% and many of them were acutely ill, and it did not increase mortality, but the upper target of the range should be 98% until the controversies surrounding hyperoxia are resolved. The use of pulseoximetry immediately following ROSC may be unreliable and give underestimated SpO
2 values because of decreased peripheral perfusion and possible unstable haemodynamic status. Alternative methods, such as cerebral oximetry or pulseoxymeter with a transcutaneous forehead SpO
2 sensor might come in question. The use of cerebral oximetry was found to be feasible during IHCA and OHCA [
17,
18].
We also found that patients with a long delay to ROSC were more likely to suffer of arterial hyperoxia but ROSC delay was not an independent predictor of hyperoxia exposure and thus may be related to the fact that OHCA patients in general have longer ROSC delays. How the prolonged latency to ROSC simultaneously with hyperoxia influences on survival is largely unknown since in the studies by Bellomo and Kilgannon the time to ROSC was not reported. This is paramount and should be taken into account when investigating the association between hyperoxia and mortality.
Induced mild therapeutic hypothermia has been proved to improve neurological outcomes for unconscious adult patients with ROSC after out-of-hospital VF CA [
19]. Janz and colleagues have indicated an association between hyperoxia and in-hospital mortality in CA patients undergoing mild therapeutic hypothermia [
13]. They found that patients with higher levels of maximum PaO
2 during the first 24 hours after ROSC had increased in-hospital mortality and a more unfavourable neurologic outcome. In our study therapeutic hypothermia was more often induced in patients suffering from hyperoxia, with 45% treated with hypothermia. How arterial hyperoxia influences outcome in patients treated with therapeutic hypothermia in CA patients needs further studies.
Hyperglycaemia is common after resuscitation from CA arrest and it is generally believed to be the result of a stress response. In our trial we found a statistically significant difference in glucose values between patients exposed and those not exposed to hyperoxia: hyperoxic patients had higher values than non hyperoxic patients. The difference may not be causal and it may be explained by that patients suffering from hyperoxia had an OHCA with prolonged resuscitation resulting in a greater stress response. But further evaluation of this is warranted, as in an animal study, hyperoxia-induced hyperglycemia has been seen in newborn piglets, during ventilator and cardiopulmonary bypass (CPB) and in the absence of CPB [
20,
21]. With reduction of the oxygen levels to normoxia the hyperglycemic response in the newborns abolished.
Competing interests
We declare that there is no financial or other competing interest for any of the authors.
Authors’ contributions
MBS and MP designed the study. The data was collected by MBS. The data was analysed by AN who drafted the manuscript. MBS and MP revised the manuscript draft. All authors have read and approved the final version.