Design of the PRINCESS Trial

Pre-Hospital Resuscitation Intra-Nasal Cooling Effectiveness Survival Study (PRINCESS)

Per Nordberg; Fabio Silvio Taccone; Maaret Castren; Anatolij Truhlár; Didier Desruelles; Sune Forsberg; Jacob Hollenberg; Jean-Louis Vincent; Leif Svensoon


BMC Emerg Med. 2013;13(21) 

In This Article


Sudden cardiac death is one of the major health issues of the industrialized world.[1] Despite decades of efforts to promote cardiopulmonary resuscitation (CPR) education and the introduction of automated external defibrillators, less than 50% of cardiac arrest (CA) victims achieve a return of spontaneous circulation (ROSC) and this percentage drops to 20% or less for those patients that live in rural areas or do not have an initial rhythm that can be defibrillated (e.g., pulseless electrical activity, PEA, and asystole).[2–4] Even fewer of these patients are alive on hospital admission and most of them will eventually die because of extended post-anoxic brain injury.[5–8]

In 2002, two randomized clinical trials demonstrated the benefit of therapeutic hypothermia (TH) on neurologically intact survival in patients who were cooled in-hospital for 12 to 24 hours to 32–34°C within few hours from ROSC following an out-of-hospital cardiac arrest (OHCA) with ventricular fibrillation (VF) or ventricular tachycardia (VT) as first rhythm.[9,10] Based on these studies, the International Liaison Committee on Resuscitation have recommended the use of TH as a routine treatment of OHCA patients with VF/VT as first rhythm during post-resuscitation care. Despite the absence of randomised trials, current guidelines recommend that TH should be considered also in patients presenting with non-shockable rhythms.[11] In addition, these guidelines stated that patients resuscitated from OHCA should be cooled as soon as possible; however, the optimal timing to initiate TH in this setting remains unknown.

Several clinical studies have assessed the impact of early cooling using cold saline infusion shortly after return of spontaneous circulation (ROSC). In 2007, Kim et al. performed a feasibility study in 123 patients, which demonstrated that early use of cold fluids was safe and that the core temperature could be lowered 1.2 degrees upon arrival to hospital. Also, there was a trend towards increased survival to discharge in patients with VF/VT.[8] Recently Bernard et al. published a randomized trial on post-ROSC early cooling with cold fluids compared to in-hospital TH in 234 VF-patients. Rapid cooling decreased core temperature of patients at hospital arrival but did not improve outcome at hospital discharge compared with cooling commenced in the hospital.[12]

Recent data suggested that initiating TH during CPR, before the reperfusion phase, would provide additional beneficial effects against post-anoxic brain injury. Animal studies have shown that cooling induced during CPR and prior to ROSC, the so-called "intra-arrest hypothermia" (IATH), improved neurological outcome when compared to animals that are cooled post-ROSC.[13–17] To date, there are no sufficiently large human studies that have evaluated the effects IATH compared to standard TH initiated in-hospital on neurological outcome and mortality.[18] In a retrospective analysis of 542 patients where 208 were treated with intra-arrest cold intravenous fluids, the use of IATH associated with improved ROSC rate but not with increased overall survival to hospital discharge.[19] Importantly, only 13% of the whole cohort received in-hospital TH.

Nevertheless, not all methods to induce IATH may produce the same effects on brain recovery after CA. In animal studies, global IATH has been induced by various techniques/devices, including ice packs, intravascular catheters, cold metal plates or total lung ventilation with perfluorocarbons (PFC). Moreover, some devices may selectively cool the brain primarily with less effect on core body temperature and thus more rapidly protect cerebral cells from ischemia/reperfusion injury. Only three experimental studies have compared different IATH techniques on specific outcomes.[20–22] Interestingly, cardiac function was significantly improved by IATH induced by an intravascular system compared to cold fluids;[20] in this study, IATH using cold fluids resulted in a lower coronary perfusion pressure, a greater need for epinephrine and a longer duration of CPR. In another study, PFC-total lung ventilation achieved more easily ROSC than intra-arrest cold fluids.[21] Finally, in a model of prolonged CA, trans-nasal evaporative cooling (TNEC) initiated during CPR improved the success of resuscitation compared with IATH induced by cold fluids and reduced the duration of CPR.[18] These studies supported the concept that IATH induced by cold fluids may have some deleterious effects on cardiac perfusion during CPR and may not as effective as other techniques to reduce brain injury and improve survival after CA.

TNEC is a method that has been developed to rapidly induce IATH and achieve hypothermia for human CA. The technique takes advantage of the nose as a natural orifice into the head to overcome the obstacle of cooling through the skull. The upper nasal pathways provide a large diffuse surface area and vascularity that is in close proximity to the cerebral circulation. Cooling in the nasopharynx also offers the ability to cool via direct conductive mechanisms that do not rely on spontaneous circulation.[22] In the only randomized study using such approach to induce IATH,[23] 200 OHCA patients were randomized during CPR, irrespective of their rhythm, to receive either TNEC or standard of care (including post-ROSC cooling at hospital). This feasibility study showed that the method was safe for pre-hospital use. Overall survival rates were similar in the two groups (15% vs. 13%). Among patients admitted to the hospital, overall survival to hospital discharge was improved, although not significantly, during IATH (44% vs. 31%, p = 0.16). In the post-hoc analysis, the sub-group of patients with time to CPR less than 10 minutes had an increased survival rate when treated by IATH (56% vs. 29%, p = 0.04). Also, TNEC increased, although not significantly (p = 0.14), the intact neurological outcome rate from 21% to 34% when compared to the control group; these beneficial effects were more pronounced in the subgroup of patients with time to CPR less than 10 minutes (43% vs. 17%, p = 0.03).

Given these supportive data, we are conducting a randomized controlled trial comparing TNEC to conventional post-ROSC cooling. The aim is to determine whether TNEC used during CPR would improve neurological outcome in patients being resuscitated from OHCA and with a time to CPR less than 15 minutes.