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No room for hyperoxia or hypertonic saline in septic shock
Comment
So many questions need to be addressed in critical care medicine that researchers sometimes like to tackle two questions simultaneously. This is what Pierre Asfar and colleagues1 did in their recent study, using a factorial design to investigate, at the same time, the possible harmful effects of hyperoxia and the possible place of hypertonic solutions in patients with septic shock. This multicentre trial randomly assigned 442 patients with septic shock to receive mechanical ventilation with an inspired oxygen fraction (FiO2) of 1·0 (hyperoxia) or an FiO2 set to target an arterial haemoglobin oxygen saturation of 88–95% (normoxia) during the first 24 h of septic shock and, at the same time, to receive 280 mL boluses of 3·0% (hypertonic) saline or 0·9% (isotonic) saline for fluid resuscitation during the first 72 h. The primary endpoint was mortality at day 28. The trial was stopped prematurely for safety reasons because the mortality was somewhat higher in both experimental groups: 43% in the hyperoxia group versus 35% in the normoxia group (HR 1·27, 95% CI 0·94–1·72; p=0·12), and 42% in the hypertonic group versus 37% in the isotonic group (1·19, 0·88–1·61; p=0·25). Although some experts might criticise the study because of this premature termination, I believe the Data and Safety Monitoring Board reached the right decision to suggest that the trial be stopped for possible harm. Asfar and colleagues should be commended for this well performed study. Like all studies, it has several limitations, which are well discussed by the authors.1 Let us briefly consider the two components of this study separately. The background for the use of hypertonic solutions in patients with septic shock is weak. The idea is certainly not new because the possibility that hypertonic solutions could be beneficial in shock states (including septic shock) has been considered for more than 30 years.2 It is well established that in the initial resuscitation phase, hypertonic solutions can reduce the total amount of fluid required, thus potentially limiting the negative effects of fluid overload, but this effect is not maintained over a more prolonged period. Experimentally, these solutions can have some beneficial effects on endothelial cell function, but these are unlikely to be sufficient to affect survival. Moreover, administration of hypertonic saline delivers not only large amounts of sodium but also of chloride, and there
is increasing evidence that hyperchloremic acidosis can be harmful to the kidneys and other tissues.3 The use of hypertonic lactate to replace chloride might not be a good alternative.4 Hypertonic solutions in shock states should, therefore, probably be reserved for very specific situations in which the supply of intravenous fluids is difficult; the best example being the resuscitation of trauma victims on a battlefield. Because sepsis is associated with tissue hypoxia, ensuring adequate oxygenation is a key aspect of management, but the role of hyperoxia in these patients is controversial.5 An important limitation of the hyperoxia part of the study by Asfar and colleagues1 was the systematic application of a high FiO2 to all patients in the hyperoxia group, even though prolonged ventilation with high FiO2 has been known, for at least the past 50 years, to induce lung damage.6 It would have been better to use an individualised approach adjusted to each patient’s SaO2 value.5 So, where does this leave us? Is another randomised controlled trial on liberal versus restricted oxygen administration in critically ill patients needed? In fact, several studies are ongoing to address this issue, so the question might seem rather irrelevant. However, for several reasons, I am not sure whether these new trials are really necessary. First, in nature, and by contrast with virtually all other biochemical abnormalities, no animal is ever exposed to hyperoxia. As such, no rationale based on physiology or evolution exists to support use of hyperoxia. Why would the body benefit from hyperoxia, when the small increase in haemoglobin saturation does not increase oxygen delivery to any significant extent? By contrast, there is good evidence from basic science to suggest that excessive oxygen tensions can result in lung damage (when FiO2 is high for prolonged periods)6 and in altered cellular function through enhanced oxidative stress and microcirculatory alterations; these effects can be documented even in healthy people.7 Substantial evidence now exists that hyperoxia can be harmful in various groups of patients, including after cardiac arrest, stroke, or traumatic brain injury,5,8 and guidelines already recommend that hyperoxia be avoided after cardiac arrest. Another recent randomised clinical trial in 434 critically ill patients9 showed that a conservative strategy to maintain a normal PaO2 with an
www.thelancet.com/respiratory Published online February 14, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30047-4
Burger/Phanie/Science Photo Library
No room for hyperoxia or hypertonic saline in septic shock
Lancet Respir Med 2017 Published Online February 14, 2017 http://dx.doi.org/10.1016/ S2213-2600(17)30047-4 See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(17)30046-2
1
Comment
SpO2 between 94% and 98% was associated with lower mortality than treatment to achieve an SpO2 between 97% and 100%, although questions have been raised because of the large difference in mortality between groups, especially for a single-centre study. In view of these arguments, why is a policy of normoxia not implemented, thus avoiding the harmful effects of hypoxaemia and hyperoxia? Importantly, this approach is easily achievable. If, as in the past, repeated measurement of arterial blood gases were necessary to monitor oxygenation, we could argue that this strategy was invasive, time-consuming, and costly, but this is no longer true now that reliable oximeters are available. Admittedly, oximeters cannot provide a reliable signal during the very acute phase of acute circulatory failure, but this phase is transient. As such, a recommendation to keep SpO2 within the low-normal range of 92–96% in all critically ill patients is easily achievable with minimum effort and little cost. The study by Asfar and colleagues1 seems to have provided answers to two important questions: hyperoxia and hypertonic saline have no place in the current management of patients with sepsis.
2
Jean-Louis Vincent Department of Intensive Care, Erasme University Hospital, Université de Bruxelles, 1070 Brussels, Belgium [email protected] I declare no competing interests. 1
2 3
4 5
6
7 8
9
Asfar P, Schortgen F, Boisramé-Helms J, et al. Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial. Lancet Respir Med 2017; published online Feb 14. http://dx.doi.org/10.1016/S2213-2600(17)30046-2. Luypaert P, Vincent JL, Domb M, et al. Fluid resuscitation with hypertonic saline in endotoxic shock. Circ Shock 1986; 20: 311–20. Vincent JL, De Backer D. Saline versus balanced solutions: are clinical trials comparing two crystalloid solutions really needed? Crit Care 2016; 20: 250. Su F, Xie K, He X, et al. The harmful effects of hypertonic sodium lactate administration in hyperdynamic septic shock. Shock 2016; 46: 663–71. Vincent JL, Taccone FS, He X. Harmful effects of hyperoxia in post-cardiac arrest, sepsis, traumatic brain injury or stroke: the importance of individualized oxygen therapy in critically ill patients. Can Respir J 2017; 2017: 2834956. Nash G, Blennerhassett JB, Pontoppidan H. Pulmonary lesions associated with oxygen therapy and artifical ventilation. N Engl J Med 1967; 276: 368–74. Orbegozo Cortes D, Puflea F, et al. Normobaric hyperoxia alters the microcirculation in healthy volunteers. Microvasc Res 2015; 98: 23–28. Damiani E, Adrario E, Girardis M, et al. Arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis. Crit Care 2014; 18: 711. Girardis M, Busani S, Damiani E, et al. Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit: the oxygen-ICU randomized clinical trial. JAMA 2016; 316: 1583–89.
www.thelancet.com/respiratory Published online February 14, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30047-4
So many questions need to be addressed in critical care medicine that researchers sometimes like to tackle two questions simultaneously. This is what Pierre Asfar and colleagues1 did in their recent study, using a factorial design to investigate, at the same time, the possible harmful effects of hyperoxia and the possible place of hypertonic solutions in patients with septic shock. This multicentre trial randomly assigned 442 patients with septic shock to receive mechanical ventilation with an inspired oxygen fraction (FiO2) of 1·0 (hyperoxia) or an FiO2 set to target an arterial haemoglobin oxygen saturation of 88–95% (normoxia) during the first 24 h of septic shock and, at the same time, to receive 280 mL boluses of 3·0% (hypertonic) saline or 0·9% (isotonic) saline for fluid resuscitation during the first 72 h. The primary endpoint was mortality at day 28. The trial was stopped prematurely for safety reasons because the mortality was somewhat higher in both experimental groups: 43% in the hyperoxia group versus 35% in the normoxia group (HR 1·27, 95% CI 0·94–1·72; p=0·12), and 42% in the hypertonic group versus 37% in the isotonic group (1·19, 0·88–1·61; p=0·25). Although some experts might criticise the study because of this premature termination, I believe the Data and Safety Monitoring Board reached the right decision to suggest that the trial be stopped for possible harm. Asfar and colleagues should be commended for this well performed study. Like all studies, it has several limitations, which are well discussed by the authors.1 Let us briefly consider the two components of this study separately. The background for the use of hypertonic solutions in patients with septic shock is weak. The idea is certainly not new because the possibility that hypertonic solutions could be beneficial in shock states (including septic shock) has been considered for more than 30 years.2 It is well established that in the initial resuscitation phase, hypertonic solutions can reduce the total amount of fluid required, thus potentially limiting the negative effects of fluid overload, but this effect is not maintained over a more prolonged period. Experimentally, these solutions can have some beneficial effects on endothelial cell function, but these are unlikely to be sufficient to affect survival. Moreover, administration of hypertonic saline delivers not only large amounts of sodium but also of chloride, and there
is increasing evidence that hyperchloremic acidosis can be harmful to the kidneys and other tissues.3 The use of hypertonic lactate to replace chloride might not be a good alternative.4 Hypertonic solutions in shock states should, therefore, probably be reserved for very specific situations in which the supply of intravenous fluids is difficult; the best example being the resuscitation of trauma victims on a battlefield. Because sepsis is associated with tissue hypoxia, ensuring adequate oxygenation is a key aspect of management, but the role of hyperoxia in these patients is controversial.5 An important limitation of the hyperoxia part of the study by Asfar and colleagues1 was the systematic application of a high FiO2 to all patients in the hyperoxia group, even though prolonged ventilation with high FiO2 has been known, for at least the past 50 years, to induce lung damage.6 It would have been better to use an individualised approach adjusted to each patient’s SaO2 value.5 So, where does this leave us? Is another randomised controlled trial on liberal versus restricted oxygen administration in critically ill patients needed? In fact, several studies are ongoing to address this issue, so the question might seem rather irrelevant. However, for several reasons, I am not sure whether these new trials are really necessary. First, in nature, and by contrast with virtually all other biochemical abnormalities, no animal is ever exposed to hyperoxia. As such, no rationale based on physiology or evolution exists to support use of hyperoxia. Why would the body benefit from hyperoxia, when the small increase in haemoglobin saturation does not increase oxygen delivery to any significant extent? By contrast, there is good evidence from basic science to suggest that excessive oxygen tensions can result in lung damage (when FiO2 is high for prolonged periods)6 and in altered cellular function through enhanced oxidative stress and microcirculatory alterations; these effects can be documented even in healthy people.7 Substantial evidence now exists that hyperoxia can be harmful in various groups of patients, including after cardiac arrest, stroke, or traumatic brain injury,5,8 and guidelines already recommend that hyperoxia be avoided after cardiac arrest. Another recent randomised clinical trial in 434 critically ill patients9 showed that a conservative strategy to maintain a normal PaO2 with an
www.thelancet.com/respiratory Published online February 14, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30047-4
Burger/Phanie/Science Photo Library
No room for hyperoxia or hypertonic saline in septic shock
Lancet Respir Med 2017 Published Online February 14, 2017 http://dx.doi.org/10.1016/ S2213-2600(17)30047-4 See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(17)30046-2
1
Comment
SpO2 between 94% and 98% was associated with lower mortality than treatment to achieve an SpO2 between 97% and 100%, although questions have been raised because of the large difference in mortality between groups, especially for a single-centre study. In view of these arguments, why is a policy of normoxia not implemented, thus avoiding the harmful effects of hypoxaemia and hyperoxia? Importantly, this approach is easily achievable. If, as in the past, repeated measurement of arterial blood gases were necessary to monitor oxygenation, we could argue that this strategy was invasive, time-consuming, and costly, but this is no longer true now that reliable oximeters are available. Admittedly, oximeters cannot provide a reliable signal during the very acute phase of acute circulatory failure, but this phase is transient. As such, a recommendation to keep SpO2 within the low-normal range of 92–96% in all critically ill patients is easily achievable with minimum effort and little cost. The study by Asfar and colleagues1 seems to have provided answers to two important questions: hyperoxia and hypertonic saline have no place in the current management of patients with sepsis.
2
Jean-Louis Vincent Department of Intensive Care, Erasme University Hospital, Université de Bruxelles, 1070 Brussels, Belgium [email protected] I declare no competing interests. 1
2 3
4 5
6
7 8
9
Asfar P, Schortgen F, Boisramé-Helms J, et al. Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial. Lancet Respir Med 2017; published online Feb 14. http://dx.doi.org/10.1016/S2213-2600(17)30046-2. Luypaert P, Vincent JL, Domb M, et al. Fluid resuscitation with hypertonic saline in endotoxic shock. Circ Shock 1986; 20: 311–20. Vincent JL, De Backer D. Saline versus balanced solutions: are clinical trials comparing two crystalloid solutions really needed? Crit Care 2016; 20: 250. Su F, Xie K, He X, et al. The harmful effects of hypertonic sodium lactate administration in hyperdynamic septic shock. Shock 2016; 46: 663–71. Vincent JL, Taccone FS, He X. Harmful effects of hyperoxia in post-cardiac arrest, sepsis, traumatic brain injury or stroke: the importance of individualized oxygen therapy in critically ill patients. Can Respir J 2017; 2017: 2834956. Nash G, Blennerhassett JB, Pontoppidan H. Pulmonary lesions associated with oxygen therapy and artifical ventilation. N Engl J Med 1967; 276: 368–74. Orbegozo Cortes D, Puflea F, et al. Normobaric hyperoxia alters the microcirculation in healthy volunteers. Microvasc Res 2015; 98: 23–28. Damiani E, Adrario E, Girardis M, et al. Arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis. Crit Care 2014; 18: 711. Girardis M, Busani S, Damiani E, et al. Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit: the oxygen-ICU randomized clinical trial. JAMA 2016; 316: 1583–89.
www.thelancet.com/respiratory Published online February 14, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30047-4