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The importance of surface area for the cooling efficacy of mild therapeutic hypothermia
Resuscitation 82 (2011) 74–78
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Experimental paper
The importance of surface area for the cooling efficacy of mild therapeutic hypothermia夽,夽夽 Wolfgang Weihs a , Alexandra Schratter a , Fritz Sterz a,∗ , Andreas Janata a , Sandra Högler b , Michael Holzer a , Udo M. Losert c , Harald Herkner a , Wilhelm Behringer a a
Department of Emergency Medicine, Medical University of Vienna, Austria Department of Pathobiology, University of Veterinary Medicine Vienna, Austria c Core Center of Biomedical Research, Medical University of Vienna, Austria b
a r t i c l e
i n f o
Article history: Received 1 May 2010 Received in revised form 31 August 2010 Accepted 25 September 2010 Keywords: Hypothermia Methodology Post-resuscitation period Safety Temperature
a b s t r a c t Aim of the study: Mild hypothermia after cardiac arrest should be induced as soon as possible. There is a need for improved feasibility and efficacy of surface cooling in ambulances. We investigated which and how much area of the body surface should be covered to guarantee a sufficient cooling rate. Methods: Each of five adult, human-sized pigs (88–105 kg) was randomly cooled in three phases with pads that covered different areas of the body surface corresponding to humans (100% or 30% [thorax and abdomen] or 7% [neck]). The goal was to quickly lower brain temperature (Tbr) from 38 to 33 ◦ C within a maximum of 120 min. Linear regression analysis was used to test the association between cooling efficacy and surface area. Data are presented as mean ± standard deviation. Results: The 100% and 30% cooling pads decreased the pigs’ Tbr from 38 to 33 ◦ C within 33 ± 7 min (8.2 ± 1.6 ◦ C/h) and 92 ± 24 min (3.6 ± 1.1 ◦ C/h). The 7% achieved a final Tbr of 35.8 ± 0.7 ◦ C after 120 min (1.1 ± 0.4 ◦ C/h). The 30% and 7% cooling surface areas achieved 37 ± 11% and 15 ± 7% of the cooling rate compared to the 100% cooling pads. For every additional percent of surface area cooled, the cooling rate increased linearly by 0.07 ◦ C/h (95% CI 0.05–0.09, p = 0.001). No skin lesions were observed. Conclusions: The cooling pads were effective and safe for rapid induction of mild hypothermia in adult, human-sized pigs, depending on the percentage of body surface area covered. Covering only the neck, chest, and abdomen might achieve satisfactory cooling rates. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction About 375,000 patients suffer a sudden cardiac arrest with global cerebral ischemia yearly in Europe, and only a small number recover without residual neurological damage.1 Guidelines recommend the use of therapeutic mild hypothermia (32–34 ◦ C) in patients resuscitated from cardiac arrest2 to mitigate the cascades of neuronal damage resulting from the start of reperfusion.3,4 To optimise the beneficial effect, it might be necessary to induce therapeutic mild hypothermia as soon as possible after successful resuscitation from cardiac arrest.5 It can also be expected that
夽 A Spanish translated version of the abstract of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2010.09.472. 夽夽 The work was performed at the Core Center of Biomedical Research, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. ∗ Corresponding author at: Universitätsklinik für Notfallmedizin, Medizinische Universität Wien Waehringer Guertel 18-20/6D, 1090 Vienna, Austria. Tel.: +43 1 40400 1964; fax: +43 1 40400 1965. E-mail address: [email protected] (F. Sterz). 0300-9572/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.resuscitation.2010.09.472
faster cooling will further improve the cerebral outcome.6 Application of cooling systems as first aid during resuscitation seems to be favourable.7–9 Various cooling techniques for induction and maintenance of mild hypothermia were developed in recent years, including non-invasive and invasive techniques.10–14 These cooling techniques are impractical for out-of-hospital use by paramedics at the scene of cardiac arrest or in ambulances because they depend on electrically powered cooling systems. In addition, ice packs or cooling helmets only have a limited cooling capacity.15–17 Therefore, novel cooling methods should provide fast cooling rates and easy application in the out-of-hospital setting, to quickly stop or decrease the pathological effects of ischemia and reperfusion. One of the promising developments could be cooling with evaporative perfluorochemical through the nasal cavity.18,19 Recently, a newly developed cooling blanket (Emcools-pad® ; Emergency Medical Cooling Systems AG, Vienna, Austria) that does not require outside energy sources during cooling showed fast and safe induction of mild hypothermia in adult, human-sized pigs20 and in humans.21 For out-of-hospital use by paramedics, the body surface area to be covered with cooling pads might determine feasibility.
W. Weihs et al. / Resuscitation 82 (2011) 74–78
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Fig. 1. Location and percentage of cooling pads coverage of the body surface in adult, human-sized pigs (n = 5).
The aim of this study was to investigate the influence of the optimal location and percent of body surface coverage on cooling rates in adult, human-sized pigs. 2. Methods In an observational crossover study, five healthy pigs (Large White breed) weighing 88–105 kg received a sequence of three different randomised cooling treatments with pads covering 100% (standard), 30%, and 7% of body surface areas (Fig. 1). The sizes were calculated according to the corresponding human bodyweight. Repeated measures of brain temperature were recorded. The institutional review board for the care of animal subjects approved the experimental protocol. 2.1. Anaesthesia, preparation and monitoring The pigs were fasted for 12 h before the experiment but had access to water. They were premedicated with atropine sulphate (0.5 mg i.m.), ketamine hydrochloride (12 mg/kg i.m.), and acepromazine maleate (1.08 mg/kg i.m.). Anaesthesia was started with propofol (2 mg/kg as i.v. bolus) and maintained with propofol (20 mg/kg/h), piritramide (0.75 mg/kg i.v. every h), and pancuronium (0.015 mg/kg/h). The pigs were intubated and ventilated with a tidal volume of 10 ml/kg, a positive end-expiratory pressure of 5 cm H2 O, an FIO2 of 0.3, and a ratio of inspiration to expiration of 1:2. The respiratory rate was adjusted to achieve a PaCO2 between 35 and 40 mm Hg. During preparation, the animals were kept at a baseline temperature of 38.0 ± 0.2 ◦ C with infrared lamps, surface warming blankets (Warm Air® Hyperthermiasystem 134, CSZ Cincinnati Subzeroproducts, Ohio, US), or fans if needed. After preparation, heparin (80 IU/kg) was injected i.v. Norepinephrine was used to maintain arterial pressure in physiological ranges (60–80 mm Hg). Electrocardiogram (ECG) electrodes were attached to the extremities, a pulse-oximeter probe was placed on the tail, and a gastric tube was inserted. Brain temperature (Tbr) was measured with temperature probes (generic thermocouple probe, BiosysTM , Vienna, Austria) inserted via a cranial borehole 1.5 cm lateral to the sagittal suture and 1.5 cm in front of the coronal suture into the right and left frontal lobe. The lower temperature was the target temperature. The bladder temperature (Tbl) was measured with a Foley catheter (Ruesch Sensor Ch12, Ruesch, Kernen, Germany). The tympanic temperature (Tty) was measured with a contact thermistor (General Purpose Sensor 9F, Nellcor, Pleasanton, CA) in the left and right ear. Oesophagus temperature (Tes) was measured with a contact thermistor (Mon-a-therm, General Purpose Temperature Probe, Mallinckrodt Medical, Ireland) in the oesophagus on a level with the heart. The subcutaneous temperature (Tsc) was measured with a contact thermistor (General Purpose Sensor 9F, Nellcor, Pleasanton, CA) inserted 3 cm under the skin
near the rib bow on the right side. The Seldinger technique was used to insert a conventional central venous catheter into the left brachial artery to measure arterial pressure and to take blood samples. Another conventional central venous catheter was inserted via the right external jugular vein to monitor central venous pressure (CVP) and to administer medications and infusions. The data were continuously monitored and stored using a computerised data management system (VIPDAS, Biosys, Vienna, Austria). 2.2. Surface cooling (Fig. 1) The external cooling blanket, which has a self-adhesive surface, consisted of multiple cooling pads made of a thin latex layer and filled with an ice-graphite mixture (prototype provided by Emergency Medical Cooling Systems AG, Vienna, Austria). The pads were pre-cooled to −20 ◦ C and kept in a commercially available isolated cool box until the start of the experiments. One experiment consisted of three cooling phases with each phase covering different percentages of the body surface (100%, 30% and 7%). The three different body surface percentages were calculated according to the body weight (88 cm2 /kg) equivalent in humans.21 In one phase, the (100%) neck, chest, abdomen, back, and fore- and hind-legs of the pig were covered with the cooling pads. In another phase, the (30%) chest, neck, and abdomen of the pig were covered. In the third phase, only the (7%) neck of the pig was covered with the cooling pads. The three cooling phase sequences (i.e., different coverages) were chosen randomly. Active cooling was stopped in each phase when Tbr reached 33 ◦ C or after a maximum of 2 h of cooling if the Tbr did not reach 33 ◦ C. The cooling pads were exchanged during cooling, specifically when almost 80% of the cooling pads were melted. Before each new cooling phase, re-warming to baseline Tbr 38.0 ± 0.2 ◦ C was performed with infrared lamps and surface warming blankets (Warm Air® Hyperthermiasystem 134, CSZ Cincinnati Subzeroproducts, Ohio, US). The animals were euthanised after the last cooling phase, and skin samples from five different locations exposed to the cooling pads were taken for histological examination. The samples were fixed in paraformaldehyde (3%, pH 7.4), embedded in paraffin, and cut into 2-m-thick sections. The slices were stained with hematoxylin and eosin and were evaluated using light microscopy. 2.3. Statistical analysis Continuous data are presented as the mean and standard deviation (±SD) or as the median and interquartile range (IQR) when appropriate. Categorical data are presented as absolute and relative frequencies. We used a linear regression analysis to assess the association between the covered surface area and the cooling efficacy. This was a crossover experiment, with each pig providing data for each cooling area. We allowed for correlated data in the analysis by calculating robust standard errors.22 Likewise, we plotted lines for each animal in the area versus efficacy scatter
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Fig. 2. Brain temperature curves per animal for each cooling phase with 100% (black lines), 30% (grey lines), and 7% (light shaded lines) body surface coverage.
plot instead of using unconnected points, thus explicitly allowing for this non-independence. We introduced a non-linear parameter into the model to assess deviation from linearity. Given the slightly concave shape of the scatter, we used the area squared as the most likely deviation. We used a Wald test to test this non-linear parameter. We also developed a linear random coefficient model for a sensitivity analysis and yielded virtually the same results. We compared the pulmonary artery, bladder, and continuous tympanic temperatures to the brain temperature. Data were analysed using Stata 9 (Stata Corp, College Station, TX) and MS Excel 2003. A two-sided p-value less than 0.05 was considered as statistically significant.
Fig. 3. Surface area covered (100%, 30%, 7%) versus cooling rate (◦ C/h) for each experiment (n = 5); light lines represent values of individual animals, the solid line represents mean cooling rates of all animals with certain surface areas covered. With each percent increase in covered surface area, the cooling rate increased by 0.074 ◦ C/h (95% CI 0.053–0.059, p = 0.001). Table 2 Temperatures (n = 5; mean ± SD; ◦ C) related to brain temperature during the three phases of cooling. Brain
3. Results Each of five pigs weighing 99 ± 6 kg (range 88–105 kg) were cooled in three phases with different body surface areas covered (100%, 30% or 7%) in a randomised crossover design. Coverage of 100% and 30% of the body surface area decreased the Tbr from 38 to 33 ◦ C within 33.3 ± 7.4 and 91.5 ± 24.1 min, respectively (Table 1, Fig. 2). Coverage of 7% of the body surface area decreased the Tbr to 35.8 ± 0.7 ◦ C after 120 min of cooling (Table 1, Fig. 2). Mean cooling rates and standard deviations for the 100%, 30%, and 7% body surface areas were 8.2 ± 1.6, 3.6 ± 1.1 and 1.1 ± 0.4 ◦ C/h. The 30% and 7% areas achieved 37 ± 11% and 15 ± 7% of the cooling rate of the 100% area (Table 1). Each percent of added surface area increased the cooling rate by 0.07 ◦ C/h (95% CI 0.05–0.09, p = 0.001) (Fig. 3). In the three different phases (100%, 30%, and 7% surface area coverage), the cooling pads had to be changed to new deep-frozen pads 1 (0 to 2) time, 4 (3 to 4) times, and 5 (4 to 7) times, respectively. Oesophagus temperatures (Tes) were shown to reflect the brain temperature best, whereas bladder temperatures (Tbl) and tympanic temperatures (Tty) showed more delay depending on the cooling rate (Table 2). Subcutaneous temperature (Tsc) under the attached cooling pad decreased from 36.5 ± 0.7 to a minimum temperature of 22.4 ± 2.9 ◦ C in 20.2 ± 8.2 min during the 100% surface area cooling and from 36.5 ± 0.7 to a minimum of 18.8 ± 4.3 ◦ C in 75.4 ± 17.7 min during the 30% surface area cooling. During the 100% surface area cooling in 23 ± 7 min, a total of 528 ± 220 g noradrenaline (23 ± 8 g/min) was needed to main-
Bladder
Oesophagus
100% Body surface coverage 38.0 38.0 ± 0.4 37.4 37.5 37.5 ± 0.5 36.2 37.0 37.2 ± 0.6 35.5 36.5 37.0 ± 0.7 35.0 36.0 36.7 ± 0.7 34.5 35.5 36.4 ± 0.7 34.1 35.0 36.2 ± 0.7 33.7 34.5 35.7 ± 0.8 33.2 34.0 35.4 ± 0.8 32.8 33.5 34.8 ± 0.9 32.4 33.0 34.2 ± 1.0 32.1 30% Body surface coverage 38.0 38.0 ± 0.3 37.4 37.5 37.7 ± 0.3 36.6 37.0 37.4 ± 0.4 36.0 36.5 37.0 ± 0.3 35.7 36.0 36.6 ± 0.3 35.2 35.5 36.1 ± 0.4 34.7 35.0 35.7 ± 0.4 34.2 34.5 35.0 ± 0.3 33.6 34.0 34.6 ± 0.4 33.1 33.5 34.0 ± 0.5 32.7 33.0 33.5 ± 0.4 32.1 7% Body surface coverage 38.0 37.8 ± 0.3 37.4 37.5 37.5 ± 0.2 36.9 37.0 37.1 ± 0.1 36.4 36.5 36.6 ± 0.1 35.9 36.0 36.0 ± 0.3 35.5 35.5 35.8 ± 0.1 35.5
Tympanum right
Tympanum left
± ± ± ± ± ± ± ± ± ± ±
0.9 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7
38.0 37.8 37.5 37.3 37.0 36.7 36.3 35.9 35.5 34.8 34.2
± ± ± ± ± ± ± ± ± ± ±
0.5 0.4 0.3 0.3 0.3 0.3 0.2 0.3 0.4 0.5 0.4
38.1 37.8 37.6 37.3 37.0 36.7 36.4 35.9 35.5 34.8 34.2
± ± ± ± ± ± ± ± ± ± ±
0.7 0.7 0.7 0.6 0.7 0.6 0.7 0.7 0.8 0.8 0.9
± ± ± ± ± ± ± ± ± ± ±
0.6 0.5 0.5 0.6 0.6 0.6 0.6 0.6 0.5 0.6 0.5
38.1 37.7 37.3 36.9 36.5 35.9 35.5 34.9 34.5 33.9 33.3
± ± ± ± ± ± ± ± ± ± ±
0.5 0.4 0.4 0.3 0.3 0.3 0.3 0.3 0.3 0.2 0.4
38.3 37.8 37.5 37.1 36.7 36.1 35.7 35.0 34.6 34.0 33.4
± ± ± ± ± ± ± ± ± ± ±
0.7 0.7 0.7 0.6 0.5 0.5 0.5 0.4 0.5 0.5 0.6
± ± ± ± ± ±
0.9 0.7 0.7 0.6 0.7 0.1
37.9 37.7 37.2 36.7 36.3 36.1
± ± ± ± ± ±
0.5 0.4 0.3 0.3 0.3 0.1
38.1 37.8 37.4 36.8 36.4 36.3
± ± ± ± ± ±
0.8 0.7 0.6 0.6 0.6 0.1
Table 1 Cooling efficacy according to body surface area covered with cooling pads (n = 5; mean ± SD); with each percent increase in surface area, the cooling rate increased by 0.074 ◦ C/h (95% CI 0.053–0.059, p = 0.001). Coverage of body surface (%)
Cooling duration (min)
Cooling rate (◦ C/h)
Cooling rate (in % of 100% coverage)
Noradrenaline (g/min)
100 30 7
33.3 ± 0.7 91.5 ± 24.1 >120
8.2 ± 1.6 3.6 ± 1.1 1.1 ± 0.4
Reference 37 ± 11 15 ± 7
22.8 ± 7.5 15.1 ± 10.8 13.9 ± 15.2
W. Weihs et al. / Resuscitation 82 (2011) 74–78
tain mean arterial pressures in physiological ranges (Table 1). During the 30% surface area cooling, a total of 1153 ± 1349 g noradrenaline was needed during 58.2 ± 50.7 min (15 ± 11 g/min). During the 7% surface area cooling, a total of 1520 ± 1900 g was needed in 105.8 ± 24.3 min (14 ± 15 g/min). None of the pigs developed significant arrhythmias during cooling, and no other adverse events were observed. No skin lesions were observed except a transient reddening that quickly disappeared. Histological examinations showed no pathological changes due to injury from the cooling process in any pig. Epidermal and vascular changes were not found. Sporadic sero-cellular crusts were evident in 3 pigs. In addition, one of the pigs showed a small superficial ulcus in one location. Mild dermal perivascular eosinophilic infiltration was found in 3 locations in another pig. None of these lesions are characteristic of cutaneous injury resulting from direct freezing.
4. Discussion This study showed that an external surface-cooling pad that does not require an energy source during cooling is able to effectively and safely induce therapeutic mild hypothermia with cooling rates depending on the percentage of covered body surface. The cooling rates were roughly correlated with the amount of surface area covered. Cooling of only the neck doubled its cooling capacity per unit surface area when compared to cooling of the chest and abdomen or almost the entire surface of the pig. Therefore, the neck seems to be important for effectively cooling not only the body but also the brain. To use the cooling system in out-of-hospital situations, the following considerations must be made: cooling effectiveness needs to be maintained, there is limited space in the ambulance to transport the device, and there may be ease or difficulty in manipulating the patient.21 This device was easy to use in our pig model. An important step was to shave the pigs’ skin; otherwise, the pads’ self-adhesive surface could not adhere to the skin due to the thick bristles. The cooling pads had different sizes that could easily be applied to different body regions (Fig. 1). The pads were changed when 80% of the ice-graphite mixture inside the pad was melted. The 100% coverage condition showed a cooling rate of 9.5 ± 2.1 ◦ C/h, which is impressively high. Cooling rates of 3.5 ± 1.0 ◦ C/h with 30% coverage were satisfactory, and interestingly, 1.2 ± 0.3 ◦ C/h with neck coverage showed a doubled cooling capacity when considering the surface area covered by the cooling pads (Table 1, Figs. 2 and 3). While the 30% coverage condition achieved 37% of the cooling rate of the 100% coverage condition, the neck coverage condition, consisting of 7% coverage of the body surface, achieved 15% of the cooling rate. With better cooling rates, more noradrenaline was needed to keep the mean arterial pressure in physiological ranges. Note the comparatively higher demand in the 7% coverage group, which is quite similar to that in the 30% coverage group. There is a remarkable variation in response to cooling of the five individual animals (Figs. 2 and 3). This variability could not be explained by a correlation to the body weight and/or the randomisation sequence. We managed to have no cooling overshoot of more than 1 ◦ C when using this procedure. The experimental character of this study makes direct comparison to clinical use of surface cooling methods difficult but shows that cooling overshoots can be controlled. External surface cooling methods that were used in clinical trials after cardiac arrest showed slow cooling rates, ranging from 0.3 to 1.5 ◦ C/h.15,23,24 Devices with fast cooling rates exist but demand bulky equipment25 and are not feasible for the out-of-hospital setting. In the quest to attain faster cooling rates, more invasive cooling methods have been explored.13,26–28 The main disadvantages of
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invasive cooling methods are the demands for energy supply and for trained medical personnel. Such requirements exclude the use of invasive cooling methods after successful resuscitation outside of the hospital. The cooling rate of 9.5 ± 2.1◦ /h in the 100% coverage condition was considerably higher when compared to results obtained with more invasive cooling methods such as veno-venous blood-shunt cooling (8.2 ± 2.8 ◦ C/h) or endovascular cooling (2.6 ± 2.8 ◦ C/h), which were investigated in the same large swine model.29 The cooling under the 30% and 7% coverage conditions was comparable to cooling rates determined in other studies.15,21,24,30–32 The findings in this study confirm the findings of Keller et al.33 in a head–neck model: the frontal part of the neck, especially the carotid triangle region, is important for induction of hypothermia. Cooling of the dorsal neck regions in that model was as ineffective as cooling of the head surface itself, which only cooled superficial brain layers. In addition, Sukstanskii and Yablonskiy describe the importance of incoming arterial blood temperature for brain hypothermia in their analytical model of temperature distribution in the brain.34 Wandaller et al.35 showed that cooling with a head cooling device alone required additional endovascular cooling to reach the target temperature, whereas head cooling in combination with neck cooling reached the target temperature without further cooling; this also indicates the importance of neck cooling. Other studies with head cooling devices suggest the same conclusion.15,36 There are several limitations in the present study. We used healthy animals without heart or vascular disease, which is in contrast to human cardiac arrest victims. Although pig skin is the closest alternative to human skin, slight structural differences should be mentioned including bristles, which were shaved in our case, more subcutaneous fat and less vasculature.37 We tested the new cooling pads during spontaneous circulation without cardiac arrest. Hemodynamics and the efficacy of external cooling methods might differ after a period of no-flow. Non-investigated endpoints in this study included survival, neurological outcome, and histological brain damage. The study was designed to test the feasibility of the cooling blanket.
5. Conclusions The cooling pads were effective and safe for rapid induction of mild hypothermia in adult, human-sized pigs, depending on the percentage of body surface area covered. For out-of-hospital use in ambulances, coverage of only the neck, chest, and abdomen might achieve satisfactory cooling rates. The neck region seems to be important for therapeutic hypothermia, especially in the brain.
Conflict of interest statement Dr. Behringer is a paid consultant and stockowner of Emcools, Emergency Medical Cooling Systems AG, Vienna, Austria. Both Dr. Behringer and Dr. Sterz hold patent rights regarding the reported cooling method invented by Emcools, Emergency Medical Cooling Systems AG. All other authors have no conflicts of interest.
Acknowledgments The study was made possible through generous support from Supplementary Assignment of the Austrian Council for Development of Research and Technology (BMBWK GZ: 11.100/6VII/1/2002 3.6.2002). Emcools, Emergency Medical Cooling Systems AG, Vienna, Austria generously provided the cooling pads.
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The authors gratefully acknowledge the help of all the nurses, lab technicians, nightshift students and especially our animal keeper Sandra P. of the Core Center of Biomedical Research. References 1. Vreede-Swagemakers JJ, Gorgels AP, Dubois-Arbouw WI, et al. Out-of-hospital cardiac arrest in the 1990’s: a population-based study in the Maastricht area on incidence, characteristics and survival. J Am Coll Cardiol 1997;30: 1500–5. 2. Nolan JP, Deakin CD, Soar J, Bottiger BW, Smith G. European Resuscitation Council guidelines for resuscitation 2005. Section 4. Adult advanced life support. Resuscitation 2005;67(Suppl. 1):S39–86. 3. White BC, Sullivan JM, DeGracia DJ, et al. Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J Neurol Sci 2000;179:1–33. 4. Idris AH, Roberts LJ, Caruso L, et al. Oxidant injury occurs rapidly after cardiac arrest, cardiopulmonary resuscitation, and reperfusion. Crit Care Med 2005;33:2043–8. 5. 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 [see comments]. Crit Care Med 1993;21:1348–58. 6. 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. 7. Behringer W, Arrich J, Holzer M, Sterz F. Out-of-hospital therapeutic hypothermia in cardiac arrest victims. Scand J Trauma Resusc Emerg Med 2009;17:52. 8. Kamarainen A, Virkkunen I, Tenhunen J, Yli-Hankala A, Silfvast T. Prehospital therapeutic hypothermia for comatose survivors of cardiac arrest: a randomized controlled trial. Acta Anaesthesiol Scand 2009;53:900–7. 9. Janata A, Bayegan K, Weihs W, et al. Emergency preservation and resuscitation improve survival after 15 minutes of normovolemic cardiac arrest in pigs. Crit Care Med 2007;35:2785–91. 10. Bernard S. Therapeutic hypothermia after cardiac arrest: now a standard of care. Crit Care Med 2006;34:923–4. 11. Sterz F, Behringer W, Holzer M. Global hypothermia for neuroprotection after cardiac arrest. Acute Card Care 2006;8:25–30. 12. Holzer M, Mullner M, Sterz F, et al. Efficacy and safety of endovascular cooling after cardiac arrest: cohort study and Bayesian approach. Stroke 2006;37:1792–7. 13. Don CW, Longstreth Jr WT, Maynard C, et al. Active surface cooling protocol to induce mild therapeutic hypothermia after out-of-hospital cardiac arrest: a retrospective before-and-after comparison in a single hospital. Crit Care Med 2009;37:3062–9. 14. Riter HG, Brooks LA, Pretorius AM, Ackermann LW, Kerber RE. Intra-arrest hypothermia: both cold liquid ventilation with perfluorocarbons and cold intravenous saline rapidly achieve hypothermia, but only cold liquid ventilation improves resumption of spontaneous circulation. Resuscitation 2009;80: 561–6. 15. Hachimi-Idrissi S, Corne L, Ebinger G, Michotte Y, Huyghens L. Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation 2001;51:275–81. 16. Merchant RM, Abella BS, Peberdy MA, et al. Therapeutic hypothermia after cardiac arrest: Unintentional overcooling is common using ice packs and conventional cooling blankets. Crit Care Med 2006;34:S490–4.
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Experimental paper
The importance of surface area for the cooling efficacy of mild therapeutic hypothermia夽,夽夽 Wolfgang Weihs a , Alexandra Schratter a , Fritz Sterz a,∗ , Andreas Janata a , Sandra Högler b , Michael Holzer a , Udo M. Losert c , Harald Herkner a , Wilhelm Behringer a a
Department of Emergency Medicine, Medical University of Vienna, Austria Department of Pathobiology, University of Veterinary Medicine Vienna, Austria c Core Center of Biomedical Research, Medical University of Vienna, Austria b
a r t i c l e
i n f o
Article history: Received 1 May 2010 Received in revised form 31 August 2010 Accepted 25 September 2010 Keywords: Hypothermia Methodology Post-resuscitation period Safety Temperature
a b s t r a c t Aim of the study: Mild hypothermia after cardiac arrest should be induced as soon as possible. There is a need for improved feasibility and efficacy of surface cooling in ambulances. We investigated which and how much area of the body surface should be covered to guarantee a sufficient cooling rate. Methods: Each of five adult, human-sized pigs (88–105 kg) was randomly cooled in three phases with pads that covered different areas of the body surface corresponding to humans (100% or 30% [thorax and abdomen] or 7% [neck]). The goal was to quickly lower brain temperature (Tbr) from 38 to 33 ◦ C within a maximum of 120 min. Linear regression analysis was used to test the association between cooling efficacy and surface area. Data are presented as mean ± standard deviation. Results: The 100% and 30% cooling pads decreased the pigs’ Tbr from 38 to 33 ◦ C within 33 ± 7 min (8.2 ± 1.6 ◦ C/h) and 92 ± 24 min (3.6 ± 1.1 ◦ C/h). The 7% achieved a final Tbr of 35.8 ± 0.7 ◦ C after 120 min (1.1 ± 0.4 ◦ C/h). The 30% and 7% cooling surface areas achieved 37 ± 11% and 15 ± 7% of the cooling rate compared to the 100% cooling pads. For every additional percent of surface area cooled, the cooling rate increased linearly by 0.07 ◦ C/h (95% CI 0.05–0.09, p = 0.001). No skin lesions were observed. Conclusions: The cooling pads were effective and safe for rapid induction of mild hypothermia in adult, human-sized pigs, depending on the percentage of body surface area covered. Covering only the neck, chest, and abdomen might achieve satisfactory cooling rates. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction About 375,000 patients suffer a sudden cardiac arrest with global cerebral ischemia yearly in Europe, and only a small number recover without residual neurological damage.1 Guidelines recommend the use of therapeutic mild hypothermia (32–34 ◦ C) in patients resuscitated from cardiac arrest2 to mitigate the cascades of neuronal damage resulting from the start of reperfusion.3,4 To optimise the beneficial effect, it might be necessary to induce therapeutic mild hypothermia as soon as possible after successful resuscitation from cardiac arrest.5 It can also be expected that
夽 A Spanish translated version of the abstract of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2010.09.472. 夽夽 The work was performed at the Core Center of Biomedical Research, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. ∗ Corresponding author at: Universitätsklinik für Notfallmedizin, Medizinische Universität Wien Waehringer Guertel 18-20/6D, 1090 Vienna, Austria. Tel.: +43 1 40400 1964; fax: +43 1 40400 1965. E-mail address: [email protected] (F. Sterz). 0300-9572/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.resuscitation.2010.09.472
faster cooling will further improve the cerebral outcome.6 Application of cooling systems as first aid during resuscitation seems to be favourable.7–9 Various cooling techniques for induction and maintenance of mild hypothermia were developed in recent years, including non-invasive and invasive techniques.10–14 These cooling techniques are impractical for out-of-hospital use by paramedics at the scene of cardiac arrest or in ambulances because they depend on electrically powered cooling systems. In addition, ice packs or cooling helmets only have a limited cooling capacity.15–17 Therefore, novel cooling methods should provide fast cooling rates and easy application in the out-of-hospital setting, to quickly stop or decrease the pathological effects of ischemia and reperfusion. One of the promising developments could be cooling with evaporative perfluorochemical through the nasal cavity.18,19 Recently, a newly developed cooling blanket (Emcools-pad® ; Emergency Medical Cooling Systems AG, Vienna, Austria) that does not require outside energy sources during cooling showed fast and safe induction of mild hypothermia in adult, human-sized pigs20 and in humans.21 For out-of-hospital use by paramedics, the body surface area to be covered with cooling pads might determine feasibility.
W. Weihs et al. / Resuscitation 82 (2011) 74–78
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Fig. 1. Location and percentage of cooling pads coverage of the body surface in adult, human-sized pigs (n = 5).
The aim of this study was to investigate the influence of the optimal location and percent of body surface coverage on cooling rates in adult, human-sized pigs. 2. Methods In an observational crossover study, five healthy pigs (Large White breed) weighing 88–105 kg received a sequence of three different randomised cooling treatments with pads covering 100% (standard), 30%, and 7% of body surface areas (Fig. 1). The sizes were calculated according to the corresponding human bodyweight. Repeated measures of brain temperature were recorded. The institutional review board for the care of animal subjects approved the experimental protocol. 2.1. Anaesthesia, preparation and monitoring The pigs were fasted for 12 h before the experiment but had access to water. They were premedicated with atropine sulphate (0.5 mg i.m.), ketamine hydrochloride (12 mg/kg i.m.), and acepromazine maleate (1.08 mg/kg i.m.). Anaesthesia was started with propofol (2 mg/kg as i.v. bolus) and maintained with propofol (20 mg/kg/h), piritramide (0.75 mg/kg i.v. every h), and pancuronium (0.015 mg/kg/h). The pigs were intubated and ventilated with a tidal volume of 10 ml/kg, a positive end-expiratory pressure of 5 cm H2 O, an FIO2 of 0.3, and a ratio of inspiration to expiration of 1:2. The respiratory rate was adjusted to achieve a PaCO2 between 35 and 40 mm Hg. During preparation, the animals were kept at a baseline temperature of 38.0 ± 0.2 ◦ C with infrared lamps, surface warming blankets (Warm Air® Hyperthermiasystem 134, CSZ Cincinnati Subzeroproducts, Ohio, US), or fans if needed. After preparation, heparin (80 IU/kg) was injected i.v. Norepinephrine was used to maintain arterial pressure in physiological ranges (60–80 mm Hg). Electrocardiogram (ECG) electrodes were attached to the extremities, a pulse-oximeter probe was placed on the tail, and a gastric tube was inserted. Brain temperature (Tbr) was measured with temperature probes (generic thermocouple probe, BiosysTM , Vienna, Austria) inserted via a cranial borehole 1.5 cm lateral to the sagittal suture and 1.5 cm in front of the coronal suture into the right and left frontal lobe. The lower temperature was the target temperature. The bladder temperature (Tbl) was measured with a Foley catheter (Ruesch Sensor Ch12, Ruesch, Kernen, Germany). The tympanic temperature (Tty) was measured with a contact thermistor (General Purpose Sensor 9F, Nellcor, Pleasanton, CA) in the left and right ear. Oesophagus temperature (Tes) was measured with a contact thermistor (Mon-a-therm, General Purpose Temperature Probe, Mallinckrodt Medical, Ireland) in the oesophagus on a level with the heart. The subcutaneous temperature (Tsc) was measured with a contact thermistor (General Purpose Sensor 9F, Nellcor, Pleasanton, CA) inserted 3 cm under the skin
near the rib bow on the right side. The Seldinger technique was used to insert a conventional central venous catheter into the left brachial artery to measure arterial pressure and to take blood samples. Another conventional central venous catheter was inserted via the right external jugular vein to monitor central venous pressure (CVP) and to administer medications and infusions. The data were continuously monitored and stored using a computerised data management system (VIPDAS, Biosys, Vienna, Austria). 2.2. Surface cooling (Fig. 1) The external cooling blanket, which has a self-adhesive surface, consisted of multiple cooling pads made of a thin latex layer and filled with an ice-graphite mixture (prototype provided by Emergency Medical Cooling Systems AG, Vienna, Austria). The pads were pre-cooled to −20 ◦ C and kept in a commercially available isolated cool box until the start of the experiments. One experiment consisted of three cooling phases with each phase covering different percentages of the body surface (100%, 30% and 7%). The three different body surface percentages were calculated according to the body weight (88 cm2 /kg) equivalent in humans.21 In one phase, the (100%) neck, chest, abdomen, back, and fore- and hind-legs of the pig were covered with the cooling pads. In another phase, the (30%) chest, neck, and abdomen of the pig were covered. In the third phase, only the (7%) neck of the pig was covered with the cooling pads. The three cooling phase sequences (i.e., different coverages) were chosen randomly. Active cooling was stopped in each phase when Tbr reached 33 ◦ C or after a maximum of 2 h of cooling if the Tbr did not reach 33 ◦ C. The cooling pads were exchanged during cooling, specifically when almost 80% of the cooling pads were melted. Before each new cooling phase, re-warming to baseline Tbr 38.0 ± 0.2 ◦ C was performed with infrared lamps and surface warming blankets (Warm Air® Hyperthermiasystem 134, CSZ Cincinnati Subzeroproducts, Ohio, US). The animals were euthanised after the last cooling phase, and skin samples from five different locations exposed to the cooling pads were taken for histological examination. The samples were fixed in paraformaldehyde (3%, pH 7.4), embedded in paraffin, and cut into 2-m-thick sections. The slices were stained with hematoxylin and eosin and were evaluated using light microscopy. 2.3. Statistical analysis Continuous data are presented as the mean and standard deviation (±SD) or as the median and interquartile range (IQR) when appropriate. Categorical data are presented as absolute and relative frequencies. We used a linear regression analysis to assess the association between the covered surface area and the cooling efficacy. This was a crossover experiment, with each pig providing data for each cooling area. We allowed for correlated data in the analysis by calculating robust standard errors.22 Likewise, we plotted lines for each animal in the area versus efficacy scatter
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Fig. 2. Brain temperature curves per animal for each cooling phase with 100% (black lines), 30% (grey lines), and 7% (light shaded lines) body surface coverage.
plot instead of using unconnected points, thus explicitly allowing for this non-independence. We introduced a non-linear parameter into the model to assess deviation from linearity. Given the slightly concave shape of the scatter, we used the area squared as the most likely deviation. We used a Wald test to test this non-linear parameter. We also developed a linear random coefficient model for a sensitivity analysis and yielded virtually the same results. We compared the pulmonary artery, bladder, and continuous tympanic temperatures to the brain temperature. Data were analysed using Stata 9 (Stata Corp, College Station, TX) and MS Excel 2003. A two-sided p-value less than 0.05 was considered as statistically significant.
Fig. 3. Surface area covered (100%, 30%, 7%) versus cooling rate (◦ C/h) for each experiment (n = 5); light lines represent values of individual animals, the solid line represents mean cooling rates of all animals with certain surface areas covered. With each percent increase in covered surface area, the cooling rate increased by 0.074 ◦ C/h (95% CI 0.053–0.059, p = 0.001). Table 2 Temperatures (n = 5; mean ± SD; ◦ C) related to brain temperature during the three phases of cooling. Brain
3. Results Each of five pigs weighing 99 ± 6 kg (range 88–105 kg) were cooled in three phases with different body surface areas covered (100%, 30% or 7%) in a randomised crossover design. Coverage of 100% and 30% of the body surface area decreased the Tbr from 38 to 33 ◦ C within 33.3 ± 7.4 and 91.5 ± 24.1 min, respectively (Table 1, Fig. 2). Coverage of 7% of the body surface area decreased the Tbr to 35.8 ± 0.7 ◦ C after 120 min of cooling (Table 1, Fig. 2). Mean cooling rates and standard deviations for the 100%, 30%, and 7% body surface areas were 8.2 ± 1.6, 3.6 ± 1.1 and 1.1 ± 0.4 ◦ C/h. The 30% and 7% areas achieved 37 ± 11% and 15 ± 7% of the cooling rate of the 100% area (Table 1). Each percent of added surface area increased the cooling rate by 0.07 ◦ C/h (95% CI 0.05–0.09, p = 0.001) (Fig. 3). In the three different phases (100%, 30%, and 7% surface area coverage), the cooling pads had to be changed to new deep-frozen pads 1 (0 to 2) time, 4 (3 to 4) times, and 5 (4 to 7) times, respectively. Oesophagus temperatures (Tes) were shown to reflect the brain temperature best, whereas bladder temperatures (Tbl) and tympanic temperatures (Tty) showed more delay depending on the cooling rate (Table 2). Subcutaneous temperature (Tsc) under the attached cooling pad decreased from 36.5 ± 0.7 to a minimum temperature of 22.4 ± 2.9 ◦ C in 20.2 ± 8.2 min during the 100% surface area cooling and from 36.5 ± 0.7 to a minimum of 18.8 ± 4.3 ◦ C in 75.4 ± 17.7 min during the 30% surface area cooling. During the 100% surface area cooling in 23 ± 7 min, a total of 528 ± 220 g noradrenaline (23 ± 8 g/min) was needed to main-
Bladder
Oesophagus
100% Body surface coverage 38.0 38.0 ± 0.4 37.4 37.5 37.5 ± 0.5 36.2 37.0 37.2 ± 0.6 35.5 36.5 37.0 ± 0.7 35.0 36.0 36.7 ± 0.7 34.5 35.5 36.4 ± 0.7 34.1 35.0 36.2 ± 0.7 33.7 34.5 35.7 ± 0.8 33.2 34.0 35.4 ± 0.8 32.8 33.5 34.8 ± 0.9 32.4 33.0 34.2 ± 1.0 32.1 30% Body surface coverage 38.0 38.0 ± 0.3 37.4 37.5 37.7 ± 0.3 36.6 37.0 37.4 ± 0.4 36.0 36.5 37.0 ± 0.3 35.7 36.0 36.6 ± 0.3 35.2 35.5 36.1 ± 0.4 34.7 35.0 35.7 ± 0.4 34.2 34.5 35.0 ± 0.3 33.6 34.0 34.6 ± 0.4 33.1 33.5 34.0 ± 0.5 32.7 33.0 33.5 ± 0.4 32.1 7% Body surface coverage 38.0 37.8 ± 0.3 37.4 37.5 37.5 ± 0.2 36.9 37.0 37.1 ± 0.1 36.4 36.5 36.6 ± 0.1 35.9 36.0 36.0 ± 0.3 35.5 35.5 35.8 ± 0.1 35.5
Tympanum right
Tympanum left
± ± ± ± ± ± ± ± ± ± ±
0.9 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7
38.0 37.8 37.5 37.3 37.0 36.7 36.3 35.9 35.5 34.8 34.2
± ± ± ± ± ± ± ± ± ± ±
0.5 0.4 0.3 0.3 0.3 0.3 0.2 0.3 0.4 0.5 0.4
38.1 37.8 37.6 37.3 37.0 36.7 36.4 35.9 35.5 34.8 34.2
± ± ± ± ± ± ± ± ± ± ±
0.7 0.7 0.7 0.6 0.7 0.6 0.7 0.7 0.8 0.8 0.9
± ± ± ± ± ± ± ± ± ± ±
0.6 0.5 0.5 0.6 0.6 0.6 0.6 0.6 0.5 0.6 0.5
38.1 37.7 37.3 36.9 36.5 35.9 35.5 34.9 34.5 33.9 33.3
± ± ± ± ± ± ± ± ± ± ±
0.5 0.4 0.4 0.3 0.3 0.3 0.3 0.3 0.3 0.2 0.4
38.3 37.8 37.5 37.1 36.7 36.1 35.7 35.0 34.6 34.0 33.4
± ± ± ± ± ± ± ± ± ± ±
0.7 0.7 0.7 0.6 0.5 0.5 0.5 0.4 0.5 0.5 0.6
± ± ± ± ± ±
0.9 0.7 0.7 0.6 0.7 0.1
37.9 37.7 37.2 36.7 36.3 36.1
± ± ± ± ± ±
0.5 0.4 0.3 0.3 0.3 0.1
38.1 37.8 37.4 36.8 36.4 36.3
± ± ± ± ± ±
0.8 0.7 0.6 0.6 0.6 0.1
Table 1 Cooling efficacy according to body surface area covered with cooling pads (n = 5; mean ± SD); with each percent increase in surface area, the cooling rate increased by 0.074 ◦ C/h (95% CI 0.053–0.059, p = 0.001). Coverage of body surface (%)
Cooling duration (min)
Cooling rate (◦ C/h)
Cooling rate (in % of 100% coverage)
Noradrenaline (g/min)
100 30 7
33.3 ± 0.7 91.5 ± 24.1 >120
8.2 ± 1.6 3.6 ± 1.1 1.1 ± 0.4
Reference 37 ± 11 15 ± 7
22.8 ± 7.5 15.1 ± 10.8 13.9 ± 15.2
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tain mean arterial pressures in physiological ranges (Table 1). During the 30% surface area cooling, a total of 1153 ± 1349 g noradrenaline was needed during 58.2 ± 50.7 min (15 ± 11 g/min). During the 7% surface area cooling, a total of 1520 ± 1900 g was needed in 105.8 ± 24.3 min (14 ± 15 g/min). None of the pigs developed significant arrhythmias during cooling, and no other adverse events were observed. No skin lesions were observed except a transient reddening that quickly disappeared. Histological examinations showed no pathological changes due to injury from the cooling process in any pig. Epidermal and vascular changes were not found. Sporadic sero-cellular crusts were evident in 3 pigs. In addition, one of the pigs showed a small superficial ulcus in one location. Mild dermal perivascular eosinophilic infiltration was found in 3 locations in another pig. None of these lesions are characteristic of cutaneous injury resulting from direct freezing.
4. Discussion This study showed that an external surface-cooling pad that does not require an energy source during cooling is able to effectively and safely induce therapeutic mild hypothermia with cooling rates depending on the percentage of covered body surface. The cooling rates were roughly correlated with the amount of surface area covered. Cooling of only the neck doubled its cooling capacity per unit surface area when compared to cooling of the chest and abdomen or almost the entire surface of the pig. Therefore, the neck seems to be important for effectively cooling not only the body but also the brain. To use the cooling system in out-of-hospital situations, the following considerations must be made: cooling effectiveness needs to be maintained, there is limited space in the ambulance to transport the device, and there may be ease or difficulty in manipulating the patient.21 This device was easy to use in our pig model. An important step was to shave the pigs’ skin; otherwise, the pads’ self-adhesive surface could not adhere to the skin due to the thick bristles. The cooling pads had different sizes that could easily be applied to different body regions (Fig. 1). The pads were changed when 80% of the ice-graphite mixture inside the pad was melted. The 100% coverage condition showed a cooling rate of 9.5 ± 2.1 ◦ C/h, which is impressively high. Cooling rates of 3.5 ± 1.0 ◦ C/h with 30% coverage were satisfactory, and interestingly, 1.2 ± 0.3 ◦ C/h with neck coverage showed a doubled cooling capacity when considering the surface area covered by the cooling pads (Table 1, Figs. 2 and 3). While the 30% coverage condition achieved 37% of the cooling rate of the 100% coverage condition, the neck coverage condition, consisting of 7% coverage of the body surface, achieved 15% of the cooling rate. With better cooling rates, more noradrenaline was needed to keep the mean arterial pressure in physiological ranges. Note the comparatively higher demand in the 7% coverage group, which is quite similar to that in the 30% coverage group. There is a remarkable variation in response to cooling of the five individual animals (Figs. 2 and 3). This variability could not be explained by a correlation to the body weight and/or the randomisation sequence. We managed to have no cooling overshoot of more than 1 ◦ C when using this procedure. The experimental character of this study makes direct comparison to clinical use of surface cooling methods difficult but shows that cooling overshoots can be controlled. External surface cooling methods that were used in clinical trials after cardiac arrest showed slow cooling rates, ranging from 0.3 to 1.5 ◦ C/h.15,23,24 Devices with fast cooling rates exist but demand bulky equipment25 and are not feasible for the out-of-hospital setting. In the quest to attain faster cooling rates, more invasive cooling methods have been explored.13,26–28 The main disadvantages of
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invasive cooling methods are the demands for energy supply and for trained medical personnel. Such requirements exclude the use of invasive cooling methods after successful resuscitation outside of the hospital. The cooling rate of 9.5 ± 2.1◦ /h in the 100% coverage condition was considerably higher when compared to results obtained with more invasive cooling methods such as veno-venous blood-shunt cooling (8.2 ± 2.8 ◦ C/h) or endovascular cooling (2.6 ± 2.8 ◦ C/h), which were investigated in the same large swine model.29 The cooling under the 30% and 7% coverage conditions was comparable to cooling rates determined in other studies.15,21,24,30–32 The findings in this study confirm the findings of Keller et al.33 in a head–neck model: the frontal part of the neck, especially the carotid triangle region, is important for induction of hypothermia. Cooling of the dorsal neck regions in that model was as ineffective as cooling of the head surface itself, which only cooled superficial brain layers. In addition, Sukstanskii and Yablonskiy describe the importance of incoming arterial blood temperature for brain hypothermia in their analytical model of temperature distribution in the brain.34 Wandaller et al.35 showed that cooling with a head cooling device alone required additional endovascular cooling to reach the target temperature, whereas head cooling in combination with neck cooling reached the target temperature without further cooling; this also indicates the importance of neck cooling. Other studies with head cooling devices suggest the same conclusion.15,36 There are several limitations in the present study. We used healthy animals without heart or vascular disease, which is in contrast to human cardiac arrest victims. Although pig skin is the closest alternative to human skin, slight structural differences should be mentioned including bristles, which were shaved in our case, more subcutaneous fat and less vasculature.37 We tested the new cooling pads during spontaneous circulation without cardiac arrest. Hemodynamics and the efficacy of external cooling methods might differ after a period of no-flow. Non-investigated endpoints in this study included survival, neurological outcome, and histological brain damage. The study was designed to test the feasibility of the cooling blanket.
5. Conclusions The cooling pads were effective and safe for rapid induction of mild hypothermia in adult, human-sized pigs, depending on the percentage of body surface area covered. For out-of-hospital use in ambulances, coverage of only the neck, chest, and abdomen might achieve satisfactory cooling rates. The neck region seems to be important for therapeutic hypothermia, especially in the brain.
Conflict of interest statement Dr. Behringer is a paid consultant and stockowner of Emcools, Emergency Medical Cooling Systems AG, Vienna, Austria. Both Dr. Behringer and Dr. Sterz hold patent rights regarding the reported cooling method invented by Emcools, Emergency Medical Cooling Systems AG. All other authors have no conflicts of interest.
Acknowledgments The study was made possible through generous support from Supplementary Assignment of the Austrian Council for Development of Research and Technology (BMBWK GZ: 11.100/6VII/1/2002 3.6.2002). Emcools, Emergency Medical Cooling Systems AG, Vienna, Austria generously provided the cooling pads.
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