Physiological interventions in cardiac arrest: passing the pilot phase

Intensive Care Medicine, Dec 2018

Niklas Nielsen, Alain Cariou, Christian Hassager

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Physiological interventions in cardiac arrest: passing the pilot phase

Intensive Care Medicine pp 1–3 | Cite as Physiological interventions in cardiac arrest: passing the pilot phase AuthorsAuthors and affiliations Niklas NielsenAlain CariouChristian Hassager Open Access Editorial First Online: 10 December 2018 1 Shares 288 Downloads The damaging processes leading to a poor outcome after cardiac arrest start at the onset of ischemia and continues during the reperfusion phase. Intensive care treatment in resuscitated patients relies on organ support restoring normal physiology with attention to brain protection. Drugs have not proven beneficial in randomised trials. To date induced hypothermia, or targeted temperature management (TTM), is the only specific intervention implemented in clinical practice. Nevertheless, its final role and configuration are still under debate and are currently being investigated. Easily modifiable clinical physiological and metabolic parameters could be ideal treatment candidates to possibly attenuate brain damage. In a pilot trial, strict glucose control was tested versus standard care with no significant difference in the outcome, and the concept has not been further challenged [1]. In recent years three possible physiological candidates have been investigated in several observational cohorts indicating better outcome with higher mean arterial pressure (MAP), moderately elevated partial pressure of oxygen (PaO2) and mildly elevated partial pressure of carbon dioxide (PaCO2) [2, 3, 4]. Other reports have indicated worse outcome with increasing doses of vasopressors, hypotension, hypocapnia, severe hypercapnia and severe hyperoxia [5, 6, 7]. Also, completely neutral reports have been published [8]. A pilot trial of mild hypercapnia versus normocapnia (standard care) suggested better outcome and lower levels of biomarkers of brain damage with mildly elevated carbon dioxide levels [9]. The well-known limitations of observational inferences have called for randomised trials. In this issue of Intensive Care Medicine, a Finnish/Danish group has, in two publications, reported an elegant 2 × 3 factorial multicentre pilot trial in 123 comatose cardiac arrest patients—the COMACARE trial. The patients were randomised to one of eight groups with either high or low normal MAP, high or low normal PaCO2 and normal or moderately elevated PaO2. Being a pilot trial feasibility was an important outcome and the authors demonstrated clear and distinct separation between the groups for MAP, PaO2 and PaCO2. The primary effect outcome was serum level of neuron specific enolase (NSE) at 48 h after the arrest, a time point where this prognostic biomarker of brain damage separates good from poor outcome. Interestingly there were no detectable differences in 48-h NSE for any of the three interventions, and secondary outcomes such as NSE over time, the biomarker S100B, cardiac troponin, global electroencephalographic pattern, survival and functional outcome at 6 months were also neutral. The overall outcome was strikingly good for a cardiac arrest cohort and it is worth emphasizing that the patient group was positively selected in terms of age, initial rhythm and a presumed cardiac cause of the arrest. The single statistically significant finding was higher cerebral oxygen saturation, up to approximately 10% absolute difference, with higher levels for high normal PaO2 and PaCO2 and with the figures suggesting more difference for PaCO2 than PaO2. Vasodilation due to elevated PaCO2 and increased cerebral blood flow (CBF) may thus be more powerful in terms of increasing oxygen delivery with the chosen intervention targets. In this trial CBF was, however, not measured and its correlation to regional cerebral saturation is not fully elucidated. Since oxygen content typically increases marginally between 10 and 25 kPa and the content of oxygen in blood is more influential on CBF than PaO2, it is reasonable not to expect a tremendous effect on CBF or cerebral saturation with the oxygen intervention in this trial [10]. Importantly the changes in cerebral saturation were not translated to any other outcome differences. Higher MAP did not influence cerebral saturation (or any other outcome), perhaps because of the adequate cerebral perfusion pressure obtained already at the low normal level of MAP. In contrast, a recent randomised trial, presented at American Heart Association 2018, did report that a higher target MAP (85–100 mmHg) improved cerebral perfusion and oxygenation [11]. Signs of anoxic brain damage on magnetic resonance imaging and functional outcome were, however, neutral. NSE has been used as a surrogate outcome in several cardiac arrest trials as it is a good discriminator of poor and good outcome [12]. A considerable drawback with NSE is the sensitivity to haemolysis due to leakage of NSE from red blood cells [13]. The authors report that seven analyses were excluded as a result of haemolysis and only one sample at the 48-h primary outcome. However, haemolysis was only analysed in one of the participating countries and the cut-off level for exclusion due to haemolysis was very high (> 500 mg free haemoglobin/L). A value of 300 mg/L is already considered visible haemolysis, and NSE levels are heavily influenced at much lower degrees of haemolysis and dependent on the relationship between NSE and haemolysis [14]. With lower serum levels of NSE little haemolysis can be tolerated, while with higher levels more haemolysis is tolerated. With the modest median levels of NSE reported in this trial a much lower cut-off level for exclusion due to haemolysis should have been employed, and significant haemolysis was therefore likely higher than reported. The influence on the trial results are difficult to appreciate. Reassuringly, NSE findings were in line with all other outcomes and the levels were not used for prognostication but for comparison between groups. For future trials, other biomarkers such as protein-tau or neurofilament, not or less sensitive to haemolysis, may prove better surrogate outcomes [15]. A common critique of clinical trials includes questions of timing and dose of the intervention. In this trial the interventions were introduced immediately after emergency randomisation with deferred consent. In light of other trials in which manipulating oxygen levels in the ambulance was associated with problems with hypoxia [16], that airways are often not secured prior to hospital admission, and that the initial phase after return of spontaneous circulation seldom allows for fine tuning of haemodynamics, the 3-h median delay seems difficult to shorten and likely will reflect clinical practice if any of the interventions are implemented. The authors designed the trial elegantly, randomising to extremes of normal levels for two of the three target interventions, and thus most of the patients were treated within standard care. Although statistically different, the interventions may thus have been separated too little to produce a meaningful clinical difference. Also, the trial was indeed a pilot with a very optimistic predefined power calculation (50% reduction of NSE) and a larger trial may very well have indicated more robust signals. The main and important conclusion of the COMACARE trial must be that the targets can be readily obtained for all three interventions and that adequately powered trials may follow, in which carbon dioxide manipulation possibly has the most intriguing physiological rationale. References 1. Oksanen T, Skrifvars MB, Varpula T, Kuitunen A, Pettila V, Nurmi J, Castren M (2007) Strict versus moderate glucose control after resuscitation from ventricular fibrillation. Intensive Care Med 33:2093–2100CrossRefPubMedGoogle Scholar 2. Elmer J, Scutella M, Pullalarevu R, Wang B, Vaghasia N, Trzeciak S, Rosario-Rivera BL, Guyette FX, Rittenberger JC, Dezfulian C, Pittsburgh Post-Cardiac Arrest Service (PCAS) (2015) The association between hyperoxia and patient outcomes after cardiac arrest: analysis of a high-resolution database. Intensive Care Med 41:49–57CrossRefGoogle Scholar 3. Roberts BW, Kilgannon JH, Hunter BR, Puskarich MA, Shea L, Donnino M, Jones C, Fuller BM, Kline JA, Jones AE, Shapiro NI, Abella BS, Trzeciak S (2018) Association between elevated mean arterial blood pressure and neurologic outcome after resuscitation from cardiac arrest: results from a multicenter prospective cohort study. Crit Care Med. 4. Vaahersalo J, Bendel S, Reinikainen M, Kurola J, Tiainen M, Raj R, Pettila V, Varpula T, Skrifvars MB, FINNRESUSCI Study Group (2014) Arterial blood gas tensions after resuscitation from out-of-hospital cardiac arrest: associations with long-term neurologic outcome. Crit Care Med 42:1463–1470CrossRefPubMedGoogle Scholar 5. Bro-Jeppesen J, Annborn M, Hassager C, Wise MP, Pelosi P, Nielsen N, Erlinge D, Wanscher M, Friberg H, Kjaergaard J, TTM Investigators (2015) Hemodynamics and vasopressor support during targeted temperature management at 33 degrees C versus 36 degrees C after out-of-hospital cardiac arrest: a post hoc study of the target temperature management trial. Crit Care Med 43:318–327CrossRefPubMedGoogle Scholar 6. McKenzie N, Williams TA, Tohira H, Ho KM, Finn J (2017) A systematic review and meta-analysis of the association between arterial carbon dioxide tension and outcomes after cardiac arrest. Resuscitation 111:116–126CrossRefPubMedGoogle Scholar 7. Roberts BW, Kilgannon JH, Hunter BR, Puskarich MA, Pierce L, Donnino M, Leary M, Kline JA, Jones AE, Shapiro NI, Abella BS, Trzeciak S (2018) Association between early hyperoxia exposure after resuscitation from cardiac arrest and neurological disability: prospective multicenter protocol-directed cohort study. Circulation 137:2114–2124CrossRefPubMedGoogle Scholar 8. Ebner F, Harmon MBA, Aneman A, Cronberg T, Friberg H, Hassager C, Juffermans N, Kjaergaard J, Kuiper M, Mattsson N, Pelosi P, Ullen S, Unden J, Wise MP, Nielsen N (2018) Carbon dioxide dynamics in relation to neurological outcome in resuscitated out-of-hospital cardiac arrest patients: an exploratory target temperature management trial substudy. Crit Care 22:196CrossRefPubMedPubMedCentralGoogle Scholar 9. Eastwood GM, Schneider AG, Suzuki S, Peck L, Young H, Tanaka A, Martensson J, Warrillow S, McGuinness S, Parke R, Gilder E, McCarthy L, Galt P, Taori G, Eliott S, Lamac T, Bailey M, Harley N, Barge D, Hodgson CL, Morganti-Kossmann MC, Pebay A, Conquest A, Archer JS, Bernard S, Stub D, Hart GK, Bellomo R (2016) Targeted therapeutic mild hypercapnia after cardiac arrest: a phase II multi-centre randomised controlled trial (the CCC trial). Resuscitation 104:83–90CrossRefPubMedGoogle Scholar 10. Johnston AJ, Steiner LA, Gupta AK, Menon DK (2003) Cerebral oxygen vasoreactivity and cerebral tissue oxygen reactivity. Br J Anaesth 90:774–786CrossRefPubMedGoogle Scholar 11. Ameloot K, De Deyne C, Ferdinande B, Dupont M, Palmers PJ, Petit T, Eertmans W, Moonen C, Belmans A, Lemmens R, Dens J, Janssens S (2017) Mean arterial pressure of 65 mm Hg versus 85–100 mm Hg in comatose survivors after cardiac arrest: rationale and study design of the Neuroprotect post-cardiac arrest trial. Am Heart J 191:91–98CrossRefPubMedGoogle Scholar 12. Stammet P, Collignon O, Hassager C, Wise MP, Hovdenes J, Aneman A, Horn J, Devaux Y, Erlinge D, Kjaergaard J, Gasche Y, Wanscher M, Cronberg T, Friberg H, Wetterslev J, Pellis T, Kuiper M, Gilson G, Nielsen N, TTM-Trial Investigators (2015) Neuron-specific enolase as a predictor of death or poor neurological outcome after out-of-hospital cardiac arrest and targeted temperature management at 33 degrees C and 36 degrees C. J Am Coll Cardiol 65:2104–2114CrossRefPubMedGoogle Scholar 13. Ramont L, Thoannes H, Volondat A, Chastang F, Millet MC, Maquart FX (2005) Effects of hemolysis and storage condition on neuron-specific enolase (NSE) in cerebrospinal fluid and serum: implications in clinical practice. Clin Chem Lab Med 43:1215–1217CrossRefPubMedGoogle Scholar 14. Petinos P, Gay S, Badrick T (2015) Variation in laboratory reporting of haemolysis—a need for harmonisation. Clin Biochem Rev 36:133–137PubMedPubMedCentralGoogle Scholar 15. Moseby-Knappe M, Mattsson N, Nielsen N, Zetterberg H, Blennow K, Dankiewicz J, Dragancea I, Friberg H, Lilja G, Insel PS, Rylander C, Westhall E, Kjaergaard J, Wise MP, Hassager C, Kuiper MA, Stammet P, Wanscher MCJ, Wetterslev J, Erlinge D, Horn J, Pellis T, Cronberg T (2018) Serum neurofilament light chain for prognosis of outcome after cardiac arrest. JAMA Neurol. 16. Young P, Bailey M, Bellomo R, Bernard S, Dicker B, Freebairn R, Henderson S, Mackle D, McArthur C, McGuinness S, Smith T, Swain A, Weatherall M, Beasley R (2014) HyperOxic Therapy OR NormOxic Therapy after out-of-hospital cardiac arrest (HOT OR NOT): a randomised controlled feasibility trial. Resuscitation 85:1686–1691CrossRefPubMedGoogle Scholar Copyright information © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (, which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Authors and Affiliations Niklas Nielsen1Email authorAlain Cariou23Christian Hassager41.Department of Clinical Sciences Lund, Anesthesia and Intensive CareLund University, Helsingborg HospitalLundSweden2.Medical Intensive Care UnitAP-HP, Cochin HospitalParisFrance3.Paris Descartes UniversityParisFrance4.Departments of Cardiology and Clinical MedicineRigshospitalet, University of CopenhagenCopenhagenDenmark

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Niklas Nielsen, Alain Cariou, Christian Hassager. Physiological interventions in cardiac arrest: passing the pilot phase, Intensive Care Medicine, 2018, 1-3, DOI: 10.1007/s00134-018-5492-2