Oxygen Treatment in Intensive Care and Emergency Medicine
Background: Oxygen treatment is often life-saving, but multiple studies in recent years have yielded evidence that the indiscriminate administration of oxygen to patients in the intensive care unit and emergency room can cause hyperoxia and thereby elevate mortality.
Methods: This review is based on prospective, randomized trials concerning the optimum use of oxygen in adult medicine, which were retrieved by a selective search in PubMed, as well as on pertinent retrospective studies and guideline recommendations.
Results: 13 prospective, randomized trials involving a total of 17 213 patients were analyzed. In patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) and in ventilated intensive-care patients, normoxia was associated with a lower mortality than hyperoxia (2% vs. 9%). In patients with myocardial infarction, restrictive oxygen administration was associated with a smaller infarct size on cardiac MRI at 6 months compared to oxygen administration at 8 L/min (13.1 g vs. 20.3 g). For patients with stroke, the currently available data do not reveal any benefit or harm from oxygen administration. None of the trials showed any benefit from the administration of oxygen to non-hypoxemic patients; in fact, this was generally associated with increased morbidity or mortality.
Conclusion: Hypoxemia should certainly be avoided, but the fact that the liberal administration of oxygen to patients in intensive care units and emergency rooms tends to increase morbidity and mortality implies the advisability of a conservative, normoxic oxygenation strategy.
In emergency situations, oxygen therapy can be life-saving for patients with hypoxemia, but harmful effects of exposure to high oxygen concentrations (oxygen toxicity) have long been known (e1, e2). Within a few years of the introduction of oxygen therapy, the issue of potential oxygen toxicity was raised (e3). Today, we know that increased concentrations of oxygen free radicals cause cellular damage which can lead to apoptosis or necrosis, especially in the presence of other factors, such as, for example, infection. Cell death triggers the release of mediators, causing, in combination with oxygen free radicals, further cell damage; thereby a vicious cycle is initiated and maintained (e2).
In recent years, several studies have shown that hyperoxia is associated with increased mortality in various subgroups of critically ill patients (1, e4, e5). In a multivariate analysis of more than 30 000 patients with a hospital mortality of 31% (1) above an arterial partial pressure of oxygen (paO2) of 123 mmHg, the odds ratio for mortality was 1.23 (95% confidence interval [CI] : [1,13; 1,34]). Previous reviews have focused on special patient groups and not taken into account data from the most recently published large prospective randomized trials (e6–e9). Therefore, this article provides an overview of the role of oxygen therapy in the management of various conditions in intensive care and emergency medicine.
This review is based on pertinent publications that were retrieved by a selective search for prospective randomized trials on the target ranges of normobaric oxygen administration to treat adult intensive care or emergency patients. The search was performed in the PubMed database; the search criteria are listed in the eTable. Two of the authors (J. G., V. F.) independently identified studies on outcome parameters. To compensate for the scarcity of studies on this topic, selective retrospective studies as well as recommendations of specialist societies were also included (Table 1). Ongoing studies were searched and identified in the study registries of the United States (ClinicalTrials), Europa (EudraCT) and the United Kingdom (ISRCTN) (Table 2).
Chronic obstructive pulmonary disease (COPD)
One study on patients with acute exacerbation of COPD was identified. It included 405 patients treated in the prehospital situation with titration of oxygen therapy to pulse-oximetry oxygen saturation (SpO2) levels between 88% and 92%, using oxygen flow rates of 8 to 10 L/min (2). In the group treated with titrated oxygen therapy, mortality was reduced from 9% to 2% (risk ratio 0.22) and the mean pH value was found increased by 0.12 compared to the group having received high-dose oxygen therapy.
Five randomized studies with a total of 7458 patients evaluated the use of supplemental oxygen in patients with myocardial infarction. A first randomized study, carried out in 1976, evaluated 157 patients with uncomplicated myocardial infarction who were treated for 24 hours with 6 L/min oxygen versus ambient air. No significant differences with regard to mortality (ambient air: 4% versus oxygen: 11%) or the reduction of cardiac arrhythmia were found (3).
Among 136 patients with ST-segment elevation myocardial infarction (STEMI) without hypoxemia, mortality (6 L/min: 1% versus titrated: 3%) and infarct size did not differ significantly between oxygen therapy titrated to the SpO2 target of 93% and oxygen administration of 6 L/min; however, the authors noted that the sample size was inadequate to detect a difference between the two treatments (4).
A small randomized study evaluating 95 patients treated with either 10 L/min oxygen or ambient air found no benefit of oxygen administration (left-ventricular infarct size 16 ± 10% versus 16 ± 11%) (6)
In the AVOID study, STEMI patients were already randomized in the prehospital situation to receive either 8 L/min oxygen (the oxygen group) or to only receive oxygen if SpO2 levels were <94% (5). Of the 441 patients included in this study, those in the oxygen group showed a significant increase in creatine kinase levels, more re-infarctions and more arrhythmias. Furthermore, cardiac MRI at 6 months after myocardial infarction showed an increased infarct size (20.3 g versus 13.1 g).
In 2017, the so far largest study on this topic with more than 6000 patients was published (DETO2X-AMI). This randomized study evaluated the impact of routine oxygen supplementation at a rate of 6 L/min versus no oxygen in patients with STEMI or non-ST-segment elevation myocardial infarction (NSTEMI) with SpO2 levels of ≥ 90% on morbidity and mortality (7). No differences were found for mortality after 1 year (oxygen: 5.0% versus ambient air: 5.1%), reinfarction (3.8% versus 3.3%), atrial fibrillation (2.8% versus 3.1%), and cardiogenic shock (1.0% versus 1.1%).
No randomized studies evaluating the effect of oxygen administration on post-resuscitation outcome have so far been published, except for a pilot study with only 28 analyzed patients (8). It is known that during cardiopulmonary resuscitation an initially high paO2 increases the likelihood of restoration of spontaneous circulation (15). However, during the further course of treatment, hyperoxia during the first 24 hours seems to increase mortality, as suggested by 2 meta-analyses (16, 17). The largest two cohort studies included here analyzed 6326 (e4) and 12 108 patients (18), respectively. In the latter study, the negative effect of hyperoxia was no longer detectable after multivariate analysis for severity.
So far, 3 randomized studies on oxygen therapy in patients with stroke, including a total of 8343 patients, have been published. In a pilot study, 289 stroke patients were randomly assigned to two groups, receiving over a period of 72 hours either no oxygen or 2–3 L/min oxygen. No difference was found between the 2 groups (modified Rankin scale [mRS]] 3 versus 3) (9, e10). By contrast, another study found an mRS improvement associated with oxygen administration; however, the study was small, including only 51 patients (10). A quasi-randomized trial with 550 stroke patients, receiving either no oxygen or for 1 day supplemental oxygen at a rate of 3 L/min found no differences between the two groups with regard to mortality and neurological outcome after 1 year (19).
In the recently published SO2S study, 8003 stroke patients were randomly assigned to one of 3 groups: Over a period of 72 hours, oxygen was given (1) only at night, (2) continuously or (3) not at all. After 90 days, no difference in mRS scores was found between the groups (11); this also applied to subgroups differing in disease severity. One point of criticism of this study is that it included many patients with comparatively mild stroke (median score on the National Institutes of Health Stroke Scale [NIHSS] of 5).
Until now, no randomized study on oxygen therapy in patients with intracerebral hemorrhage has been published. A post-hoc analysis of a prospective randomized hypothermia trial with patients after severe traumatic brain injury indicated a potential positive effect of hyperoxia; however, both groups of this study had very high paO2 levels (242 versus 193 mmHg) and consequently no normoxic values (20).
So far, several retrospective analyses have been published, none of which has shown an advantage of hyperoxia. Among 2643 ventilated patients with stroke, no correlation between mortality and paO2 was found (21), while in 2894 patients hyperoxia (paO2 of ≥ 300 mmHg) during the first 24 hours was an independent risk factor for in-hospital mortality (22). In patients with traumatic intracerebral hemorrhage, paO2 levels ≥ 300 mmHg were associated with increased mortality (23) and in another study this association was also found for paO2 levels >200 mmHg (24); however, if hyperoxia is defined as paO2 levels of >100 mmHg or >150 mmHg, there is no association between mortality and hyperoxia (25, 26).
Intensive care patients
Three prospective randomized trials in intensive care patients, including a total of 979 persons, were identified. In the first study (OXYGEN-ICU), 434 intensive care patients with a length of stay in an intensive care unit (ICU) of 3 days or longer were analyzed (12). Two thirds of the evaluated patients received mechanical ventilation. In the conventional group (target: SpO2 of 97–100%, median paO2 = 102 mmHg), the number of patient deaths was higher compared to the conservative group (target: SpO2 of 94–98%, median paO2 = 87 mmHg) in the ICU (20.2% versus 11.6%, risk ratio 0.57, p = 0.01; primary endpoint) and overall hospital mortality was also increased (33.9% versus 24.2%, risk ratio 0.71, p = 0.03). Furthermore, the median ventilation time was shorter among patients treated with less oxygen.
In a feasibility study, 103 mechanically ventilated intensive care patients were randomly assigned to either a conservative oxygenation strategy (SpO2 of 88–92%) or a liberal oxygenation strategy (SpO2 of ≥ 96%) (14). No significant differences were found between the groups with regard to new organ dysfunction, or ICU mortality or 90-day mortality.
The recently published HYPER2S study evaluating the administration of hypertonic versus isotonic saline and mechanical ventilation with hyperoxia versus with normoxia among ICU patients with septic shock was terminated early after inclusion of 442 patients because of safety concerns. In the hyperoxia group, a significantly higher rate of severe side effects, including muscle weakness and atelectasis, was noted (85% versus 76%, p = 0.02) (13).
Earlier, several retrospective studies indicated that hyperoxia was associated with increased mortality. An analysis of more than 36 000 intensive care patients with mechanical ventilation found that paO2 levels of about 70–80 mmHg during the first day after hospital admission was associated with the lowest mortality. Mortality increased with both lower and higher paO2 levels. This effect persisted even after multivariate adjustment for disease severity (1).
In another retrospective analysis of more than 150 000 intensive care patients during the first 24 hours of ICU admission, these results were only partially confirmed as it was shown that after multivariate adjustment for disease severity a general association between hyperoxia and increased mortality was no longer present, only for hypoxia (27). In an observational study with 105 patients, restrictive oxygen supplementation was no longer associated with increased complications after reduction the oxygen target range (28).
This review, which analyzed 13 prospective randomized trials, did not find evidence indicating an advantage of oxygen supplementation in non-hypoxemic patients in any of these studies. Since it was even associated with increased mortality or morbidity in the majority of studies, adjuvant oxygen therapy should always be critically assessed.
Until now, only few prospective randomized studies with adequate power have been published. The majority of recommendations for oxygen therapy is based on retrospective analyses which is a limitation of many studies. Furthermore, there is inconstancy in the paO2 ranges used to define hypoxia, normoxia and hyperoxia. While in some studies, a paO2 of >100 mmHg is already defined as hyperoxia, in others it is still considered within the normoxic range which extends up to a paO2 of 300 mmHg. Thus, comparability between studies is absent.
Even though paO2 levels between 100 and 300 mmHg are no longer within the physiological range and can only be reached by artificially supplying oxygen, many researchers included them in their definitions of normoxia. Since in recent randomized studies the boundary between normoxia and hyperoxia in essentially identical with the one between physiological and non-physiological paO2 levels, and a difference between the groups has been demonstrated, it is conceivable that various endpoints in the studies with “non-physiological“ normoxia/hyperoxia boundaries could not be reached because those patients defined as normoxic were actually already hyperoxic.
Despite these potential negative effects of hyperoxia, it should not be forgotten that there are certain conditions, such as carbon monoxide (CO) intoxication which require the use of therapeutic hyperoxia (e11). However, the assumption that perioperative hyperoxia reduces the incidence of abdominal surgery-related wound infection proved to be wrong (e12), especially since patients treated with hyperoxia were even years later still at an increased risk of myocardial infarction (e13).
Prospective randomized trials comparing hypoxia with normoxia are not available due to ethical and medical concerns, as hypoxia can cause hypoxia-related organ damage. These concerns are supported by retrospective analyses demonstrating hypoxia-related increases in mortality among ICU patients (1, 27).
In patients with COPD, restrictive use of oxygen therapy is advisable because these patients characteristically are at risk of hypercapnic pulmonary failure. In these patients, hyperoxia may further decrease the respiratory drive, leading to increased hypercapnia. In addition—presumably as the result of a deterioration of the ventilation-perfusion ratio—improved perfusion of poorly ventilated alveoli ultimately increases the pulmonary shunt fraction. For these reasons, restrictive oxygen therapy has widely been adopted in clinical practice as the management strategy for COPD patients for many years now. The target defined in the recently published German clinical practice guideline is an SpO2 of 91–92% (29).
In patients with myocardial ischemia, resulting from an imbalance between oxygen availability and oxygen requirement, the strategy of oxygen supplementation appears to be plausible from the perspective of pathophysiology to improve symptoms, reduce ischemic tissue injury and ultimately mortality. However, since studies failed to demonstrate any benefit from oxygen therapy, it appears that the negative effects of hyperoxia, such as reperfusion damage due to free radicals (e14) and reduction in coronary perfusion, outweigh conceivable positive effects (e8). Therefore, the current European guidelines for the management of STEMI and NSTEMI do only recommend the use of oxygen therapy in patient with oxygen saturations of <90% (30, 31).
According to the current recommendations for post-cardiac arrest management, oxygen therapy should only be administered in patients with oxygen saturation levels of <94% (target: oxygen saturation levels of 94–98%) (32). Further studies on post-resuscitation management are being planned or ongoing to develop strategies to more precisely define the optimum oxygen partial pressure after resuscitation, for example the REOX study (NCT01881243) and the REOX-II study (NCT02698826).
According to the US guideline for stroke management, the routine use of oxygen therapy is not recommended; however, measures should be taken to achieve an oxygen saturation of >94% (33).
Even though the two largest randomized studies on ventilated ICU patients were terminated early, the Italian single-center study found a lower mortality in the group with restrictive oxygen therapy (11.6% versus 20.2%) (12). In any case, normoxia is not associated with an additional risk. Therefore, the recently published German clinical practice guideline for invasive ventilation recommends a paO2 target range of 60–80 mm Hg (34). To also increase our understanding of the association between oxygenation and mortality in special patient populations, further studies are currently being planned or conducted, including, among others, the LOCO2 study on acute respiratory distress syndrome (ARDS), the HO2TorNO2T study on sepsis and the O2-ICU study on systemic inflammatory response syndrome (SIRS).
Independent of the desired target range for oxygen therapy, the route of administration also plays an important role (e15). For example, one study demonstrated the superiority of high-flow oxygen through nasal cannula (50 L/min) over noninvasive ventilation via a face mask in patients with non-hypercapnic respiratory failure (e16). However, in case of hypercapnic respiratory failure, non-invasive ventilation is preferred as it offers advantages over invasive ventilation via an endotracheal tube (e17).
In a randomized controlled trial, oxygen therapy for non-hypoxemic palliative care patients with refractory dyspnea showed no advantages (e18). Thus, palliative oxygen should not be offered to this patient population.
Very recently, a meta-analysis of oxygen therapy including 25 studies with a total of 16 037 patients has been published, comparing a liberal with a conservative oxygen strategy in patients with non-elective hospital admission (e19). It showed an increased mortality (risk ratio for in-hospital mortality: 1.21; [95% confidence interval (CI): 1.03; 1.43]) in the group with liberal oxygen therapy; thus, supplemental oxygen should not be given to patients with SpO2 levels above 94 to 96%.
Future studies should aim to identify the optimum paO2 range to achieve the best possible outcome for patients. Furthermore, prospective randomized trials on oxygen therapy are needed to overcome the limitations of retrospective analyses.
Conflict of interest statement
Prof. Kluge received consultancy fees from Baxter, Fresenius und Xenios. He received reimbursement of travel and accommodation expenses as well as lecture fees from Baxter, Fresenius, Sorin, and Xenios. He received consumables for the conduct of clinical and preclinical studies from ETView Ltd und Fisher & Paykel as well as funds from Xenios.
Dr. Grensemann and PD Dr. Fuhrmann declare no conflict of interest.
Manuscript received on 2 November 2017, revised version accepted on 26 March 2018
Translated from the original German by Ralf Thoene, MD.
Prof. Dr. med. Stefan Kluge, Dr. med. Jörn Grensemann
Klinik für Intensivmedizin Universitätsklinikum Hamburg-Eppendorf
Martinistraße 52, 20246 Hamburg, Germany
For eReferences please refer to:
Dr. med. Jörn
PD Dr. med. Valentin Fuhrmann,
Prof. Dr. med. Stefan Kluge
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