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Rapid induction of mild therapeutic hypothermia by extracorporeal veno-venous blood cooling in humans
Resuscitation 84 (2013) 1051–1055
Contents lists available at ScienceDirect
Resuscitation journal homepage: www.elsevier.com/locate/resuscitation
Clinical paper
Rapid induction of mild therapeutic hypothermia by extracorporeal veno-venous blood cooling in humans夽 Christoph Testori a , Michael Holzer a , Fritz Sterz a , Peter Stratil a , Zeno Hartner d , Francesco Moscato b,c , Heinrich Schima b,c,d , Wilhelm Behringer a,∗ a
Department of Emergency Medicine, Medical University of Vienna, Austria Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Austria c Ludwig-Boltzmann-Cluster for Cardiovascular Research, Vienna, Austria d Department of Cardiac Surgery, Medical University of Vienna, Austria b
a r t i c l e
i n f o
Article history: Received 9 January 2013 Received in revised form 20 February 2013 Accepted 6 March 2013 Keywords: Cardiac arrest Induced hypothermia Cardiopulmonary resuscitation (CPR) Heart arrest Resuscitation Return of spontaneous circulation
a b s t r a c t Aim: Mild therapeutic hypothermia is beneficial in patients successfully resuscitated from non-traumatic out-of-hospital cardiac arrest. The effect of fast induction of hypothermia in these patients remains to be investigated. The aim of this study was to evaluate the efficacy and safety of extracorporeal veno-venous blood cooling in humans successfully resuscitated from cardiac arrest. Methods: We performed an interventional study in patients after successful resuscitation from cardiac arrest admitted to the emergency department of a tertiary care centre. The extracorporeal veno-venous circulation was established via a percutaneously introduced double lumen dialysis catheter in the femoral vein, and a tubing circuit and heat exchanger. A paediatric cardiopulmonary bypass roller pump and a heater-cooler system were used to circulate the blood. Main outcome measures were feasibility, efficacy, and safety. Results: We included eight consecutive cardiac arrest patients with a median oesophageal temperature of 35.9 ◦ C (interquartile range 34.9–37.0). A median time of 8 min elapsed (interquartile range 5–15 min) to reach oesophageal temperatures below 34 ◦ C, which reflects a cooling rate of 12.2 ◦ C/h (interquartile range 10.8 ◦ C/h to 14.1 ◦ C/h). The predefined target temperature of 33.0 ◦ C was reached after 14 min (interquartile range 8–21 min). No device or method related adverse events were reported. Conclusion: Extracorporeal veno-venous blood cooling is a feasible, safe, and very fast approach for induction of mild therapeutic hypothermia in patients successfully resuscitated from cardiac arrest. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Background Mild therapeutic hypothermia is a recommended therapy in patients successfully resuscitated from non-traumatic out-ofhospital cardiac arrest.1 Animal data indicate that early and fast cooling after restoration of spontaneous circulation is essential.2–5 Prospective randomized6,7 and retrospective non-randomized clinical trials8–13 show conflicting results concerning the benefit of early and fast cooling. One reason for the conflicting results in these studies might be the lack of a fast and reliable cooling method.14 For a future definite trial to investigate the need for
夽 A Spanish translated version of the summary of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2013.03.013. ∗ Corresponding author at: Universitätsklinik für Notfallmedizin, Medizinische Universität Wien, Allgemeines Krankenhaus der Stadt Wien, Währinger Gürtel 1820/6D, 1090 Wien, Austria. E-mail address: [email protected] (W. Behringer). 0300-9572/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.resuscitation.2013.03.013
early and fast cooling, it would be essential to have a very rapid and reliable cooling device. With surface cooling of the trunk, skin temperature has to be reduced substantially first, in order to achieve a mild hypothermic core temperature. Current surface cooling devices are limited to cooling rates of 3.3 ◦ C/h maximum.15 Cardiopulmonary bypass, once vessel access is achieved, is an effective tool to rapidly decrease whole-body temperature,16 but its clinical use is limited to certain hospitals. Novel endovascular cooling devices, using cold fluid pumped through a catheter inserted into the superior or inferior vena cava, are already used clinically17,18 reaching cooling rates up to 4.8 ◦ C/h.19 Two animal studies using veno-venous blood-shunt-cooling described a theoretical cooling rate of 40.4 ◦ C/h in small dogs (approximately 25 kg), and 8.2 ◦ C/h in human sized pigs (approximately 70 kg).20,21 The aim of this study was to evaluate the efficacy and safety of this promising cooling technique with extracoroporeal veno-venous blood cooling in humans successfully resuscitated from cardiac arrest.
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2. Methods This was a prospective interventional study in a cohort of eight consecutive patients admitted to the emergency department of a tertiary care centre. The study was conducted according to the principles of the declaration of Helsinki (Version 4, 2004) and was approved by the local ethical review board. The requirement of informed consent at the time of inclusion into the study was waived in accordance with the guidelines of good clinical practice and Austrian laws and regulations. In case of survival and favourable outcome the participant was asked to provide written informed consent. If the patient did not regain consciousness, the legal representative had to consent. 2.1. Study setting and population Consecutive patients with an age of 18–75 years successfully resuscitated from witnessed or non-witnessed out-of-hospital cardiac arrest (irrespective of the first monitored cardiac rhythm) and remaining comatose (Glasgow coma scale lower than 8) after restoration of spontaneous circulation were included in the study. Exclusion criteria were cardiac arrest due to trauma or intracranial bleeding, terminal illness before cardiac arrest, a known preexisting coagulopathy, and pregnancy. 2.2. Study objectives and endpoints The primary objective of this explorative study was to evaluate the efficacy and safety of extracorporeal veno-venous blood cooling in patients successfully resuscitated from cardiac arrest. Target temperature was 33 ◦ C oesophageal temperature. Secondary endpoints were survival up to six month and best neurologic outcome within six month. Neurologic outcome was evaluated in terms of Pittsburgh cerebral performance categories (Category 1: conscious and normal, without disability; Category 2: conscious with moderate disability; Category 3: conscious with severe disability; Category 4: comatose or vegetative state; Category 5: death). 2.3. The veno-venous cooling system The extracorporeal veno-venous circulation was established via a percutaneously introduced double lumen dialysis catheter (Double Lumen EXTRA FLOW short term, 14 french, length 20 cm, Joline GmbH, Germany) in the femoral vein, and a tubing circuit (Safeline Treatment, Maquet Cardiopulmonary AG, Germany) and heat exchanger (Plegiox, Maquet Cardiopulmonary AG, Germany). A paediatric cardiopulmonary bypass roller pump and a heatercooler system (CAPS, Computer Aided Perfusion System, Stöckert Instruments, Germany) were used to circulate the blood with a flow of 200 ml/min. The priming volume of the total circuit was 100 ml. The tubing and heat exchanger were heparin-coated. System pressure was measured prior and after the heat exchanger. Alarm systems were installed to stop the pump and occlude the circuit if the pressure is outside the predefined limits, or if the ultrasonic bubble detector indicated the presence of air. 2.4. Temperature control and monitoring Temperature on admission was measured with an infrared tympanic thermometer (Ototemp LighTouch® , Exergen Corporation, MA, USA). Further temperature measurements were made with two oesophageal temperature probes (Mon-a-therm® General Purpose, 12 french, Mallinckrodt Medical Inc., St. Louis, MO, USA) as the main temperature site. One probe was connected to the monitor and the other one to the cooling device. Blood temperature was measured at the outflow connector of the heat exchanger. A
urine bladder temperature probe (Foley catheter, Medtronic Electronics Inc. Parker, CO, USA) was used for additional temperature monitoring. An arterial catheter was placed in the radial or femoral artery for continuous invasive blood pressure monitoring and blood sampling. ECG, peripheral oxygen saturation, end-tidal CO2 , and respiratory rate as standardized intensive care monitoring was established. With initiation of the veno-venous circulation, blood was cooled with the heat exchanger water temperature set to 10 ◦ C until an oesophageal temperature of 33.5 ◦ C was reached. Once the oesophageal temperature of 33.5 ◦ C was reached, the threestate temperature remote control algorithm (heat-off-cool) of the heater-cooler system was activated to keep the oesophageal temperature automatically at 33 ◦ C for 6 h. The time of device application was limited, because the heat exchanger was only certified for a period of 6 h. After this time period cooling was switched to a standard surface cooling method (Arctic Sun Temperature Management System, Bard Medical, CO, USA) for maintaining hypothermia up to a cumulative time of 24 h and for controlled rewarming with a rate of 0.4 ◦ C/h. 2.5. Treatment We used midazolam with a dose of 0.125 mg/kg/h and fentanyl 0.002 mg/kg/h, titrated as clinically indicated to achieve an adequate level of sedation and analgesia. To avoid shivering, a continuous infusion of rocuronium was given until oesophageal temperature reached 35 ◦ C during rewarming. Arterial saturation of was kept >95% e.g. paO2 100–150 mmHg; ventilation was set to maintain normocapnia with a partial pressure of CO2 between 35 and 45 mmHg. Arterial pH was kept between 7.3 and 7.5. Electrolytes were substituted if necessary and kept in normal ranges. Mean arterial blood pressure was kept >60 mmHg. Pressure drops were treated primarily with crystalloid fluids or hydroxyl ethyl starch. If sufficient blood pressure control was not achieved with fluids alone, vasopressors (i.e. norepinephrine) were used. Serum blood glucose was kept between 110 and 180 mg/dl. Laboratory data analyses were performed as clinically indicated, but at least on admission as well as 6, 12, 24 and 48 h after return of spontaneous circulation. Arterial blood-gas analyses were performed at least every 4 h during the first 24 h. 2.6. Safety variables and measurements All adverse events (serious and non-serious) for all enrolled patients were collected from the time of enrolment until discharge from hospital. Serious adverse events included, but were are not limited to: re-arrest due to arrhythmias or heart failure, major bleeding, (i.e. intracranial haemorrhage, spontaneous bleeding, bleeding at any instrumented site, retroperitoneal bleeding, or bleeding associated with a drop in haemoglobin of >5.0 g/dl), emergency or urgent cardiac surgery and stroke. A non-serious adverse event was accounted in case of minor bleeding (gross haematuria or hematemesis, observed blood loss associated with a drop in haemoglobin of 3–5 g/dl, or no evidence of bleeding but a drop in haemoglobin of 3–5 g/l), signs of haemolysis (2× rise in free haemoglobin and lactate dehydrogenase), and pneumonia (signs of infiltration in chest X-ray with elevation of C-reactive protein, fibrinogen, or white blood cells). 2.7. Data analysis Continuous variables are given as mean ± standard deviation, or as median and interquartile range, if not normally distributed. Nominal data are given as counts and percentage of total number.
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Cooling rates were calculated by the time needed from baseline temperature to an oesophageal temperature of 33.9 ◦ C. In this feasibility trial no formal hypothesis testing or group comparison were performed. To compare changes in vital signs and laboratory values from the time of cooling initiation, the paired t-test or Wicoxon sigend-rank test were used. A two-sided p-value <0.05 was considered for statistical significance. SPSS software (version 20.0 for Mac, IBM Inc., IL, USA) and Microsoft Excel (version 12.0 for Mac, Microsoft Corp., WA, USA) were used for statistical analysis. 3. Results The 8 participants (2 female) had a median age of 61 years (interquartile range 54–71 years), and a median body mass index of 23.3 kg/m2 (interquartile range 20.8–26.7 kg/m2 ). Cardiac arrest was witnessed in seven cases (88%). Initial rhythm was ventricular fibrillation in three, asystole in four, and pulseless electric activity in one case. The median epinephrine dose during resuscitation was two milligrams (interquartile range 1–6 mg). Detailed demographic and baseline data are listed in Table 1. One patient was excluded from maintenance cooling after initial cooling to 33 ◦ C due to occlusion of the double lumen catheter after initial cooling.
Table 1 Baseline characteristics. n=8 Age Median years (interquartile range) Female sex No./total no. (%) Height Median centimetre (interquartile range) Weight Median kilogram (interquartile range) Body mass index Kilogram per square metre (interquartile range) Presumed cardiac cause No./total no. (%) Witnessed cardiac arrest No./total no. (%) Bystander CPRa No./total no. (%) Initial shockable rhythmb No./total no. (%) Total dose of epinephrine Milligram (interquartile range) Interval between collapse and start of life support Minutes (interquartile range) Interval between start of life support until ROSCc Minutes (interquartile range) a b c
3.1. Cooling Median baseline temperature on admission was 36.3 ◦ C (interquartile range 35.2–37.0 ◦ C). A median time of 118 min (interquartile range 90–146 min) elapsed from restoration of spontaneous circulation to cooling initiation. At the time of cooling start median oesophageal temperature was 35.9 ◦ C (interquartile range 34.9–37.0 ◦ C). After initiation of the extracorporeal circuit, it took a median time of 8 min (interquartile range 5–15 min) to reach mild therapeutic hypothermia of <34 ◦ C, which reflects a cooling rate of 12.2 ◦ C/h (interquartile range 10.8–14.1 ◦ C/h). It took a median time of 6 min (interquartile range 3–7 min) from 33.9 ◦ C to reach the predefined target temperature of 33.0 ◦ C. During cooling induction median blood temperature at the outflow connector of heat exchanger was 10.0 ◦ C (interquartile range 9.2–10.8 ◦ C). During maintainance, median temperature was 33.0 ◦ C (interquartile range 32.9–33.1 ◦ C). In Fig. 1 the individual oesophageal temperature curves for all eight patients are shown.
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61 (54–71) 2/8 (25%) 175 (174–180) 83 (75–96) 23.3 (20.8–26.7) 2/8 (25%) 7/8 (88%) 3/8 (38%) 2/8 (25%) 2 (1–6) 1 (0–8) 25 (21–38)
Cardio pulmonary resuscitation. Ventricular fibrillation or pulseless ventricular tachycardia. Return of spontaneous circulation.
3.2. Vital signs and safety After 30 min of cooling we found no uncontrollable drop in mean arterial pressure from baseline. Heart rate returned from tachycardia to a physiological level after initial cooling (Fig. 2). There were no laboratory or clinical sings of haemolysis during the cooling with the veno-venous cooling device (Fig. 2). In one patient, two units of blood had to be transfused due to thoracic haemorrhage, which was caused by rib fracture. In this case, bleeding became relevant after completion of the 6-h time-period of maintenance cooling with the investigational device. Therefore further cooling attempts were stopped after a cumulative cooling time of 8 h. In one patient veno-venous cooling has to be stopped after an occlusion of the double lumen catheter due to kinking of the catheter. No device related or not device related serious or non-serious adverse events were observed.
Fig. 1. Individual temperature curves for all eight patients.
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Fig. 2. Boxplot of mean arterial pressure and heart rate at baseline and 30 min after cooling initiation (upper figure); haemoglobin, free haemoglobin, and lactate dehydrogenase levels at baseline and after 8 h of cooling (lower figure).
3.3. Outcomes Four of the eight included patients (50%) survived up to sixmonth follow-up. A good neurologic outcome defined as a cerebral performance category of 1 or 2 was seen in three of eight patients (38%). All four non-survivors died due to cerebral cause and a subsequent withdrawal of intensive care. 4. Discussion Our study showed that extracorporeal veno-venous blood cooling is a very fast and safe method for induction of mild therapeutic hypothermia after cardiac arrest. Apart of one non-device and non-method related major bleeding, no adverse reactions were observed. We found a median time of 8 min after initiation of cooling to reach therapeutic ranges of mild hypothermia <34 ◦ C, and 14 min to reach 33.0 ◦ C, translating into median cooling rate of 12.2 ◦ C/h. Extracorporeal Veno-venous blood cooling is currently the most rapid cooling approach tested in humans after cardiac arrest so far. Clinical data concerning the benefit of early and fast cooling after successful resuscitation show conflicting results.6–13 Two randomized trials investigated the benefit of early and fast cooling after resuscitation on neurologic outcome by comparing start of cooling out of hospital versus in hospital; the study population of one study consisted of patients with shockable rhythm,6 whereas the
study population of the other study consisted of patients with nonshockable rhythm.7 Both studies could not show a benefit of out of hospital cooling on neurologic outcome. The results of the two studies are limited by the cooling methods used to induce and maintain mild hypothermia. Only few patients achieved the target temperature of 33 ◦ C, and only approx. 50% of the patients were kept in the therapeutic range below 34 ◦ C.14 Future studies with reliable and fast cooling methods are needed to investigate the true value of early and fast cooling. Surface cooling devices are limited to cooling rates of up to 3.3 ◦ C/h.15 Even if combined with the rapid infusion of cold saline cooling rates remain relatively low.23,24 Currently available endovascular cooling devices are limited to cooling rates up to 4.8 ◦ C/h.19 Veno-venous cooling with a cooling rate of more than 10 ◦ C/h could be the cooling method of choice to investigate the benefit of fast cooling in patients resuscitated from cardiac arrest. Provided early and fast cooling proves to be beneficial, then it would make most sense to start veno-venous cooling already in the prehospital setting, best combinded with cold saline22 and/or cooling pads.15 In 2005 a French study group showed improved outcomes in patients after cardiac arrest using isovolumic high-volume hemofiltration.25 Veno-venous cooling could be easily combined with a standard haemofilter system for further evaluation of this promising approach, serving as a two-in-one device. As an adjunctive to primary coronary intervention, mild therapeutic hypothermia might be a promising therapeutic option in patients with acute ST-segment elevation myocardial infarction. Animal data26–29 and subgroup analysis of human data18 show consistently that mild hypothermia has to be achieved before reperfusion, and that the protective effect of hypothermia is completely lost if onset of cooling is delayed into reperfusion. A recent randomized study in myocardial infarction patients confirmed that achieving a core temperature below 35 ◦ C prior to reperfusion reduced infarct size.30 Provided veno-venous cooling is tolerated in awake patients, this might offer a new approach to achieve target temperatures without a significant delay of door-to-balloon time. Our study is limited by the sample size of eight consecutive patients. However, we are rather confident about the efficacy of the cooling method due to the small variation in cooling rates between the individual patients. Concerning the safety measures, a study group of eight patients is subjected to a considerable type II error; considering that veno-venous blood pumping is used in daily dialysis routine we would not expect any adverse effects on haemolysis due to the extracorporeal cooling method. As we had to limit maintenance cooling to 6 h, we have no data about the ability for controlled rewarming with this cooling method. Finally, we did not investigate the impact of ultra-fast cooling on neurologic outcome. As the current device was investigational, bulky and heavy, the industry is encouraged to provide a small and easy to use venovenous cooling device with a small pump and small but efficient heat exchanger for further prospective randomized trials investigating the effect of early and fast cooling on neurologic outcome in patients resuscitated from cardiac arrest.
5. Conclusion Extracorporeal veno-venous blood cooling demonstrated to be a fast and safe method for induction of mild therapeutic hypothermia in patients after cardiac arrest. Further investigation is needed to determine the effect of early and fast cooling on neurologic outcome in patients resuscitated from cardiac arrest.
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Conflict of interest statement There have been no study sponsors, who could have had a role in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript, and in the decision to submit the manuscript for publication. Role of the funding source This study was supported by the funds of the Oesterreichische Nationalbank (Anniversary Fund, project number 11110) and by the Medical Scientific Fund of the Mayor of the City of Vienna. Acknowledgements We are indebted to the nurses and staff for their enthusiastic cooperation and to the patients who participated in this study for their trust and support. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.resuscitation. 2013.03.013. References 1. Nolan JP, Soar J, Zideman DA, et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 1. Executive summary. Resuscitation 2010;81:1219–76. 2. Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H. Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med 1993;21:1348–58. 3. Colbourne F, Corbett D. Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection. J Neurosci 1995;15:7250–60. 4. Carroll M, Beek O. Protection against hippocampal CA1 cell loss by post-ischemic hypothermia is dependent on delay of initiation and duration. Metab Brain Dis 1992;7:45–50. 5. Takata K, Takeda Y, Sato T, Nakatsuka H, Yokoyama M, Morita K. Effects of hypothermia for a short period on histologic outcome and extracellular glutamate concentration during and after cardiac arrest in rats. Crit Care Med 2005;33:1340–5. 6. Bernard SA, Smith K, Cameron P, et al. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial. Circulation 2010;122:737–42. 7. Bernard SA, Smith K, Cameron P, et al. Induction of prehospital therapeutic hypothermia after resuscitation from nonventricular fibrillation cardiac arrest. Crit Care Med 2012;40:747–53. 8. Wolff B, Machill K, Schumacher D, Schulzki I, Werner D. Early achievement of mild therapeutic hypothermia and the neurologic outcome after cardiac arrest. Int J Cardiol 2009;133:223–8. 9. Nielsen N, Hovdenes J, Nilsson F, et al. Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand 2009;53:926–34.
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10. Haugk M, Testori C, Sterz F, et al. Relationship between time to target temperature and outcome in patients treated with therapeutic hypothermia after cardiac arrest. Crit Care 2011;15:R101. 11. Sendelbach S, Hearst MO, Johnson PJ, Unger BT, Mooney MR. Effects of variation in temperature management on cerebral performance category scores in patients who received therapeutic hypothermia post cardiac arrest. Resuscitation 2012;83:829–34. 12. Italian Cooling Experience (ICE) Study Group. Early- versus late-initiation of therapeutic hypothermia after cardiac arrest: preliminary observations from the experience of 17 Italian intensive care units. Resuscitation 2012;83: 823–8. 13. Benz-Woerner J, Delodder F, Benz R, et al. Body temperature regulation and outcome after cardiac arrest and therapeutic hypothermia. Resuscitation 2012;83:338–42. 14. Behringer W, Arrich J. The Gretchen question: when to cool patients after cardiac arrest? Crit Care Med 2012;40:984–5. 15. Uray T, Malzer R, Vienna Hypothermia After Cardiac Arrest (HACA) study group. Out-of-hospital surface cooling to induce mild hypothermia in human cardiac arrest: a feasibility trial. Resuscitation 2008;77:331–8. 16. Nagao K, Hayashi N, Kanmatsuse K, et al. Cardiopulmonary cerebral resuscitation using emergency cardiopulmonary bypass, coronary reperfusion therapy and mild hypothermia in patients with cardiac arrest outside the hospital. J Am Coll Cardiol 2000;36:776–83. 17. Keller E, Imhof H-G, Gasser S, Terzic A, Yonekawa Y. Endovascular cooling with heat exchange catheters: a new method to induce and maintain hypothermia. Intensive Care Med 2003;29:939–43. 18. Dixon SR, Whitbourn RJ, Dae MW, et al. Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction. J Am Coll Cardiol 2002;40:1928–34. 19. Yon S, Magers M, Dobak J, Klos B. A novel system for mild hypothermia. Biomed Instrum Technol 2004;38:241–6. 20. Behringer W, Safar P, Wu X, et al. Veno-venous extracorporeal blood shunt cooling to induce mild hypothermia in dog experiments and review of cooling methods. Resuscitation 2002;54:89–98. 21. Janata A, Holzer M, Sterz F, et al. Extracorporeal veno-venous cooling versus endovascular cooling in pigs. Prelim Results Circ 2003;108:A1042–3 (Abstract). 22. Kim F, Olsufka M, Longstreth WT, et al. Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline. Circulation 2007;115: 3064–70. 23. Granja C, Ferreira P, Ribeiro O, Pina J. Improved survival with therapeutic hypothermia after cardiac arrest with cold saline and surfacing cooling: keep it simple. Emerg Med Int 2011:395813. 24. Kory P, Weiner J, Mathew JP, et al. A rapid, safe, and low-cost technique for the induction of mild therapeutic hypothermia in post-cardiac arrest patients. Resuscitation 2011;82:15–20. 25. Laurent I, Adrie C, Vinsonneau C, et al. High-volume hemofiltration after out-ofhospital cardiac arrest: a randomized study. J Am Coll Cardiol 2005;46:432–7. 26. Miki T, Liu GS, Cohen MV, Downey JM. Mild hypothermia reduces infarct size in the beating rabbit heart: a practical intervention for acute myocardial infarction? Basic Res Cardiol 1998;93:372–83. 27. Schwartz DS, Bremner RM, Baker CJ, et al. Regional topical hypothermia of the beating heart: preservation of function and tissue. Ann Thorac Surg 2001;72:804–9. 28. Hamamoto H, Sakamoto H, Leshnower BG, et al. Very mild hypothermia during ischemia and reperfusion improves postinfarction ventricular remodeling. Ann Thorac Surg 2009;87:172–7. 29. Wakida Y, Haendchen RV, Kobayashi S, Nordlander R, Corday E. Percutaneous cooling of ischemic myocardium by hypothermic retroperfusion of autologous arterial blood: effects on regional myocardial temperature distribution and infarct size. J Am Coll Cardiol 1991;18:293–300. 30. Götberg M, Olivecrona GK, Koul S, et al. A pilot study of rapid cooling by cold saline and endovascular cooling before reperfusion in patients with ST-elevation myocardial infarction. Circ Cardiovasc Interv 2010;3:400–7.
Contents lists available at ScienceDirect
Resuscitation journal homepage: www.elsevier.com/locate/resuscitation
Clinical paper
Rapid induction of mild therapeutic hypothermia by extracorporeal veno-venous blood cooling in humans夽 Christoph Testori a , Michael Holzer a , Fritz Sterz a , Peter Stratil a , Zeno Hartner d , Francesco Moscato b,c , Heinrich Schima b,c,d , Wilhelm Behringer a,∗ a
Department of Emergency Medicine, Medical University of Vienna, Austria Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Austria c Ludwig-Boltzmann-Cluster for Cardiovascular Research, Vienna, Austria d Department of Cardiac Surgery, Medical University of Vienna, Austria b
a r t i c l e
i n f o
Article history: Received 9 January 2013 Received in revised form 20 February 2013 Accepted 6 March 2013 Keywords: Cardiac arrest Induced hypothermia Cardiopulmonary resuscitation (CPR) Heart arrest Resuscitation Return of spontaneous circulation
a b s t r a c t Aim: Mild therapeutic hypothermia is beneficial in patients successfully resuscitated from non-traumatic out-of-hospital cardiac arrest. The effect of fast induction of hypothermia in these patients remains to be investigated. The aim of this study was to evaluate the efficacy and safety of extracorporeal veno-venous blood cooling in humans successfully resuscitated from cardiac arrest. Methods: We performed an interventional study in patients after successful resuscitation from cardiac arrest admitted to the emergency department of a tertiary care centre. The extracorporeal veno-venous circulation was established via a percutaneously introduced double lumen dialysis catheter in the femoral vein, and a tubing circuit and heat exchanger. A paediatric cardiopulmonary bypass roller pump and a heater-cooler system were used to circulate the blood. Main outcome measures were feasibility, efficacy, and safety. Results: We included eight consecutive cardiac arrest patients with a median oesophageal temperature of 35.9 ◦ C (interquartile range 34.9–37.0). A median time of 8 min elapsed (interquartile range 5–15 min) to reach oesophageal temperatures below 34 ◦ C, which reflects a cooling rate of 12.2 ◦ C/h (interquartile range 10.8 ◦ C/h to 14.1 ◦ C/h). The predefined target temperature of 33.0 ◦ C was reached after 14 min (interquartile range 8–21 min). No device or method related adverse events were reported. Conclusion: Extracorporeal veno-venous blood cooling is a feasible, safe, and very fast approach for induction of mild therapeutic hypothermia in patients successfully resuscitated from cardiac arrest. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Background Mild therapeutic hypothermia is a recommended therapy in patients successfully resuscitated from non-traumatic out-ofhospital cardiac arrest.1 Animal data indicate that early and fast cooling after restoration of spontaneous circulation is essential.2–5 Prospective randomized6,7 and retrospective non-randomized clinical trials8–13 show conflicting results concerning the benefit of early and fast cooling. One reason for the conflicting results in these studies might be the lack of a fast and reliable cooling method.14 For a future definite trial to investigate the need for
夽 A Spanish translated version of the summary of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2013.03.013. ∗ Corresponding author at: Universitätsklinik für Notfallmedizin, Medizinische Universität Wien, Allgemeines Krankenhaus der Stadt Wien, Währinger Gürtel 1820/6D, 1090 Wien, Austria. E-mail address: [email protected] (W. Behringer). 0300-9572/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.resuscitation.2013.03.013
early and fast cooling, it would be essential to have a very rapid and reliable cooling device. With surface cooling of the trunk, skin temperature has to be reduced substantially first, in order to achieve a mild hypothermic core temperature. Current surface cooling devices are limited to cooling rates of 3.3 ◦ C/h maximum.15 Cardiopulmonary bypass, once vessel access is achieved, is an effective tool to rapidly decrease whole-body temperature,16 but its clinical use is limited to certain hospitals. Novel endovascular cooling devices, using cold fluid pumped through a catheter inserted into the superior or inferior vena cava, are already used clinically17,18 reaching cooling rates up to 4.8 ◦ C/h.19 Two animal studies using veno-venous blood-shunt-cooling described a theoretical cooling rate of 40.4 ◦ C/h in small dogs (approximately 25 kg), and 8.2 ◦ C/h in human sized pigs (approximately 70 kg).20,21 The aim of this study was to evaluate the efficacy and safety of this promising cooling technique with extracoroporeal veno-venous blood cooling in humans successfully resuscitated from cardiac arrest.
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2. Methods This was a prospective interventional study in a cohort of eight consecutive patients admitted to the emergency department of a tertiary care centre. The study was conducted according to the principles of the declaration of Helsinki (Version 4, 2004) and was approved by the local ethical review board. The requirement of informed consent at the time of inclusion into the study was waived in accordance with the guidelines of good clinical practice and Austrian laws and regulations. In case of survival and favourable outcome the participant was asked to provide written informed consent. If the patient did not regain consciousness, the legal representative had to consent. 2.1. Study setting and population Consecutive patients with an age of 18–75 years successfully resuscitated from witnessed or non-witnessed out-of-hospital cardiac arrest (irrespective of the first monitored cardiac rhythm) and remaining comatose (Glasgow coma scale lower than 8) after restoration of spontaneous circulation were included in the study. Exclusion criteria were cardiac arrest due to trauma or intracranial bleeding, terminal illness before cardiac arrest, a known preexisting coagulopathy, and pregnancy. 2.2. Study objectives and endpoints The primary objective of this explorative study was to evaluate the efficacy and safety of extracorporeal veno-venous blood cooling in patients successfully resuscitated from cardiac arrest. Target temperature was 33 ◦ C oesophageal temperature. Secondary endpoints were survival up to six month and best neurologic outcome within six month. Neurologic outcome was evaluated in terms of Pittsburgh cerebral performance categories (Category 1: conscious and normal, without disability; Category 2: conscious with moderate disability; Category 3: conscious with severe disability; Category 4: comatose or vegetative state; Category 5: death). 2.3. The veno-venous cooling system The extracorporeal veno-venous circulation was established via a percutaneously introduced double lumen dialysis catheter (Double Lumen EXTRA FLOW short term, 14 french, length 20 cm, Joline GmbH, Germany) in the femoral vein, and a tubing circuit (Safeline Treatment, Maquet Cardiopulmonary AG, Germany) and heat exchanger (Plegiox, Maquet Cardiopulmonary AG, Germany). A paediatric cardiopulmonary bypass roller pump and a heatercooler system (CAPS, Computer Aided Perfusion System, Stöckert Instruments, Germany) were used to circulate the blood with a flow of 200 ml/min. The priming volume of the total circuit was 100 ml. The tubing and heat exchanger were heparin-coated. System pressure was measured prior and after the heat exchanger. Alarm systems were installed to stop the pump and occlude the circuit if the pressure is outside the predefined limits, or if the ultrasonic bubble detector indicated the presence of air. 2.4. Temperature control and monitoring Temperature on admission was measured with an infrared tympanic thermometer (Ototemp LighTouch® , Exergen Corporation, MA, USA). Further temperature measurements were made with two oesophageal temperature probes (Mon-a-therm® General Purpose, 12 french, Mallinckrodt Medical Inc., St. Louis, MO, USA) as the main temperature site. One probe was connected to the monitor and the other one to the cooling device. Blood temperature was measured at the outflow connector of the heat exchanger. A
urine bladder temperature probe (Foley catheter, Medtronic Electronics Inc. Parker, CO, USA) was used for additional temperature monitoring. An arterial catheter was placed in the radial or femoral artery for continuous invasive blood pressure monitoring and blood sampling. ECG, peripheral oxygen saturation, end-tidal CO2 , and respiratory rate as standardized intensive care monitoring was established. With initiation of the veno-venous circulation, blood was cooled with the heat exchanger water temperature set to 10 ◦ C until an oesophageal temperature of 33.5 ◦ C was reached. Once the oesophageal temperature of 33.5 ◦ C was reached, the threestate temperature remote control algorithm (heat-off-cool) of the heater-cooler system was activated to keep the oesophageal temperature automatically at 33 ◦ C for 6 h. The time of device application was limited, because the heat exchanger was only certified for a period of 6 h. After this time period cooling was switched to a standard surface cooling method (Arctic Sun Temperature Management System, Bard Medical, CO, USA) for maintaining hypothermia up to a cumulative time of 24 h and for controlled rewarming with a rate of 0.4 ◦ C/h. 2.5. Treatment We used midazolam with a dose of 0.125 mg/kg/h and fentanyl 0.002 mg/kg/h, titrated as clinically indicated to achieve an adequate level of sedation and analgesia. To avoid shivering, a continuous infusion of rocuronium was given until oesophageal temperature reached 35 ◦ C during rewarming. Arterial saturation of was kept >95% e.g. paO2 100–150 mmHg; ventilation was set to maintain normocapnia with a partial pressure of CO2 between 35 and 45 mmHg. Arterial pH was kept between 7.3 and 7.5. Electrolytes were substituted if necessary and kept in normal ranges. Mean arterial blood pressure was kept >60 mmHg. Pressure drops were treated primarily with crystalloid fluids or hydroxyl ethyl starch. If sufficient blood pressure control was not achieved with fluids alone, vasopressors (i.e. norepinephrine) were used. Serum blood glucose was kept between 110 and 180 mg/dl. Laboratory data analyses were performed as clinically indicated, but at least on admission as well as 6, 12, 24 and 48 h after return of spontaneous circulation. Arterial blood-gas analyses were performed at least every 4 h during the first 24 h. 2.6. Safety variables and measurements All adverse events (serious and non-serious) for all enrolled patients were collected from the time of enrolment until discharge from hospital. Serious adverse events included, but were are not limited to: re-arrest due to arrhythmias or heart failure, major bleeding, (i.e. intracranial haemorrhage, spontaneous bleeding, bleeding at any instrumented site, retroperitoneal bleeding, or bleeding associated with a drop in haemoglobin of >5.0 g/dl), emergency or urgent cardiac surgery and stroke. A non-serious adverse event was accounted in case of minor bleeding (gross haematuria or hematemesis, observed blood loss associated with a drop in haemoglobin of 3–5 g/dl, or no evidence of bleeding but a drop in haemoglobin of 3–5 g/l), signs of haemolysis (2× rise in free haemoglobin and lactate dehydrogenase), and pneumonia (signs of infiltration in chest X-ray with elevation of C-reactive protein, fibrinogen, or white blood cells). 2.7. Data analysis Continuous variables are given as mean ± standard deviation, or as median and interquartile range, if not normally distributed. Nominal data are given as counts and percentage of total number.
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Cooling rates were calculated by the time needed from baseline temperature to an oesophageal temperature of 33.9 ◦ C. In this feasibility trial no formal hypothesis testing or group comparison were performed. To compare changes in vital signs and laboratory values from the time of cooling initiation, the paired t-test or Wicoxon sigend-rank test were used. A two-sided p-value <0.05 was considered for statistical significance. SPSS software (version 20.0 for Mac, IBM Inc., IL, USA) and Microsoft Excel (version 12.0 for Mac, Microsoft Corp., WA, USA) were used for statistical analysis. 3. Results The 8 participants (2 female) had a median age of 61 years (interquartile range 54–71 years), and a median body mass index of 23.3 kg/m2 (interquartile range 20.8–26.7 kg/m2 ). Cardiac arrest was witnessed in seven cases (88%). Initial rhythm was ventricular fibrillation in three, asystole in four, and pulseless electric activity in one case. The median epinephrine dose during resuscitation was two milligrams (interquartile range 1–6 mg). Detailed demographic and baseline data are listed in Table 1. One patient was excluded from maintenance cooling after initial cooling to 33 ◦ C due to occlusion of the double lumen catheter after initial cooling.
Table 1 Baseline characteristics. n=8 Age Median years (interquartile range) Female sex No./total no. (%) Height Median centimetre (interquartile range) Weight Median kilogram (interquartile range) Body mass index Kilogram per square metre (interquartile range) Presumed cardiac cause No./total no. (%) Witnessed cardiac arrest No./total no. (%) Bystander CPRa No./total no. (%) Initial shockable rhythmb No./total no. (%) Total dose of epinephrine Milligram (interquartile range) Interval between collapse and start of life support Minutes (interquartile range) Interval between start of life support until ROSCc Minutes (interquartile range) a b c
3.1. Cooling Median baseline temperature on admission was 36.3 ◦ C (interquartile range 35.2–37.0 ◦ C). A median time of 118 min (interquartile range 90–146 min) elapsed from restoration of spontaneous circulation to cooling initiation. At the time of cooling start median oesophageal temperature was 35.9 ◦ C (interquartile range 34.9–37.0 ◦ C). After initiation of the extracorporeal circuit, it took a median time of 8 min (interquartile range 5–15 min) to reach mild therapeutic hypothermia of <34 ◦ C, which reflects a cooling rate of 12.2 ◦ C/h (interquartile range 10.8–14.1 ◦ C/h). It took a median time of 6 min (interquartile range 3–7 min) from 33.9 ◦ C to reach the predefined target temperature of 33.0 ◦ C. During cooling induction median blood temperature at the outflow connector of heat exchanger was 10.0 ◦ C (interquartile range 9.2–10.8 ◦ C). During maintainance, median temperature was 33.0 ◦ C (interquartile range 32.9–33.1 ◦ C). In Fig. 1 the individual oesophageal temperature curves for all eight patients are shown.
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61 (54–71) 2/8 (25%) 175 (174–180) 83 (75–96) 23.3 (20.8–26.7) 2/8 (25%) 7/8 (88%) 3/8 (38%) 2/8 (25%) 2 (1–6) 1 (0–8) 25 (21–38)
Cardio pulmonary resuscitation. Ventricular fibrillation or pulseless ventricular tachycardia. Return of spontaneous circulation.
3.2. Vital signs and safety After 30 min of cooling we found no uncontrollable drop in mean arterial pressure from baseline. Heart rate returned from tachycardia to a physiological level after initial cooling (Fig. 2). There were no laboratory or clinical sings of haemolysis during the cooling with the veno-venous cooling device (Fig. 2). In one patient, two units of blood had to be transfused due to thoracic haemorrhage, which was caused by rib fracture. In this case, bleeding became relevant after completion of the 6-h time-period of maintenance cooling with the investigational device. Therefore further cooling attempts were stopped after a cumulative cooling time of 8 h. In one patient veno-venous cooling has to be stopped after an occlusion of the double lumen catheter due to kinking of the catheter. No device related or not device related serious or non-serious adverse events were observed.
Fig. 1. Individual temperature curves for all eight patients.
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Fig. 2. Boxplot of mean arterial pressure and heart rate at baseline and 30 min after cooling initiation (upper figure); haemoglobin, free haemoglobin, and lactate dehydrogenase levels at baseline and after 8 h of cooling (lower figure).
3.3. Outcomes Four of the eight included patients (50%) survived up to sixmonth follow-up. A good neurologic outcome defined as a cerebral performance category of 1 or 2 was seen in three of eight patients (38%). All four non-survivors died due to cerebral cause and a subsequent withdrawal of intensive care. 4. Discussion Our study showed that extracorporeal veno-venous blood cooling is a very fast and safe method for induction of mild therapeutic hypothermia after cardiac arrest. Apart of one non-device and non-method related major bleeding, no adverse reactions were observed. We found a median time of 8 min after initiation of cooling to reach therapeutic ranges of mild hypothermia <34 ◦ C, and 14 min to reach 33.0 ◦ C, translating into median cooling rate of 12.2 ◦ C/h. Extracorporeal Veno-venous blood cooling is currently the most rapid cooling approach tested in humans after cardiac arrest so far. Clinical data concerning the benefit of early and fast cooling after successful resuscitation show conflicting results.6–13 Two randomized trials investigated the benefit of early and fast cooling after resuscitation on neurologic outcome by comparing start of cooling out of hospital versus in hospital; the study population of one study consisted of patients with shockable rhythm,6 whereas the
study population of the other study consisted of patients with nonshockable rhythm.7 Both studies could not show a benefit of out of hospital cooling on neurologic outcome. The results of the two studies are limited by the cooling methods used to induce and maintain mild hypothermia. Only few patients achieved the target temperature of 33 ◦ C, and only approx. 50% of the patients were kept in the therapeutic range below 34 ◦ C.14 Future studies with reliable and fast cooling methods are needed to investigate the true value of early and fast cooling. Surface cooling devices are limited to cooling rates of up to 3.3 ◦ C/h.15 Even if combined with the rapid infusion of cold saline cooling rates remain relatively low.23,24 Currently available endovascular cooling devices are limited to cooling rates up to 4.8 ◦ C/h.19 Veno-venous cooling with a cooling rate of more than 10 ◦ C/h could be the cooling method of choice to investigate the benefit of fast cooling in patients resuscitated from cardiac arrest. Provided early and fast cooling proves to be beneficial, then it would make most sense to start veno-venous cooling already in the prehospital setting, best combinded with cold saline22 and/or cooling pads.15 In 2005 a French study group showed improved outcomes in patients after cardiac arrest using isovolumic high-volume hemofiltration.25 Veno-venous cooling could be easily combined with a standard haemofilter system for further evaluation of this promising approach, serving as a two-in-one device. As an adjunctive to primary coronary intervention, mild therapeutic hypothermia might be a promising therapeutic option in patients with acute ST-segment elevation myocardial infarction. Animal data26–29 and subgroup analysis of human data18 show consistently that mild hypothermia has to be achieved before reperfusion, and that the protective effect of hypothermia is completely lost if onset of cooling is delayed into reperfusion. A recent randomized study in myocardial infarction patients confirmed that achieving a core temperature below 35 ◦ C prior to reperfusion reduced infarct size.30 Provided veno-venous cooling is tolerated in awake patients, this might offer a new approach to achieve target temperatures without a significant delay of door-to-balloon time. Our study is limited by the sample size of eight consecutive patients. However, we are rather confident about the efficacy of the cooling method due to the small variation in cooling rates between the individual patients. Concerning the safety measures, a study group of eight patients is subjected to a considerable type II error; considering that veno-venous blood pumping is used in daily dialysis routine we would not expect any adverse effects on haemolysis due to the extracorporeal cooling method. As we had to limit maintenance cooling to 6 h, we have no data about the ability for controlled rewarming with this cooling method. Finally, we did not investigate the impact of ultra-fast cooling on neurologic outcome. As the current device was investigational, bulky and heavy, the industry is encouraged to provide a small and easy to use venovenous cooling device with a small pump and small but efficient heat exchanger for further prospective randomized trials investigating the effect of early and fast cooling on neurologic outcome in patients resuscitated from cardiac arrest.
5. Conclusion Extracorporeal veno-venous blood cooling demonstrated to be a fast and safe method for induction of mild therapeutic hypothermia in patients after cardiac arrest. Further investigation is needed to determine the effect of early and fast cooling on neurologic outcome in patients resuscitated from cardiac arrest.
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Conflict of interest statement There have been no study sponsors, who could have had a role in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript, and in the decision to submit the manuscript for publication. Role of the funding source This study was supported by the funds of the Oesterreichische Nationalbank (Anniversary Fund, project number 11110) and by the Medical Scientific Fund of the Mayor of the City of Vienna. Acknowledgements We are indebted to the nurses and staff for their enthusiastic cooperation and to the patients who participated in this study for their trust and support. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.resuscitation. 2013.03.013. References 1. Nolan JP, Soar J, Zideman DA, et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 1. Executive summary. Resuscitation 2010;81:1219–76. 2. Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H. Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med 1993;21:1348–58. 3. Colbourne F, Corbett D. Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection. J Neurosci 1995;15:7250–60. 4. Carroll M, Beek O. Protection against hippocampal CA1 cell loss by post-ischemic hypothermia is dependent on delay of initiation and duration. Metab Brain Dis 1992;7:45–50. 5. Takata K, Takeda Y, Sato T, Nakatsuka H, Yokoyama M, Morita K. Effects of hypothermia for a short period on histologic outcome and extracellular glutamate concentration during and after cardiac arrest in rats. Crit Care Med 2005;33:1340–5. 6. Bernard SA, Smith K, Cameron P, et al. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial. Circulation 2010;122:737–42. 7. Bernard SA, Smith K, Cameron P, et al. Induction of prehospital therapeutic hypothermia after resuscitation from nonventricular fibrillation cardiac arrest. Crit Care Med 2012;40:747–53. 8. Wolff B, Machill K, Schumacher D, Schulzki I, Werner D. Early achievement of mild therapeutic hypothermia and the neurologic outcome after cardiac arrest. Int J Cardiol 2009;133:223–8. 9. Nielsen N, Hovdenes J, Nilsson F, et al. Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand 2009;53:926–34.
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