|Year : 2020 | Volume
| Issue : 1 | Page : 41-50
The relation between arterial hyperoxia and mortality among intensive care unit patients with septic shock
Tayseer M Zaytoun, Hany E Elsayed, Samar E Elsayed
Department of Critical Care Medicine, Faculty of Medicine, Alexandria University, Alexandria, Egypt
|Date of Submission||04-Nov-2018|
|Date of Acceptance||10-Sep-2019|
|Date of Web Publication||16-Apr-2020|
Hany E Elsayed
Mostafa Kamel Street at Intersection with Street 313, El-Marwa Building, Smouha, Alexandria
Source of Support: None, Conflict of Interest: None
Context Oxygen should be regarded as any other drug with potential dose and time-dependent adverse effects. Health care practitioners are more likely to accept supranormal arterial oxygen levels as a wider safety buffer. Furthermore, the latest guidelines in the management of septic shock did not define upper limits for oxygenation in mechanically ventilated patients with septic shock.
Aim To investigate whether hyperoxia is associated with higher mortality in patients with septic shock.
Patients and methods This study was carried out on 200 patients with septic shock. After fulfilling the inclusion criteria, we recorded the clinical data, severity scoring systems, source of sepsis, ventilatory data, oxygenation status data, and the outcome parameters. We categorized the patients into two groups: group I (nonhyperoxic group), whose arterial oxygen tension was less than 120 mmHg in all arterial blood gas analyses during the ICU stay, and group II (hyperoxic group), whose arterial oxygen tension was more than or equal to 120 mmHg in at least one arterial blood gas analysis during ICU stay.
Results Group I included 40 patients, whereas group II included 160 patients. Mortality rate was 57.5 and 89.4% in groups I and II, respectively. In group II, there were 16 patients who were exposed to 1 day of hyperoxia with a mortality rate of 75%, whereas there were 144 patients who were exposed to hyperoxia more than 1 day with a mortality rate of 91%.
Conclusion Hyperoxia was associated with increased mortality, number of mechanical ventilation days, length of ICU stay, and hospital stay.
Keywords: arterial hyperoxia, outcome, septic shock
|How to cite this article:|
Zaytoun TM, Elsayed HE, Elsayed SE. The relation between arterial hyperoxia and mortality among intensive care unit patients with septic shock. Res Opin Anesth Intensive Care 2020;7:41-50
|How to cite this URL:|
Zaytoun TM, Elsayed HE, Elsayed SE. The relation between arterial hyperoxia and mortality among intensive care unit patients with septic shock. Res Opin Anesth Intensive Care [serial online] 2020 [cited 2020 May 31];7:41-50. Available from: http://www.roaic.eg.net/text.asp?2020/7/1/41/282596
| Introduction|| |
Sepsis is a significant health problem worldwide. Its cost and economic burden to society extends well beyond the lives lost. Adult sepsis may cost hospitals up to US$20 000 per patient .
The reported incidence of sepsis is rising likely owing to the high prevalence of comorbidities in the aging populations, greater recognition in some countries, and improved disease coding . Although the accurate incidence rate is unknown, conservative estimates indicate that sepsis is a major cause of mortality and critical illness ,. Additionally, the patients who survive sepsis often experience long-term psychological, physical, and cognitive disabilities with significant social and health care implications .
Septic shock is a subset of sepsis in which particularly severe cellular, circulatory, and metabolic abnormalities are associated with a higher risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by the need to vasopressor to maintain a mean arterial pressure of 65 mmHg or greater and serum lactate level less than 2 mmol/l (<18 mg/dl) in the absence of hypovolemia .
Oxygen (O2) administration is the most commonly prescribed therapy in the critically ill patients and frequently represents a life-saving measure .
Since hypoxemia is generally recognized as dangerous to the patient, physicians fear hypoxia and borderline O2 status, and they may tend to use higher levels of fraction of inspired oxygen (FiO2) to increase arterial oxygen tension (PaO2) to supernormal levels and induce hyperoxia (PaO2≥120 mmHg) .
The use of supplemental O2 in various medical emergencies is supported by many guidelines ,,; 100% O2 is frequently administered during cardiopulmonary resuscitation in cardiac arrest , and normobaric O2 therapy is considered as a potential therapeutic strategy for patients with stroke or traumatic brain injury , with an underlying rationale of increased O2 delivery to the brain  and protection of the ischemic penumbra through induction of redistribution of blood from normal to ischemic areas .
It can be postulated that peripheral vasoconstriction induced by hyperoxia may be of value in hemorrhagic and septic shock, reducing the need for large-volume resuscitation and vasopressor requirements, with probable antimicrobacterial properties in humans and may even exert anti-inflammatory effects .
Hyperoxia may lead to the generation of hepatic, pulmonary, and central nervous system reactive oxygen species (ROS), which are versatile molecules that can be vital in host defense and in the regulation of intracellular signaling pathways .
Meanwhile, ROS have also repeatedly been considered to be of major significance in organ dysfunction, tissue damage, and clinical disease. ROS are generated as an undesirable byproduct of adenosine triphosphate synthesis during aerobic cellular metabolism and may also be produced in response to exogenous stimuli, such as cytokines, microbes, and xenobiotics . When the production of ROS exceeds the limits of counteraction by antioxidant responses, a cellular state of oxidative stress manifests .
Clinical and experimental data regarding the relationship between the arterial hyperoxia and outcome are conflicting. An association between mortality and arterial hyperoxia has been reported in various patient populations (postcardiac arrest, stroke, traumatic brain injury, and mechanically ventilated) . However, other studies have failed to demonstrate a relationship between hyperoxia and increased mortality . Therefore, the question whether exposure to supranormal PaO2 is safe in critically ill patients remains unanswered.
Moreover, the oxygenation target and upper limits remain vague or undefined in the latest guidelines of septic shock. We thus performed a study describing the relationship between arterial hyperoxia and mortality in patients with septic shock.
| Patients and methods|| |
The study was carried out in the Critical Care Medicine Department in Alexandria University hospitals and included 200 patients.
Patients who were meeting the following requirements were included in the study:
- Age between 18 and 60 years.
- Diagnosis of septic shock according to Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.
- Mechanically ventilated patients.
The following were the exclusion criteria:
- Pregnant women.
- Immunocompromised patients.
- Hypoxic patients despite high FiO2 (PaO2<60 mmHg on FiO2>60%).
- Patients with ICU stay less than 1 day.
| Methods|| |
Approval of the medical ethics committee of Alexandria faculty of Medicine was taken. An informed consent from patient’s next of kin was taken before enrollment of patient in the study.
The patients with septic shock were managed primarily by the ICU physicians who were blinded from the study data.
The following data were collected:
- The demographic data (age, sex, body weight, height, and BMI).
- Clinical data, including blood pressure (mmHg), pulse rate (beat/min), temperature (°C), and urine output (ml/h) every 2 h.
- Severity scoring systems (on admission and every day of ICU stay):
- Acute physiology and chronic health evaluation II score .
- Sequential organ failure assessment (SOFA) score .
- Clinical and microbiological cause of sepsis.
- Laboratory investigations every day, including the following:
- Complete blood count.
- Routine laboratory work [urea, creatinine, liver transaminases, total protein, serum albumin, electrolytes as sodium (Na) and potassium (K), prothrombin time, partial thromboplastin time, and total and direct bilirubin).
- Ventilatory data (mode, positive end expiratory pressure, and FiO2).
- Oxygenation status data:
- Pulse oximetry probe was continuously attached to the patient, and oxygen saturation (SpO2) was recorded every 2 h.
- Arterial blood gases (ABG) analysis: ABG was analyzed at least four times per day.
- Central venous SpO2: blood samples from the central venous line were analyzed four times per day.
- Patient is considered to be hyperoxic when PaO2 more than or equal to 120 mmHg at least in one ABG analysis . Duration of hyperoxia, percentage of days with hyperoxia, days of mechanical ventilation (MV), length of hospital stay, and the patient outcome were recorded.
| Results|| |
The current study was carried out on 200 consecutive adult patients who were admitted to the Critical Care Medicine Department in Alexandria University hospitals with the diagnosis of septic shock. We categorized the patients into two groups: group I (the nonhyperoxic group) (40 patients) whose PaO2 was less than 120 mmHg in all ABG analyses during the ICU stay, and group II (the hyperoxic group) (160 patients) whose PaO2 was more than or equal to 120 mmHg in at least one ABG analysis during the ICU stay.
The demographic data
Regarding the sex of the group I, there were 22 (55%) male patients and 18 (45%) female patients, and in group II, there were 77 (48.1%) male patients and 83 (51.9%) female patients. However, the age in group I ranged from 35 to 60 years, with a mean of 51.90±7.43 years, and in group II ranged from 23 to 60 years, with a mean of 50.76±7.52 years.
The BMI in group I ranged from 17.0 to 39.0 kg/m2, with a mean of 28.05±6.67 kg/m2, whereas in group II ranged from 17.0 to 42.0 kg/m2, with a mean of 27.81±6.30 kg/m2. All these differences in demographic data (sex, age, and BMI) were not statistically significant ([Table 1]).
|Table 1 Comparison between the two studied groups regarding the demographic data|
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The acute physiology and chronic health evaluation II score on admission to ICU
In group I, we found that the mean score was 7.18±3.76, whereas in group II, the mean score was 8.12±5.11, and there was no statistically significant difference between both groups ([Table 2]).
|Table 2 Comparison between the two studied groups regarding acute physiology and chronic health evaluation II score|
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The sequential organ failure assessment score
There was no statistically significant difference between both groups in the first 3 days regarding the SOFA score. The SOFA score in group II was significantly higher than group I from day 4 to day 10, and from day 11 to day 21, there was no statistically significant difference between both groups ([Table 3]).
|Table 3 Comparison between the two studied groups regarding the sequential organ failure assessment score|
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The fraction of inspired oxygen
There was no statistically significant difference between both groups in the first 3 days regarding the FiO2, whereas the FiO2 in group II was significantly higher than group I from day 4 to day 10, and it was also higher from day 11 to day 21 but without any statistically significant difference ([Table 4]).
|Table 4 Comparison between the two studied groups according to the fraction of inspired oxygen|
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The oxygen saturation as measured by pulse oximetry
The SpO2 in group II was higher than SpO2 in group I in all days, with statistically significant difference ([Table 5]).
|Table 5 Comparison between the two studied groups according to oxygen saturation|
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The outcome of the patients
In group I, 23 (57.5%) patients were discharged and 17 (42.5%) patients died. However, in group II, 17 (10.6%) patients were discharged and 143 (89.4%) patients died. So, mortality in group II was higher than that in group I, with statistically significant difference ([Figure 1]).
Regarding the length of hospital stay, ICU stay, and MV days, group I had significantly lower duration of hospital stay, ICU stay, and MV ([Figure 2]).
|Figure 2 Relation between hyperoxia and duration of hospital stay, ICU stay, and mechanical ventilation.|
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The relationship between the severity of hyperoxia and outcome
We divided the group II (160 patients) into two subgroups: a group of moderate hyperoxia (118 patients) (PaO2=120–300) and a group of severe hyperoxia (42 patients) (PaO2>300). On analyzing the results, we found that in subgroup of moderate hyperoxia, 16 (13.6%) patients were discharged and 102 (86.4%) patients died, whereas in subgroup of severe hyperoxia, one (2.3%) patient was discharged and 41 (97.7%) patients died. So, mortality in subgroup of severe hyperoxia was higher than that in subgroup of moderate hyperoxia, with statistically significant difference ([Table 6]).
The relationship between the duration of hyperoxia and outcome
In patients exposed to 1 day of hyperoxia (a total of 16 patients), four (25%) patients were discharged and 12 (75%) patients died, whereas in patients exposed to hyperoxia more than 1 day (a total of 144 patients), 13 (9%) patients were discharged and 131 (91%) patients died. So, mortality in patients exposed to hyperoxia more than 1 day was higher than that in patients exposed to hyperoxia for 1 day only, with statistically significant difference ([Table 7]).
| Discussion|| |
Septic shock is defined as a subset of sepsis in which the underlying cellular, circulatory, and metabolic abnormalities are severe enough to significantly increase mortality. There is no specific treatment for patients with sepsis, and management, therefore, relies on infection control with source removal and effective antibiotics and organ function support. There is good evidence that early treatment is associated with improved outcomes in these patients .
O2 administration is the most commonly prescribed therapy in the critically ill patients and often represents a life-saving measure. Since hypoxemia is generally considered as harmful and moderate levels of arterial hyperoxia as benign, health care practitioners tend to accept supranormal arterial O2 levels, because this provides a wider safety range .
Clinical and experimental studies focusing on the relationship between arterial hyperoxia and outcome have shown conflicting data. An association between arterial hyperoxia and mortality has been reported in various patient populations but not confirmed by other studies ,.
In the current study, we aimed to investigate whether hyperoxia is associated with higher mortality in patients with septic shock. This study was carried out on 200 patients with septic shock who were classified at the end of the study into two groups; group I (the nonhyperoxic group) (40 patients) whose PaO2 was less than 120 mmHg in all ABG analyses during the ICU stay and group II (the hyperoxic group) (160 patients) whose PaO2 was more than or equal to 120 mmHg in at least one ABG analysis during ICU stay.
The main findings of this study can be summarized in the following points:
- Hyperoxia was associated with increased number of MV days, length of ICU stay, and hospital stay. Furthermore, it was associated with an increase in the mortality among patients with septic shock.
- The severity of hyperoxia and the duration of exposure to hyperoxia could as well influence the prognosis in patients with septic shock.
Two large multicenter retrospective studies , showed a U-shaped relationship between mortality and PaO2 levels by unadjusted analysis. After adjusting for the significant cofounding factors, such as severity of illness, the association between mortality and higher PaO2 levels was confirmed only by de Jonge et al. , and this was in accordance with our findings, whereas Eastwood et al.  showed a protective effect of hyperoxia. Differences in the methodology applied for the analysis (different reference categories, PaO2 stratified in quintiles/deciles) made these studies difficult to compare.
A pilot before-and-after study was the only interventional study that has compared the conventional O2 therapy to a conservative strategy using an SpO2 target between 90 and 92% . This study was carried out on a total of 105 adult (18 years old or older) patients who required MV for more than 48 h: 51 patients during the ‘conventional’ period and 54 after a change to ‘conservative’O2 therapy, and although this study was underpowered to prove a difference in mortality, it supported the safety and feasibility of the conservative O2 therapy, which led to a marked decrease in O2 exposure without being associated with significant physiological and clinical adverse effects.
Our observations of hyperoxia and the increase in mortality were in accordance with previous experimental studies showing the potential toxic effect of high FiO2; these studies had clarified the roles of both receptor-mediated and mitochondrial cell death pathways in experimental hyperoxic lung injury. Studies in animals demonstrated that hyperoxia interacted with mechanical stretch to augment ventilator-induced lung injury .
Administration of supplemental O2 could cause lung injury. This risk was especially high in preterm babies, probably attributable to immature host defenses, underdeveloped lungs, and inadequate antioxidant systems . Exposure to hyperoxia led to diffuse pulmonary damage characterized by a severe inflammatory response and damage of the alveolar-capillary barrier leading to lung edema, impaired gas exchange, and hypoxic respiratory failure .
Lungs of mice exposed to FiO2 more than 90% for 48 h were more vulnerable to ventilator-induced lung injury than those exposed to room air . Hyperoxia also has worsened pulmonary injury following MV in mice using high tidal volumes . Moreover, hyperoxia impaired the innate immune response by decreasing the macrophage function, impairing the bacterial killing ability, and increasing the susceptibility to pneumonia in a Klebsiella pneumoniae model .
Another organ that might be injured by hyperoxia is the kidney, as hyperoxic reperfusion exacerbated renal dysfunction and histopathologic injury took place in rabbits after 30 min of complete normothermic ischemia. This hyperoxia-associated dysfunction was prevented by administering radical scavenger allopurinol, proving that oxidative injury by ROS played an essential role in postischemic renal injury .
Many studies have investigated the role of high reperfusion PaO2 following cardiac arrest and resuscitation. In a canine model of 10 min of cardiac arrest, cardiopulmonary resuscitation with 21 versus 100% FiO2 resulted in reduced levels of oxidized brain lipids and improved neurologic outcomes .
Moreover, the authors showed not only that the number of days with hyperoxia, but also ‘hyperoxemia at ICU admission,’ in other words, deliberate, iatrogenic pre-ICU hyperoxia, was an independent risk factor of VAP. The study by Six et al.  raised an important question with respect to the use of hyperoxia, that is, whether there was an optimal PaO2 target in the ICU.
In agreement with our results, the HYPERS2S study by Asfar and colleagues, a two-by-two factorial, multicenter, randomized, clinical trial, recruited patients aged 18 years and older with septic shock who were on MV from 22 centers in France. Patients were randomly assigned to four groups. Patients received, in an open-labeled manner, MV either with FiO2 at 1.0 (hyperoxia) or FiO2 set to target an arterial hemoglobin O2 saturation of 88–95% (normoxia) during the first 24 h; patients also received, in a double-blind manner, either 280 ml boluses of 3% (hypertonic) saline or 0.9% (isotonic) saline for fluid resuscitation during the first 72 h. The primary end point was mortality at day 28 after randomization in the intention-to-treat population. They clearly found that in patients with septic shock, setting FiO2 to 1.0 to induce arterial hyperoxia might increase the risk of mortality .
Jouffroy et al.  suggested the association between hyperoxia in patients with septic shock who needed ventilator support in the prehospital setting and short-term mortality. This study raised the concept that hyperoxia might be dangerous for critically ill patients and also suggested that a PaO2 between 100 and 150 mmHg might be harmful in these patients.
In one large single-center randomized controlled trial, patients were randomized either to conservative O2 therapy (PaO2 70–100 mmHg or O2 saturation 94–98%) or to conventional O2 therapy (PaO2 100–150 mmHg or SpO2 97–100%). Patients of the conservative group had less mortality rates, despite early stoppage of the study owing to lower than expected inclusion rates .
A retrospective cohort study carried out on the mechanically ventilated ICU patients has shown an increase in mortality in case of hyperoxia and in case of hypoxia as well . So far, only retrospective data were available yielding a U-shaped relationship between mortality and arterial PO2, with a nadir at PaO2 values of 110–150 mmHg  and 150–200 mmHg . Mortality sharply increased at PaO2 less than 65 mmHg and more than 225 mmHg .
A study by Kraft and colleagues did not find a correlation between hyperoxia and increased in-hospital mortality. Patients of all ages admitted to ICU and with MV for at least seven consecutive days were included in this single-center retrospective medical record audit. The main outcome measure was time-weighted PaO2 over 7 days. Logistic regression for association with in-hospital mortality and propensity score matching was performed. In their study, normoxic patients showed lower in-hospital and ICU mortality compared with hyperoxic patients, without being statistically significant . As the absolute risk reduction was close to 8% for normoxia, this was a promising trend for following investigations with a higher number of studied patients.
Against the results of our study, Eastwood and colleagues performed a retrospective cohort study in 152.680 mechanically ventilated ICU patients in different hospitals and 49.8% had hyperoxia (PaO2>120 mmHg). An association was found between increased in-hospital mortality and hypoxia, but not between hyperoxia and mortality .O2-ICU was a single-center, randomized, open-label, clinical trial conducted by Girardis et al.  that included all adults admitted from March 2010 to October 2012 with an expected length of stay of 72 h or longer to the medical-surgical ICU. The originally planned sample size was 660 patients, but this study was terminated early owing to difficulties in enrollment after inclusion of only 480 patients. Patients were randomly assigned to receive conservative O2 therapy to target PaO2 between 70 and 100 mmHg or SpO2 between 94 and 98% or to receive the standard ICU practice, allowing PaO2 values up to 150 mmHg or SpO2 values between 97 and 100%. They reported an absolute risk reduction of 8.6% in their conservative group targeting for lower PaO2 and SpO2 in ICU patients. Interestingly, they observed that patients with hyperoxia had shorter hospital length of stay and ICU length of stay, potentially attributed to the fact that patients of young age predominantly experienced episodes of hyperoxia. After propensity score matching, no differences were observed anymore. Furthermore, other than expected, episodes of hyperoxia predominantly occurred at low rather than high FiO2 settings.
Their data, therefore, suggested that typical ICU patients at risk for hyperoxia burden might be young and less severe critically ill ICU patients receiving a lower FiO2. We believed that this finding was of clinical interest and needed to be taken into consideration when tailoring for individual optimal O2 values during MV.
In our results, we found also that the ScvO2 in the hyperoxic group, which had increased mortality, was higher than the nonhyperoxic group, and this was similar to the study published by Textoris et al.  where they found that high levels of ScvO2 in patients with septic shock might be associated with increased mortality. Consequently, there was a strong signal suggesting an association between hyperoxia and increased mortality among patients with septic shock.
| Conclusion|| |
- Hyperoxia is associated with an increased number of MV days, length of ICU stay, and hospital stay and is associated with an increase in the mortality among patients with septic shock.
- The severity of hyperoxia and the duration of exposure to hyperoxia can as well influence the prognosis in patients with septic shock.
Presentation at a meeting: Poster presentation in the 24th international symposium on infections in the critically ill patient.
Organization center for biomedical research in respiratory diseases, European Society of Anesthesiology.
Date: 7th–8th February 2019.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]