Clinical trial NCT04130984: Intraosseous Versus Intravenous Vascular Access During Resuscitation Following Out-of-Hospital Cardiac Arrest
Official title: Intraosseous Versus Intravenous Vascular Access During Resuscitation Following Out-of-Hospital Cardiac Arrest: A Multicenter Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Out-of-Hospital Cardiac Arrest
Keywords: Out-of-Hospital Cardiac Arrest
Intraosseous
Intravenous
Resuscitation
Lead sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
Sponsor class: OTHER
Collaborators: name: The First Affiliated Hospital of Soochow University
name: The Sixth Affiliated Hospital of Wenzhou Medical University
name: The Affiliated Hospital of Xuzhou Medical University
name: Second Affiliated Hospital of Wenzhou Medical University
name: Shanghai 10th People's Hospital
name: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
name: The First Affiliated Hospital with Nanjing Medical University
name: West China Hospital
name: Shanghai Zhongshan Hospital
name: Ningbo Medical Center Lihuili Hospital
name: Henan Provincial People's Hospital
name: The First Affiliated Hospital of Zhengzhou University
name: Shandong Provincial Hospital
name: The Third Affiliated Hospital of Wenzhou Medical University
name: Sir Run Run Shaw Hospital
First posted: 2019-10-18
Enrollment: 2356
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 1. Background:

   Intraosseous (IO) access is a new, fast, safe and efficient route of rescue of critically ill patients. Studies found drug pharmacokinetics and pharmacodynamics of IO are similar to IV route. Compared with IV and CVC, IO is time-consuming, easy to grasp, and has high operation success rate. Guidelines recommend IO when the establishment of vascular access is difficult or impossible.

   Recent animal studies suggest that IO access have better ventricular fibrillation termination rates, ROSC rates and survival compared with IV route. However, recent retrospective clinical studies found that IO versus IV treatment was associated with a lower likelihood of ROSC and hospitalization. How routes of vascular access influence clinical outcomes after OHCA merits multicenter randomized controlled trial. We suppose IO versus IV treatment is associated with a higher likelihood of ROSC and hospital and discharge survival.
2. Materials and methods:

   Study design This study is a prospective, open, two-arm, multicenter randomized controlled trial. The study will be conducted by 22 medical centers or affiliated hospitals in China. We will enroll nearly 2356 OHCA patients by the eligibility and exclusion criteria during January 2020 to December 2022. All of the patients will be randomized to one of 2 routes of vascular access: tibial intraosseous or peripheral intravenous. Other treatment measures of two groups refer to 2015 AHA Advanced Cardiovascular Life Support guidelines.

   Statistical analysis Intention-to-treat analysis (ITT) and per-protocol set (PPS) sensitivity analysis will be conducted in our study. Categorical variables are presented as counts and percentages, and differences are analyzed using the χ2 test. Continuous variables are presented as means with standard deviations or median (interquartile range \[IQR\]), and analysis is done by the Student t test or the Mann-Whitney U test according to normal or non-normal distributions.
3. Sample Size Calculation Set the following assumptions: alpha 0.025, beta 80%, clinically significant difference of 5% and 25% ROSC rate for both arms. Assuming the sample has an equal number of subjects in each arm, the study need to include at least 1178 subjects per arm to reach statistical significance.

Detailed description: 1. Background:

   Successful vascular access is critical for the treatment of acute and critically ill patients, especially those with cardiac arrest. For cardiac arrest patients, besides high-quality chest compressions and defibrillation, timely use of rescue drugs is also important. This requires early vascular access during chest compressions. Clinical studies and animal experiments indicate that 1 min delay of administration of antiarrhythmic drugs will increase the risk of adverse outcome, also found that the time interval from cardiac arrest to the first dose of rescue medication is closely related to the return of spontaneous circulation (ROSC) and prognosis.

   Because of the circulatory failure of patients with cardiac arrest, peripheral venous network often collapses, which makes it more difficult to develop vascular access. In addition, central venous catheterization (CVC) often takes an experienced physician at least 5-10 min, and it may affect resuscitation.

   Intraosseous (IO) access is a new, fast, safe and efficient route of rescue of critically ill patients. Animal and clinical studies found drug pharmacokinetics and pharmacodynamics of IO are similar to IV route. Compared with IV and CVC, IO is time-consuming, easy to grasp, and has high operation success rate. European Resuscitation Council (ERC) 2015 guidelines recommend IO when the establishment of vascular access is difficult or impossible.

   Recent animal studies suggest that IO access have better ventricular fibrillation termination rates, ROSC rates and survival compared with IV route. However, recent retrospective clinical studies found that IO versus IV treatment was associated with a lower likelihood of ROSC and hospitalization. How routes of vascular access influence clinical outcomes after OHCA merits multicenter randomized controlled trial. We suppose IO versus IV treatment is associated with a higher likelihood of ROSC and hospital and discharge survival.
2. Materials and methods:

   Study Design:

   This study is a prospective, open, two-arm, multicenter randomized controlled trial. The study will be conducted by the Department of Emergency Medicine, Second Affiliated Hospital, Zhejiang University, and other 21 medical centers or affiliated hospitals in China.

   Selection of patients:

   We will enroll nearly 2356 patients experiencing an out of hospital cardiac arrest (OHCA) patients by the eligibility and exclusion criteria during January 2020 to December 2022.

   Randomization:

   Block randomization will be conducted in this study. Randomized sequence numbers, which will be generated by the computer random number generator from Department of Medical Statistics and Epidemiology, School of Public Health, Zhejiang University, will be put into opaque envelopes and saved by an independent third party. A section included 4 random numbers, and each reference unit has its own independent research random number segment. avoiding centers into groups selectively shift caused by uneven. Research institutions and researchers should random subjects into the groups according to the random envelope numbers without secretly opening the envelope or jumping numbers. After being unpacked, random envelopes will be uniformly sealed and saved. Patients consistent with inclusion and exclusion criteria will be randomized into IO group or peripheral venous access group (IV).

   Patients will be randomized using a random envelope method, and researchers of all centers are not aware of the length of randomized block. Preparation and production of random envelops are commissioned by the Department of Emergency Medicine, Second Affiliated Hospital, Zhejiang University. The study is an open label study. But the staff responsible for the follow-up, data collection and data analysis later does not know the specific grouping. To avoid rescue delay, random envelope will be placed in fixed position in all research centers. When an OHCA patient is enrolled, randomly open a random envelope and determine the grouping.

   Intervention:

   Group IO: The insertion site locates at 1 cm medial tibial tuberosity. EZ-IO (U.S. Teleflex® Corporation) will be used with an adult 15G needle. Pull out the needle when having a sense of frustration, withdraw the bone marrow with the syringe, bolus 20 mL of normal saline to open intramedullary path and begin drug resuscitation at the same time. The retention time of IO route should be less than 24 h, and venous access should be established after winning rescue time as soon as possible to continue treatment. If failed, the next catheterization plan will be determined by the physician in charge of the scene.

   Group IV: Any available peripheral venous can be chose to establish vascular access for the administration of drugs or fluids, the antecubital vein is preferred. If failed, the next catheterization plan will be determined by the physician in charge of the scene.

   Other treatment measures of two groups refer to 2015 AHA Advanced Cardiovascular Life Support guidelines.

   Technical Training:

   The operators of IO receive at least 1 h theoretical study and practice in training until master mold puncture technique, passing the examination before the start of the study. Operators of peripheral venipuncture have more than 1 year venipuncture experience.

   Statistical analysis:

   Intention-to-treat analysis (ITT) and per-protocol set (PPS) sensitivity analysis will be conducted in our study. Descriptive statistics are used to summarize the data. Categorical variables are presented as counts and percentages, and differences between groups are analyzed using the χ2 test. Continuous variables are presented as means with standard deviations or median (interquartile range \[IQR\]), hence analysis is done by the Student t test or the Mann-Whitney U test according to normal or non-normal distributions. Stage analysis will be performed when collected data account for 30%, 50%, 80%, 100% of anticipation. The interim analysis will follow the O'Brien-Fleming rule to assess the safety and efficacy of this study. If the results of interim study do not meet the criteria of suspension, cases will continue to be collected until the completion of the target sample size.
3. Sample Size Calculation Prior to the start of the study a sample size calculation was performed to determine study feasibility. Model assumptions were made based on prior quality assurance reviews. Sample size requirements for a non-inferiority comparison were calculated using the following assumptions: alpha 0.025, beta 80%, clinically significant difference of 5% increase in ROSC and 25% ROSC rate for both arms. Assuming the sample has an equal number of subjects in each arm, the study would need to include at least 1178 subjects per arm (2356 total) to reach statistical significance.
4. Data Management and Confidentiality

   Data Management:

   Using EDC platform+ paper version for data management and storage. The person responsible for collecting paper version will input data in EDC platform uniformly, summary paper and electronic versions for further statistical analysis and preservation.

   Security measures:

   All records related to the identity of subjects are to be confidential and not open to the public outside the scope of relevant laws or regulations.
5. Informed consent:

   Subjects must obtain written informed consent prior to the implementation, being informed of specific content of study, as detailed informed consent.
6. Adverse events reporting:

Definition of adverse events and classification of serious adverse events:

Adverse events (AE): It is defined as any adverse medical events occurred in patients, which is not necessarily a cause or result of treatment. Therefore, adverse event can be any discomfort or unconscious signs (including abnormal laboratory findings), symptom or disease generated after interventions, whether or not considered to be related to drugs.

Serious adverse events (SAE):

Death, life-threatening, hospitalization, prolonged hospitalization, persistent or significant disability / loss of function, important medical events that require medical or surgical treatment to avoid serious consequences.

Assessment of adverse events:

In each AE, researchers need to assess: intensity (severity), clinical relevance, causality (relationship between drugs and research process), results and measures taken.

Recording and reporting procedures:

During the study, researchers should record all AE in detail and report. All SAE are required to be recorded in the AE page of CRF. In addition, a completed "serious adverse events" should be sent to the competent authorities, the local Food and Drug Administration investigators and Ethics Committee involved immediately (at the latest within 24 hours). The researcher will sign and date the report, informing the other researchers involved in this clinical study at the same time.

Eligibility criteria: Inclusion Criteria:

* Out of hospital cardiac arrest patients with 18 years or more

Exclusion Criteria:

* Traumatic cardiopulmonary arrest with an indication of withholding of resuscitation, including:

  * trauma victims with injuries that are obviously incompatible with life, such as decapitation or hemicorporectomy;
  * victims of either blunt or penetrating trauma when there is evidence of prolonged cardiac arrest, including rigor mortis or dependent lividity;
  * blunt trauma patient who, on the arrival of emergency medical services (EMS) personnel, is found to be apneic, pulseless, and without organized electrocardiographic activity;
  * penetrating trauma patients who, on the arrival of EMS personnel, is found to be pulseless and apneic and there are no other signs of life, including spontaneous movement, electrocardiographic activity, and pupillary response;
* Vascular access has been established before admission;
* Return of spontaneous circulation before first attempt to establish vascular access;
* Quit resuscitation;
* Patients with contraindications of intraosseous access;

  * infection of insertion site, such as skin and soft tissue infections, osteomyelitis;
  * integrity damage of the target bone, such as fractures, artificial limbs, etc;
  * blood supply or return of the target bone is significantly affected, e.g. arteriovenous rupture;
  * burns of insertion site;
  * intraosseous attempt in same insertion site within 24 h;
  * compartment syndrome exists in same insertion site;
  * unclear anatomical structures of insertion site, such as obesity, malformations;
  * patients with severe bone diseases, such as imperfect osteogenesis, osteoporosis;
  * patients with right to left cardiac shunt (e.g. Tetralogy of Fallot, pulmonary atresia, etc).

Primary outcomes:
measure: return of spontaneous circulation (ROSC)
timeFrame: within 24 hours
Secondary outcomes:
measure: first attempt success
timeFrame: within 24 hours
measure: overall success
timeFrame: within 24 hours
measure: initial access interval
timeFrame: within 24 hours
measure: initial epinephrine administration interval
timeFrame: within 24 hours
measure: sustained ROSC
timeFrame: 24 hours
Other outcomes:
measure: survival to discharge
timeFrame: a week
measure: survival to discharge without severe neurological impairment
timeFrame: a week
measure: 1-month survival without severe neurological impairment
timeFrame: 1 month
measure: 6-month survival without severe neurological impairment
timeFrame: 6 months
measure: insertion-related complications
timeFrame: 1 day
Locations:
city: Hangzhou
country: China
facility: Second Affiliated Hospital, Zhejiang University School of Medicine & Institute of Emergency Medicine, Zhejiang University
state: Zhejiang
Study officials:
affiliation: Second Affiliated Hospital, Zhejiang Universitiy School of Medicine
name: Mao Zhang
role: PRINCIPAL_INVESTIGATOR
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