Avoid common mistakes on your manuscript.
Most resuscitated cardiac arrest patients die in the intensive care unit due to hypoxic brain injury [1]. The pathophysiological process includes disturbed cerebral autoregulation resulting in inadequate blood flow and ischemia, and means to alleviate this could include giving more oxygen or increasing the mean arterial pressure (MAP) with vasopressors [2]. Supplemental oxygen may result in hyperoxia, which has been associated with harmful reactive oxygen species [3]. Whether limiting oxygen use could decrease brain injury after cardiac arrest has received much attention. Pilot studies have shown through biomarker levels that targeting a higher MAP than the recommended 65 mmHg may alleviate brain and cardiac injury [4]. The lack of large randomized controlled trials on MAP and oxygen has been a major shortcoming [5]. In 2022, the BOX and EXACT trials (Table 1) were published, with major ramifications for post-cardiac arrest management [6,7,8,9].
The BOX trial
The BOX (Blood pressure and OXygenation targets after out-of-hospital cardiac arrest) randomized clinical trial with a 2-by-2 factorial design was performed at two Danish tertiary hospitals from 2017 to 2022 [7,8,9]. Two blood pressure targets, two oxygenation targets, and the duration of fever management with a device were compared in 789 comatose out-of-hospital cardiac arrest patients. In the sample, the bystander cardiopulmonary resuscitation (CPR) rates and proportion of patients with ventricular fibrillation were close to 90%. Using a novel method, the blood pressure intervention was double-blinded: the blood pressure monitoring devices were randomly offset to display either \(-\) 10% or \(+\) 10% of the target (70 mmHg), resulting in targeting a MAP of 63 or 77 mmHg. The oxygenation intervention was an open-label randomization to either a restrictive oxygen target of a PaO2 of 9–10 kPa (68–75 mmHg) or a liberal oxygen target of a PaO2 of 13–14 kPa (98–105 mmHg). All patients were also randomized 1:1 to active fever control with an automated feedback temperature control device for 36 or 72 h following the return of spontaneous circulation (ROSC). The primary outcome of all interventions was a composite of death from any cause or hospital discharge with a cerebral performance category of 3 or 4 within 90 days. The blood pressure, oxygen, and fever management interventions resulted in similar primary and all secondary outcomes (primary endpoint for blood pressure targets: HR [95% CI] 1.08 [0.84–1.37], p = 0.56); primary endpoint for oxygen targets HR [95% CI] 0.95 [0.75–1.21], p = 0.69). In conclusion, the current evidence suggests that a MAP target of 63 mmHg during intensive care unit (ICU) care in patients admitted comatose after being resuscitated from an out-of-hospital cardiac arrest (OHCA) seems safe. Restrictive or liberal oxygen targets within the recommended range appear equally safe [5].
The EXACT trial
The EXACT (rEduction of oXygen After Cardiac arrest Trial), a parallel-group randomized clinical trial that was performed in 2 emergency medical services and 15 hospitals in Australia [6]. It compared two oxygenation targets in the prehospital and emergency department (ED) phases of CPR post-resuscitation care of 425 comatose presumed cardiac OHCA patients with bystander rates of 80% and of whom 60% had a shockable initial rhythm. Patients were randomized to receive oxygen titration to achieve an oxygen saturation (SpO2) of either 90–94% (n = 216) or 98–100% (n = 212) until ICU arrival. The study was not blinded. Importantly both the interventional targets were outside what the current recommendations are (i.e., SpO2 of 94–98%) [5]. For most patients in the 98–100% group, oxygen titration did not occur until the ED due to the use of air-mix ventilators in the prehospital setting. Randomization in both groups occurred at a median of 36 min post-ROSC, and oxygen levels on arrival at hospital and at the ICU suggest that titration occurred in both groups with reasonable separation in SpO2 and PaO2.
The trial was stopped early due to the coronavirus disease 2019 (COVID-19) pandemic, the primary outcome showed lower survival to discharge in the group randomized to the lower oxygen target (38.3% vs 47.9%; difference − 9.6% [95% CI − 18.9 to − 0.2%]; unadjusted OR 0.68 [95% CI 0.46–1.00]; p = 0.047). The lower oxygen target group was twice as likely to experience a hypoxic episode during the intervention phase (31.3% vs 16.1%, p < 0.001). The study also showed a not statistically significant difference in mortality of those patients with a re-arrest without ROSC (10.8% vs 6.4%, p = 0.25). This trial indicates that early oxygen titration to an SpO2 of less than 95% is unsafe in the early post-resuscitation phase of OHCA in comatose patients, particularly in the complex prehospital setting, where healthcare providers are restricted in equipment for administration and monitoring.
Take-home message
The current evidence does not suggest any clear benefit from deviating from current guidelines (i.e., targeting a paO2 of 10–13 kPa and a MAP of higher than 65–70 mmHg) [10]. A meta-analysis comparing studies investigating a standard (60–70 mmHg) and higher MAP target (80–100 mmHg) after cardiac arrest is in progress, Preliminary analysis suggests that the current evidence from conducted trials can rule out a relative beneficial effect of more than 25% with a higher compared to a lower MAP target (Skrifvars, personal communication). Given outcome rate from ICU care of OHCA patients is generally in line in the range of 50–60%, this would translate into an absolute difference of 12–18% (equalling a number needed to treat of between 5 and 9). This may be an unrealistic effect size compared to other post-cardiac arrest interventions, such as targeted temperature management [11]. Observational data do suggest that the optimal MAP target in a patient with impaired cerebral autoregulation could be as high as 85–90 mmHg [12]. Larger trials on this topic are needed, also including patients with a non-cardiac cause of the arrest. With regard to oxygen, the challenge may be the non-linear U-shaped association between oxygen and outcome [13]. Although there may be no beneficial effect of targeting oxygen levels beyond normoxia, the EXACT trial clearly shows that more liberal oxygen use may be the best approach if reliable oxygen monitoring is difficult, such as during transport or care in the ED [14].
References
Perkins GD, Callaway CW, Haywood K, Neumar RW, Lilja G, Rowland MJ, Sawyer KN, Skrifvars MB, Nolan JP (2021) Brain injury after cardiac arrest. Lancet 398:1269–1278
Rosenthal G, Hemphill JC 3rd, Sorani M, Martin C, Morabito D, Obrist WD, Manley GT (2008) Brain tissue oxygen tension is more indicative of oxygen diffusion than oxygen delivery and metabolism in patients with traumatic brain injury. Crit Care Med 36:1917–1924
Singer M, Young PJ, Laffey JG, Asfar P, Taccone FS, Skrifvars MB, Meyhoff CS, Radermacher P (2021) Dangers of hyperoxia. Crit Care 25:440
Wihersaari L, Ashton NJ, Reinikainen M, Jakkula P, Pettila V, Hastbacka J, Tiainen M, Loisa P, Friberg H, Cronberg T, Blennow K, Zetterberg H, Skrifvars MB, Comacare Study G (2021) Neurofilament light as an outcome predictor after cardiac arrest: a post hoc analysis of the COMACARE trial. Intensive Care Med 47:39–48
Nolan JP, Sandroni C, Bottiger BW, Cariou A, Cronberg T, Friberg H, Genbrugge C, Haywood K, Lilja G, Moulaert VRM, Nikolaou N, Olasveengen TM, Skrifvars MB, Taccone F, Soar J (2021) European Resuscitation Council and European Society of Intensive Care Medicine guidelines 2021: post-resuscitation care. Intensive Care Med 47:369–421
Bernard SA, Bray JE, Smith K, Stephenson M, Finn J, Grantham H, Hein C, Masters S, Stub D, Perkins GD, Dodge N, Martin C, Hopkins S, Cameron P, Investigators E (2022) Effect of lower vs higher oxygen saturation targets on survival to hospital discharge among patients resuscitated after out-of-hospital cardiac arrest: the EXACT randomized clinical trial. JAMA 328:1818–1826
Hassager C, Schmidt H, Moller JE, Grand J, Molstrom S, Beske RP, Boesgaard S, Borregaard B, Bekker-Jensen D, Dahl JS, Frydland MS, Hofsten DE, Isse YA, Josiassen J, Lind Jorgensen VR, Kondziella D, Lindholm MG, Moser E, Nyholm BC, Obling LER, Sarkisian L, Sondergaard FT, Thomsen JH, Thune JJ, Veno S, Wiberg SC, Winther-Jensen M, Meyer MAS, Kjaergaard J (2022) Duration of device-based fever prevention after cardiac arrest. NEJM 388:888–897. https://doi.org/10.1056/NEJMoa2212528
Kjaergaard J, Moller JE, Schmidt H, Grand J, Molstrom S, Borregaard B, Veno S, Sarkisian L, Mamaev D, Jensen LO, Nyholm B, Hofsten DE, Josiassen J, Thomsen JH, Thune JJ, Obling LER, Lindholm MG, Frydland M, Meyer MAS, Winther-Jensen M, Beske RP, Frikke-Schmidt R, Wiberg S, Boesgaard S, Madsen SA, Jorgensen VL, Hassager C (2022) Blood-pressure targets in comatose survivors of cardiac arrest. N Engl J Med 387:1456–1466
Schmidt H, Kjaergaard J, Hassager C, Molstrom S, Grand J, Borregaard B, Roelsgaard Obling LE, Veno S, Sarkisian L, Mamaev D, Jensen LO, Nyholm B, Hofsten DE, Josiassen J, Thomsen JH, Thune JJ, Lindholm MG, Stengaard Meyer MA, Winther-Jensen M, Sorensen M, Frydland M, Beske RP, Frikke-Schmidt R, Wiberg S, Boesgaard S, Lind Jorgensen V, Moller JE (2022) Oxygen targets in comatose survivors of cardiac arrest. N Engl J Med 387:1467–1476
Young PJ, Bailey M, Bellomo R, Bernard S, Bray J, Jakkula P, Kuisma M, Mackle D, Martin D, Nolan JP, Panwar R, Reinikainen M, Skrifvars MB, Thomas M (2020) Conservative or liberal oxygen therapy in adults after cardiac arrest: an individual-level patient data meta-analysis of randomised controlled trials. Resuscitation 157:15–22
Aneman A, Frost S, Parr M, Skrifvars MB (2022) Target temperature management following cardiac arrest: a systematic review and Bayesian meta-analysis. Crit Care 26:58
Ameloot K, Genbrugge C, Meex I, Jans F, Boer W, Vander Laenen M, Ferdinande B, Mullens W, Dupont M, Dens J, DeDeyne C (2015) An observational near-infrared spectroscopy study on cerebral autoregulation in post-cardiac arrest patients: time to drop “one-size-fits-all” hemodynamic targets? Resuscitation 90:121–126
McKenzie N, Finn J, Dobb G, Bailey P, Arendts G, Celenza A, Fatovich D, Jenkins I, Ball S, Bray J, Ho KM (2021) Non-linear association between arterial oxygen tension and survival after out-of-hospital cardiac arrest: a multicentre observational study. Resuscitation 158:130–138
Elmer J, Guyette FX (2022) Early oxygen supplementation after resuscitation from cardiac arrest. JAMA 328:1811–1813
Funding
Open Access funding provided by University of Helsinki including Helsinki University Central Hospital.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
MBS reports soeakers fees from BARD Medical (Ireland). All other authors report no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
About this article
Cite this article
Skrifvars, M.B., Bray, J. & Hassager, C. Optimal oxygen and mean arterial blood pressure targets after cardiac arrest. Intensive Care Med 49, 569–571 (2023). https://doi.org/10.1007/s00134-023-07018-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00134-023-07018-7