This post hoc analysis of the HYPER2S trial aimed to assess the impact of the new Sepsis-3 septic shock criteria (vasopressor-dependent hypotension and hyperlactatemia despite adequate fluid resuscitation [1]) on the number of patients enrolled in the study and their mortality rate, and the effect of hyperoxemia. The Sepsis-3 criteria were fulfilled in 58% of the total study population, with mortality at day 28 being more than double that of the patients with vasopressor-dependent hypotension without a raised lactate level. Hyperoxia was associated with a higher mortality rate in patients fulfilling the Sepsis-3 shock criteria,
while this association was not observed in patients with vasopressor-dependent hypotension alone (Additional file 6: Table S5).
The Sepsis-3 shock criteria were derived using the Surviving Sepsis Campaign database of 18.840 unselected septic patients with organ dysfunction [17]. Patients requiring vasopressors to maintain MAP > 65 mmHg and with persisting hyperlactatemia > 2 mmol/L despite adjudged adequate fluid resuscitation had a 42.3% hospital mortality compared to 30.1% with vasopressor-dependent hypotension alone. Comparable data were seen on retrospective analysis of the VASST study database [4] and the HYPER2S study. These higher mortality rates in the Sepsis-3 shock subset were reflected by the higher illness severity scores at baseline, and the requirement for more organ support therapy.
The retrospective analysis of the VASST study [4] revealed a significant outcome benefit from vasopressin only in those patients with vasopressor-dependent hypotension alone. Mortality was identical in patients fulfilling the Sepsis-3 shock criteria.
In this present analysis, we confirm that treatment effect may vary according to the criteria used for defining septic shock. Indeed, hyperoxia had no effect on mortality albeit a longer requirement for mechanical ventilation in vasopressor-dependent hypotensive patients, whereas there was a near-significant increase in mortality (57.4% vs. 44.3% normoxia; p = 0.054) in the Sepsis-3 shock cohort. Hyperlactatemia despite adequate fluid resuscitation is considered to reflect more severe cellular and metabolic abnormalities, and thus places affected patients at higher mortality risk [17].
There is a growing evidence that hyperoxia may be associated with higher mortality and that conservative strategies may contribute to lower mortality [16, 17]. However, there is no certainty on the implicated pathophysiological mechanisms in oxygen toxicity. Indeed, the disparity in outcomes with hyperoxia only seen in those fulfilling the Sepsis-3 shock criteria suggests an additional toxic impact of oxygen in this more severe subset. Oxygen administration has long been considered a cornerstone in the management of patients with septic shock [9]. Circulatory shock is considered to “represent an imbalance between oxygen supply and oxygen requirements” [2]. While hyperoxia increases tissue oxygen tension, even in shock states with profound reduction of tissue oxygen transport [18], it can compromise macro- and microcirculatory blood flow [8, 11, 19]. After fluid resuscitation, septic shock generally has a “distributive shock” pattern, where the “main deficit lies in the periphery, …with altered oxygen extraction” [2]. In most cell types, other than erythrocytes, oxygen is crucial for sufficient adenosine triphosphate synthesis via the mitochondrial oxidative phosphorylation, acting as the final electron acceptor in the respiratory chain. Oxygen is also one of the strongest oxidizing agents capable of damaging any biological molecule due to excess production of reactive oxygen species (ROS) [20]. Although ROS can also be generated with hypoxia, ROS formation is directly related to the level of arterial and tissue oxygen tension [21]. It is tempting to speculate that under conditions of profound alterations of cellular oxygen extraction and utilization—perhaps manifest clinically as hyperlactatemia—hyperoxia, with an increase in available oxygen, may lead to excessive ROS formation with subsequent oxidative stress-induced damage. In septic shock, ROS production and damage may be amplified by impaired mitochondrial respiration and depleted antioxidant defenses [22]. Even if this study has several limitations, discussed thereafter, it could be hypothesized that hyperoxia toxicity, with an increased oxidative stress due to ROS formation, may be delayed. This mid- or long-term harmful effect of hyperoxia may explain that most variates are not significantly different between oxygenation groups, except for some major patient-centered outcome variables. Hyperlactatemia may be due to excessive peripheral production or decrease clearance such as in cirrhosis. It was suggested by a reviewer to test our hypothesis without cirrhotic patients, and these additional results support our hypothesis.
Some limitations must be underlined in this analysis. First, the HYPER2S trial was stopped prematurely for safety reason. From a strict statistical point of view, mortality difference with hyperoxia in the Sepsis-3 shock cohort was not significant (p = 0.054). However, this is no longer true when results are adjusted on confounders (multivariate analysis). This is likely related to lack of power, as the absolute and relative mortality at day 28 rates increased by 13.1% and 29.6%, respectively, in a sizeable number of patients (264). This suggests a clinical relevance of our results. Second, the post hoc character of the analysis, in a retrospective setting, may have missed some masked imbalance between groups and the frailty of multivariate analysis as well as multiple testing should be taken in account. Therefore, it is wise to consider these results as hypothesis generating, as the study has not the statistical power to conclude on a link between hyperoxia and mortality.