This is a prospective, multi-centre, randomized, single-blind, controlled study conducted by the emergency responders of different emergency medical systems (EMS). In the treatment arm, patients will be immediately cooled by paramedics and/or emergency physicians using the RhinoChill device. Intra-arrest cooling will be continued after ROSC and until hospital admission for patients who will be resuscitated while it will be interrupted at the end of CPR in case of unsuccessful resuscitation. In the control arm, patients will receive standard of care and will be treated with TH after arrival at the hospital.
The sites including patients in this study are: a) Karolinska Institutet (Stockholm, Sweden), defined as the Principal Investigator (PI); b) Hôpital Erasme (Brussels, Belgium); c) Universiteit Ziekenhuis Leuven (Leuven, Belgium); d) Emergency Medical Services of the Hradec Kralove Region (Hradec Kraklove, Czech Republic). In Belgium and Czech Republic, physicians will enroll patients while in Sweden both physicians and paramedics will recruit patients.
All victims of CA will be screened for study eligibility upon arrival of the first responding team. Inclusion criteria are: age ≥ 18 years; witnessed (heard or seen) collapse; not having a pulse. Exclusion criteria are: age ≥ 80 years; etiology of cardiac arrest due to trauma, severe bleeding, drug overdose, cerebrovascular accident, drowning, smoke inhalation, electrocution, hanging; already hypothermic (≤ 34°C at tympanic or rectal temperature); an obvious barrier to placing intra-nasal catheters (i.e., intranasal obstruction); Do Not Attempt to Resuscitate (DNAR) orders or terminal disease; known or clinically apparent pregnancy; known coagulopathy (except therapeutically induced); chronic oxygen therapy at home; response time (call to first EMS CPR) > 15 minutes.
Randomization will be carried out in blocks of four and each site will be given sets of sequentially numbered envelopes with randomization assignments provided in a 1:1 manner to distribute to the participating pre-hospital vehicles. Individual envelopes will be placed in each RhinoChill pack at the time of site initiation, and replaced as patients are enrolled. The RhinoChill pack will be carried to every potential subject, and the envelope will be opened once the subject has been qualified as meeting all inclusion and exclusion criteria. Neither EMS or hospital personnel will be blinded to treatment, since the control patients are easily distinguishable from patients undergoing device placement and nasal cooling. However, medical personnel making the final neurological assessment of the patient prior to discharge will be blinded to patient's group assignment.
The resuscitation attempt will follow current guidelines to the greatest extent possible. After airway management (i.e. laryngeal mask or intubation), patients are randomized to early cooling or standard care. In patients randomized to early cooling, the RhinoChill catheters should be placed and cooling initiated immediately. To place the nasal catheters and start cooling takes approximately 1 minute. Cooling should be performed with the oxygen flow set to 40 L/min. There should be no changes to the care received by patients randomized to the control arm. Resuscitation attempts should be continued for at least 30 minutes after EMS arrive on the scene in all patients before deciding that further interventions are futile.
The RhinoChill works by spraying a liquid coolant onto the upper surface of the nasal cavity, where it evaporates and absorbs heat from the tissue, thereby cooling the tissue and the innate vasculature that supplies blood to the brain. The coolant is an inert liquid (perfluorohexane, PFH) at one atmosphere of pressure and can carry 20 times more oxygen than saline. It has a surface tension that is lower than water so it will spread uniformly and quickly throughout the space in which it is sprayed. Oxygen or air is delivered with the liquid coolant to maximize its evaporation. Medical grade oxygen or breathing air with a supply pressure of 60 psi and sufficient quantity to provide a 40 L/min flow rate over the treatment period is required in order to operate the RhinoChill.
The coolant vapor, along with the gas, escapes the nasal cavity through the nostrils or the mouth. In the event that all the coolant is not evaporated, it is possible that it will either trickle out of the nostrils or trickle down the pharynx into the mouth or stomach. Because the coolant is immiscible in water, it is not absorbed in any significant quantity into the body. The minute quantities that may be absorbed into the blood or inhaled into the lungs are expired through the lungs in a relatively short period. Local temperatures within the nasal cavity are expected to cool to around 2°C.
The RhinoChill consists of three components: the tubing set, the control unit, and the coolant bottle. The tubing set is a single-use device that delivers the pressurized gas and coolant mixture to the patient. The proximal end attaches to the control unit to which a medical gas source is connected. Distal to the control unit is the interface for the coolant bottle; this consists of a dip tube connected to a bottle interface collar into which is incorporated a liquid flow indicator. Liquid coolant is driven out of the bottle by the pressurized gas, through a 0.22 μm filter, and then the gas and coolant are delivered to the nasal catheters. The trans-nasal catheters are joined together with a hub at the proximal ends; the catheters are mated to the gas and liquid delivery lines via an integral manifold. The catheters have separate gas and liquid capillaries that converge at each of 12 spray ports along the dorsal surface of the catheter. Close contact of the liquid PFH with the pressurized gas at each of the spray ports results in efficient nebulization of the vapor from each of these ports. Each catheter also has three pressure sensing ports along the ventral surface of the catheter that transmit the local pressure in the nasal cavity to the control unit. The control unit also has a mechanical over-pressure safety valve, which is designed to vent excess oxygen to prevent a pressure greater than 60 psi from entering the device.
The coolant bottle holds 1 liter of the evaporative coolant that will last 30 minutes when the oxygen or air flow rate is set to 40 L/min. The RhinoChill is configured for use in a stable hospital setting (e.g., hanging from an I.V. pole mount) or packaged in a backpack that integrates a 3 L (900 liters gas) oxygen or air bottle, and weighs approximately 9 kgs for use in the ambulance and field setting. It is expected that at least one tubing set and 1 L of coolant will be needed for each subject enrolled in the early cooling arm. Patients that are resuscitated after RhinoChill cooling is initiated will likely require 1–2 additional bottles of coolant before in-hospital cooling can be initiated.
Return of spontaneous circulation will be defined as obtaining an organized rhythm and palpable pulse sustained for 20 minutes. Once an organized rhythm and palpable pulse is achieved, subjects will have their temperature taken via the tympanic route, stabilized and then be transported to the hospital. If a patient wakes up after ROSC is achieved, cooling will be discontinued; on the opposite, subjects will, if needed be intravenously administered bolus doses of sedation and analgesia for transport to the hospital. Doses of sedation and analgesia will be dictated by the institutional standard cooling protocol. The oxygen supply in the transport vehicle should be used to continue RhinoChill cooling during transport to the hospital. Normal transport procedures will be used for patients randomized to the control arm. Infusions of cold saline or cooling with cold packs will not be permitted in the pre-hospital setting for either group. Upon hospital arrival, a systemic temperature probe will be placed (i.e., bladder, arterial, rectal) and core temperature will be recorded. Systemic hypothermia on arrival at Intensive Care Unit (ICU) for both patient groups (treatment and control) will be performed as follows:
Duration of hypothermia for at least 24 hours.
Target temperature 33°C ± 1°C.
Recording of core- and tympanic temperature every 15 minute during the induction period (i.e., until target temperature is reached).
Rewarming rate at 0.2–0.5°C/hour.
Control of post-cooling hyperthermia.
Subjects randomized to the early cooling group with the RhinoChill shall continue being cooled with the RhinoChill until systemic cooling procedures can be started. Intravenous sedation, analgesia and neuromuscular blockade (if used) should be initiated upon hospital arrival according to institutional cooling protocols. Doses should be adjusted as necessary over the course of cooling/re-warming. After the subject has been prepared with the standard hypothermia device, the RhinoChill should be turned off, but the intranasal catheters should be left in place while transitioning the subject to the standard hypothermia protocol.
Intermittent activation of the RhinoChill may be considered if the core temperature does not continue to drop via the systemic cooling method. Cooling via the RhinoChill system will be halted immediately if any adverse event related to the use of the RhinoChill develops.
For those patients in the control group, the standard cooling procedure will be started as soon as practical. Intravenous sedation, analgesia and neuromuscular blockade (if used) should be initiated upon hospital arrival according to institutional cooling protocols. Doses should be adjusted as necessary over the course of cooling/re-warming. Temperatures (tympanic and core) will be monitored periodically over the first 48 hours after hospital arrival for all patients. ECG, peripheral oxygen saturation, heart rate and blood pressure monitoring will continue throughout the acute care period. Ventilation settings should be adjusted to maintain arterial oxygen saturation 94–98% (e.g., PaO2 80–120 mmHg) and normocapnia (e.g., PaCO2 35–45 mmHg). A positive end-expiratory pressure (PEEP) level should be adjusted to reduce FiO2 below 60%, whenever possible. Electrolytes will be substituted as necessary to maintain normal ranges. Blood pressure should be kept above 65 mmHg at all times. Drops in pressure should be treated primarily with crystalloid fluids. If sufficient pressure control cannot be achieved with fluids alone, vasopressor drugs, such as adrenaline or norepinephrine, should be used. Serum blood glucose should be kept between 110 and 150 mg/dl with insulin administration. Enteral feeding will be initiated according to local guidelines.
Data collection concerning the cardiac arrest will include time to collapse; bystander CPR; location; time of arrival of basic and advanced life support, ALS, teams; time of emergency call; time of first emergency medical team initiated CPR, patient characteristics (i.e. gender, weight, age, comorbidities), resuscitation effort (time CPR is initiated by the first emergency medical staff, EMS, responder; time cooling initiated - if cooled; mechanical CPR, if not manual; time intravenous access obtained; first rhythm; total adrenaline/epinephrine dose; shock time, strength, and success; additional medication(s) and dose(s); time airway is secured; recurrent VF or re-arrest; time randomized; time ROSC or death declared). Also, quality of CPR, including the number and depth of chest compressions/min as well as CPR hands-off time, will be recorded whenever possible. After hospital admission, tympanic temperature; heart rate, peripheral oxygen saturation (SpO2), mean arterial pressure, end-tidal carbon dioxide (EtCO2), arterial blood gas analysis, initial ECG findings and Glasgow coma score will be recorded. Concomitant interventions (e.g., coronary angiogram, aortic balloon pump, bypass surgery, internal cardiac defibrillator placement) will also be recorded. The systemic cooling procedures, including the system used, the core temperature location, the duration and the hypothermia reversal algorithm will be recorded.
The Steering Committee has the responsibility to perform periodic and spot checks visits to monitor the progress of the clinical study. Completed Case Report Forms (CRFs) will be reviewed for completeness, compliance with the investigation plan, and appropriate device use and accountability. Case Report Forms will be provided to each site for each subject enrolled in the study. Required data concerning patient treatment and test results will be recorded on the CRFs at the time of the procedure or as soon as possible thereafter. Information recorded in the CRFs will be corroborated by data in the subject's medical records. Completed and monitored CRFs will be uploaded on a website developed by the PI, which will be overseeing data entry and data quality management. Data on safety will be provided to the Steering Committee with regular time intervals.
The Steering Committee will review study integrity, safety and risk/benefit issues at periodic intervals throughout the study. The frequency of these reviews will be dependent upon the rate of patient enrollment and relevant safety issues. Independent analyses of serious adverse events will be performed and adjudicated if the frequency or nature of serious adverse events warrants it.
Subjects treated with the RhinoChill will undergo rhinoscopic examination of the nasal cavity if it is warranted based on clinical signs of intra-nasal trauma (e.g., bleeding from the nostrils, whitening of the nose or other treatment-related observations). All patients still alive will undergo a neurological examination 72 hours after hospital admission. Neurological status will be classified using the Cerebral Performance Category (CPC). Subjects will be followed until death or at 90 days. The following data will be recorded concerning their hospital course: date/time subject wakes; date/time subject is taken off ventilator; date/time subject is discharged from ICU; date/time subject dies (if in hospital); date/time subject is discharged from hospital; discharge disposition; CPC at hospital discharge. CPC will be evaluated at 90 days through a telephone interview by an independent physician using the Glasgow Outcome Scale (GOS) and the 15D instrument. If there are difficulties in CPC-classification, the patient will be assessed by a neurologist at an out-clinic visit. Clinically significant serious adverse events will be recorded from the time ROSC is achieved through the earliest of the following three events: death, hospital discharge, or one week following admission. The nature and severity of the adverse event, the relationship to the RhinoChill Device, management and outcome will be recorded on the CRF.
The main objective of this study is to assess the impact on neurological intact survival rates at 90 days of trans-nasal IATH compared to standard treatment. Thus, the primary end-point will be the neurological intact survival rates (i.e. patients with CPC score of 1–2) at 90 days after arrest among all those admitted to the hospital.
Secondary end-points will include:
Overall survival at 90 days among patients admitted to the hospital.
Survival and neurological intact outcome at 90 days among all included patients.
Survival to hospital admission.
Proportion of patients reaching target temperature (≤ 34° Celsius) within 4 hours of call to dispatcher.
All adverse events occurring within 24 hours of beginning ALS procedures.
Serious adverse events (SAE) from the time of patient randomization through the first seven days of hospitalization.
Importantly, in the cases where withdraw of life support is decided due to poor prognosis, the reasons must be clearly stated in the CRF, as well as results of neurological examination or additional tools (i.e. brain imaging, biomarkers, electroencephalography, somatosensory evoked potentials - SSEPs), which are used. No specific recommendation on post-anoxic coma prognostication has been provided in this study.
The primary outcome measure of this study is neurological intact survival at 90 days among all patients admitted to the hospital. Considering data from the previous trial, we postulated that the using of IATH with TNEC technique could improve this primary outcome from 21% to 37%. For a 80% power and α error of 0.05, the study requires 150 patients admitted to the hospital who should be randomized in each arm: however, considering a ROSC rate around 40% and 10% of lost to follow-up, the study will require a sample size of 418 patients for each arm (836 in total), regardless of initial rhythm. Analysis of data will be based on "Intention-to-treat". A first interim analysis will be performed after 200 patients; conditional power for meeting the primary endpoint will be, if needed, recalculated at that time, and if the interim results do not correspond to the primary end-point, termination of the study for futility will be considered. In case of sample calculation exceeding 500 patients, other potential recruiting centers will be included in the study. Other interim analyses will be performed each 200 patients included. Early stopping for efficacy reasons will only be considered if major outcome differences are seen between the groups according to the Haybittle rule with a p-value ≤ 0.001.
Stratified analyses will be performed for patients whose first recorded rhythm is VF/VT versus those in whom the first recorded rhythm is PEA/asystole. Sub-group analyses will be performed for subjects where CPR was initiated within 10 minutes by a first EMS response team or where cooling was started within 15 minutes. The study is expected to last until 2016.
Because inclusion is decided as soon as possible after EMS arrival, informed consent cannot be obtained before enrollment into the study, but deferred consent will be obtained in each case. The RhinoChill device has received CE marking and did not raise any major safety issues in previous studies;[23,26] as such, local Ethics Committees (The Regional Ethical Review Board in Stockholm - reference study number: 2010/383–32; Comité d'Ethique de l'Hôpital Erasme – reference study number: P2012/321; Ethics Committee, University Hospital Hradec Kralove –reference study number: 201204 S24ZP; Commissie Medische Ethiek van Universitaire Ziekenhuizen KU Leuven; reference study number: S54255) approved study in eligible patients who are unable to provide consent prior to their treatment, as they will necessarily be comatose. Ethical consideration for treating subjects without their express consent is in accordance with the World Medical Association Helsinki Declaration of 1964, as revised at the 59th General Assembly in Seoul in 2008. For subjects admitted to the hospital after ROSC, their legal representative will be informed of the study as soon as possible and must approve for data collection and continuation of the study. Subjects who will show neurological recovery will be informed of their study participation and be asked to provide their consent for the use of their data.
Data Safety Management
The Data Safety Monitoring Committee (DSMC) is constituted and will review data every 3 months. Given that it is expected that more than half of the patients will die at the scene or during the hospital stay, and that recurrent cardiac arrest at any time is possible with standard care, it is not considered appropriate to report every death to the DSMC as a serious adverse effect. Sites will report all SAEs that occur within 7 days of enrollment directly to DMSC. A "technical device failure" is defined as a failure of the device to perform its intended function when used in accordance with the instructions for use. Technical device failures will be recorded and evaluated for possible untoward effects on the subject. All clinically significant AEs or those that appear to be related to the use of the RhinoChill (i.e., whitening of the nose; epistaxis; mucosal irritation/dryness; para-sinus emphysema) as well as those that could potentially harm the patient (i.e., pleural effusion) will be recorded on the CRF from ROSC through the end of the cooling period.
BMC Emerg Med. 2013;13(21) © 2013 BioMed Central, Ltd.