- Email: [email protected]
Reply to Letter: ‘Can therapeutic hypothermia of 33 °C itself not modulate inflammatory response after out-of-hospital cardiac arrest?’
Resuscitation 92 (2015) e3–e4
Contents lists available at ScienceDirect
Resuscitation journal homepage: www.elsevier.com/locate/resuscitation
Letter to the Editor Reply to Letter: ‘Can therapeutic hypothermia of 33 ◦ C itself not modulate inflammatory response after out-of-hospital cardiac arrest?’ Sir, We appreciate the interest by Aibiki and colleagues regarding our paper investigating the possible effect of targeted temperature management (TTM) at 33 ◦ C or 36 ◦ C on the inflammatory response after out-of-hospital cardiac arrest (OHCA).1 We are thankful for the opportunity to reply to the letter and hopefully also correct some misinterpretations. The current paper did not report data on the prognostic value of inflammatory markers as stated by Aibiki et al., however we have addressed this issue in a recent paper.2 In brief, the current paper was a sub-study including consecutive patients from the largest site in the TTM-trial. Thus, all patients were treated according to our department protocols with similar choice of sedative agents, pre-specified hemodynamic goals and standardized use of vasopressors and/or inotropic as described in the paper.3 This is important to acknowledge when interpreting the results as the present single-center population may be more homogeneous regarding post-cardiac arrest management compared to the general TTM trial population. According to the TTM protocol all patients were treated according to local protocol with no differences between temperature allocation groups. The TTM, re-warming and prognostication were protocolized. Although we have reported a significant impact of target temperature at 33 ◦ C and 36 ◦ C on hemodynamic parameters such as cardiac output and systemic vascular resistance,3 this did not translate into significant differences in levels of inflammatory cytokines between the two temperature groups. We also reported that severity of post-cardiac arrest syndrome (PCAS) was correlated with level of pro-inflammatory cytokines also including a significant association of interleukin-6 and severity of PCAS. We were not able to detect any temperature effect of a 24 h temperature protocol on severity of PCAS, nor on IL-6 levels. Whether longer duration of TTM may be beneficial in terms of improved outcome is uncertain and the use of prolonged cooling beyond 24 h is currently not supported by high quality trials nor by guidelines.4 The findings by Aibiki et al. regarding a possible temperature effect on IL-6 levels in patients with traumatic brain injury (TBI) are interesting.5 However, their sample size was relatively small, the design was non-randomized and interpretations should thus be made with caution. The role of TTM in patients with TBI has not been investigated in large well-designed clinical trials; however a recent meta-analysis could not confirm any beneficial effects of TTM on mortality or neurological outcome.6 It may also be noted that the possible effect seen in TBI patients or patients with accidental hypothermia cannot easily be extrapolated to patients with PCAS as the responsible mechanism for and duration of ischemia may be very different. http://dx.doi.org/10.1016/j.resuscitation.2015.05.003 0300-9572/© 2015 Elsevier Ireland Ltd. All rights reserved.
In conclusion, our current knowledge within the area of possible temperature modulation of the inflammatory response after OHCA suggests that in the temperature range of 33–36 ◦ C the effect may at best be modest. Whether earlier initiation of TTM or longer duration of TTM are associated with alterations in level of inflammatory markers is unknown. However, when it comes to improving outcome there is no current evidence supporting beneficial effects of pre-hospital cooling or extended protocols of TTM beyond 24 h.
Conflict of interest statement None.
References 1. Bro-Jeppesen J, Kjaergaard J, Wanscher M, et al. The inflammatory response after out-of-hospital cardiac arrest is not modified by targeted temperature management at 33 ◦ C or 36 ◦ C. Resuscitation 2014;85:1480–7. 2. Bro-Jeppesen J, Kjaergaard J, Wanscher M, et al. Systemic inflammatory response and potential prognostic implications after out-of-hospital cardiac arrest: a substudy of the target temperature management trial. Crit Care Med 2015;43:1223–32. 3. Bro-Jeppesen J, Hassager C, Wanscher M, et al. Targeted temperature management at 33 ◦ C versus 36 ◦ C and impact on systemic vascular resistance and myocardial function after out-of-hospital cardiac arrest: a sub-study of the target temperature management trial. Circ Cardiovasc Interv 2014;7:663–72. 4. Deakin CD, Nolan JP, Soar J, et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 4. Adult advanced life support. Resuscitation 2010;81:1305–52. 5. Aibiki M, Maekawa S, Ogura S, Kinoshita Y, Kawai N, Yokono S. Effect of moderate hypothermia on systemic and internal jugular plasma IL-6 levels after traumatic brain injury in humans. J Neurotrauma 1999;16:225–32. 6. Georgiou AP, Manara AR. Role of therapeutic hypothermia in improving outcome after traumatic brain injury: a systematic review. Br J Anaesth 2013;110:357–67.
John Bro-Jeppesen ∗ Jesper Kjaergaard Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Denmark Michael Wanscher Department of Cardiothoracic Anaesthesia, The Heart Centre, Rigshospitalet, University of Copenhagen, Denmark Niklas Nielsen Department of Anesthesia and Intensive Care, Lund University, Helsingborg Hospital, Helsingborg, Sweden Hans Friberg Department of Anesthesia and Intensive Care, Lund University, Skåne University Hospital, Lund, Sweden Mette Bjerre The Medical Research Laboratory, Department of Clinical Medicine, Aarhus University, Denmark
e4
Letter to the Editor / Resuscitation 92 (2015) e3–e4
Christian Hassager Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Denmark
University Hospital Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail address: [email protected] (J. Bro-Jeppesen)
∗ Corresponding author at: Department of Cardiology, The Heart Centre, Copenhagen
4 May 2015
Contents lists available at ScienceDirect
Resuscitation journal homepage: www.elsevier.com/locate/resuscitation
Letter to the Editor Reply to Letter: ‘Can therapeutic hypothermia of 33 ◦ C itself not modulate inflammatory response after out-of-hospital cardiac arrest?’ Sir, We appreciate the interest by Aibiki and colleagues regarding our paper investigating the possible effect of targeted temperature management (TTM) at 33 ◦ C or 36 ◦ C on the inflammatory response after out-of-hospital cardiac arrest (OHCA).1 We are thankful for the opportunity to reply to the letter and hopefully also correct some misinterpretations. The current paper did not report data on the prognostic value of inflammatory markers as stated by Aibiki et al., however we have addressed this issue in a recent paper.2 In brief, the current paper was a sub-study including consecutive patients from the largest site in the TTM-trial. Thus, all patients were treated according to our department protocols with similar choice of sedative agents, pre-specified hemodynamic goals and standardized use of vasopressors and/or inotropic as described in the paper.3 This is important to acknowledge when interpreting the results as the present single-center population may be more homogeneous regarding post-cardiac arrest management compared to the general TTM trial population. According to the TTM protocol all patients were treated according to local protocol with no differences between temperature allocation groups. The TTM, re-warming and prognostication were protocolized. Although we have reported a significant impact of target temperature at 33 ◦ C and 36 ◦ C on hemodynamic parameters such as cardiac output and systemic vascular resistance,3 this did not translate into significant differences in levels of inflammatory cytokines between the two temperature groups. We also reported that severity of post-cardiac arrest syndrome (PCAS) was correlated with level of pro-inflammatory cytokines also including a significant association of interleukin-6 and severity of PCAS. We were not able to detect any temperature effect of a 24 h temperature protocol on severity of PCAS, nor on IL-6 levels. Whether longer duration of TTM may be beneficial in terms of improved outcome is uncertain and the use of prolonged cooling beyond 24 h is currently not supported by high quality trials nor by guidelines.4 The findings by Aibiki et al. regarding a possible temperature effect on IL-6 levels in patients with traumatic brain injury (TBI) are interesting.5 However, their sample size was relatively small, the design was non-randomized and interpretations should thus be made with caution. The role of TTM in patients with TBI has not been investigated in large well-designed clinical trials; however a recent meta-analysis could not confirm any beneficial effects of TTM on mortality or neurological outcome.6 It may also be noted that the possible effect seen in TBI patients or patients with accidental hypothermia cannot easily be extrapolated to patients with PCAS as the responsible mechanism for and duration of ischemia may be very different. http://dx.doi.org/10.1016/j.resuscitation.2015.05.003 0300-9572/© 2015 Elsevier Ireland Ltd. All rights reserved.
In conclusion, our current knowledge within the area of possible temperature modulation of the inflammatory response after OHCA suggests that in the temperature range of 33–36 ◦ C the effect may at best be modest. Whether earlier initiation of TTM or longer duration of TTM are associated with alterations in level of inflammatory markers is unknown. However, when it comes to improving outcome there is no current evidence supporting beneficial effects of pre-hospital cooling or extended protocols of TTM beyond 24 h.
Conflict of interest statement None.
References 1. Bro-Jeppesen J, Kjaergaard J, Wanscher M, et al. The inflammatory response after out-of-hospital cardiac arrest is not modified by targeted temperature management at 33 ◦ C or 36 ◦ C. Resuscitation 2014;85:1480–7. 2. Bro-Jeppesen J, Kjaergaard J, Wanscher M, et al. Systemic inflammatory response and potential prognostic implications after out-of-hospital cardiac arrest: a substudy of the target temperature management trial. Crit Care Med 2015;43:1223–32. 3. Bro-Jeppesen J, Hassager C, Wanscher M, et al. Targeted temperature management at 33 ◦ C versus 36 ◦ C and impact on systemic vascular resistance and myocardial function after out-of-hospital cardiac arrest: a sub-study of the target temperature management trial. Circ Cardiovasc Interv 2014;7:663–72. 4. Deakin CD, Nolan JP, Soar J, et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 4. Adult advanced life support. Resuscitation 2010;81:1305–52. 5. Aibiki M, Maekawa S, Ogura S, Kinoshita Y, Kawai N, Yokono S. Effect of moderate hypothermia on systemic and internal jugular plasma IL-6 levels after traumatic brain injury in humans. J Neurotrauma 1999;16:225–32. 6. Georgiou AP, Manara AR. Role of therapeutic hypothermia in improving outcome after traumatic brain injury: a systematic review. Br J Anaesth 2013;110:357–67.
John Bro-Jeppesen ∗ Jesper Kjaergaard Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Denmark Michael Wanscher Department of Cardiothoracic Anaesthesia, The Heart Centre, Rigshospitalet, University of Copenhagen, Denmark Niklas Nielsen Department of Anesthesia and Intensive Care, Lund University, Helsingborg Hospital, Helsingborg, Sweden Hans Friberg Department of Anesthesia and Intensive Care, Lund University, Skåne University Hospital, Lund, Sweden Mette Bjerre The Medical Research Laboratory, Department of Clinical Medicine, Aarhus University, Denmark
e4
Letter to the Editor / Resuscitation 92 (2015) e3–e4
Christian Hassager Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Denmark
University Hospital Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail address: [email protected] (J. Bro-Jeppesen)
∗ Corresponding author at: Department of Cardiology, The Heart Centre, Copenhagen
4 May 2015