A Multicenter, Randomized Controlled Trial of Immediate Total-Body CT Scanning in Trauma Patients (REACT-2)

Joanne C Sierink; Teun Peter Saltzherr; Ludo FM Beenen; Jan SK Luitse; Markus W Hollmann; Johannes B Reitsma; Michael JR Edwards; Joachim Hohmann; Benn JA Beuker; Peter Patka; James W Suliburk; Marcel G W Dijkgraaf; J Carel Goslings

Disclosures

BMC Emerg Med. 2012;12(4) 

In This Article

Methods/Design

Study Objectives

The primary objective is to determine the effects of immediate total-body CT scanning during the primary trauma survey on clinical outcomes compared to patients who are evaluated with standard conventional Advanced Trauma Life Support (ATLS®) based radiological imaging. The secondary objectives are to assess the effects of total-body CT scanning on long term clinical outcomes, quality of life, clinically relevant time intervals in the early phase of trauma care and the differences in treatment strategies used.

Study Design

The REACT-2 trial is an international, multicenter randomized clinical trial in six high-volume trauma centers that will compare the effects of immediate total-body CT scanning in severely injured trauma patients with conventional imaging protocols.

Setting

In total four trauma centers in The Netherlands, one Swiss and one American trauma center will participate in the REACT-2 trial. All participating hospitals are level-1 trauma centers with a multi-slice CT scanner located in the trauma resuscitation room or at the ED.

When a patient arrives in the trauma room a brief report of the pre-hospital circumstances, medical assessment and clinically suspected injuries is presented to the trauma team leader by the ambulance personnel. The initial evaluation of trauma patients will be done according to the ATLS guidelines for the primary survey. Potential life-saving interventions during the primary survey and before any imaging include securing the airway by intubation or performing a cricothyrotomy, chest tube insertion, pericardiocenthesis or taking hemorrhage controlling measurements such as applying a pelvic binder or external pressure on bleeding sites to (temporarily) stabilize the vital functions. Usually, peripheral intravenous access is taken care of by the ambulance personnel, but if not, at least one intravenous catheter will be inserted before radiologic imaging takes place. Based on information received from the ambulance personnel and the findings during primary survey, the trauma team leader decides on the eligibility of the patient to participate in the trial. If the patient is found to be eligible randomization takes place. Figure 1 depicts the study flow chart.

Figure 1.

Study flow chart REACT-2 trial.

The intervention group will receive a total-body CT scan from head to pelvis. In the intervention group conventional radiography of the torso and FAST will be completely omitted. The CT protocol for the consists of a two-step whole-body acquisition (from vertex to pubic symphysis) starting with Head and Neck Non Enhanced CT (NECT) with arms alongside the body. The preferred technique for the second complementary scan is a split-bolus intravenous contrast directly after repositioning of the arms alongside the head, and this second scan covers thorax, abdomen and pelvis. Participating centers however are free to choose their own technique as long as intravenous contrast is given for the chest and abdominal part of the total-body CT.

The control group will be evaluated according to a conventional trauma protocol with selective CT scanning. The REACT-2 trial has been designed to maximize the applicability of the trial's results to usual care settings. Therefore, the technical details of the CT scanning done in the control group are not specified and participating centres follow their own protocols. Indications for the selective CT scanning however are pre-defined based on the combined local protocols of the participating centers. These standardized protocols provide a basis for the comparison of the two imaging approaches.

Study Population

All non-pregnant trauma patients aged 18 years and older having life-threatening (respiratory, circulatory or neurologically) conditions with compromising vital parameters, with clinical suspicion on specific injuries or with specific injury mechanisms are included. Patients in whom the scanning will hamper necessary (cardiopulmonary) resuscitation or who require an immediate operation because of imminent death (both as judged by the trauma team leader) are excluded. Detailed in- and exclusion criteria are summarized below:

Inclusion Criteria

Trauma patients with the presence of life-threatening vital problems defined as at least one of the following:

- respiratory rate ≥ 30 min of ≤ 10/min;

- pulse ≥ 120/min;

- systolic blood pressure ≤ 100 mmHg;

- estimated exterior blood loss ≥ 500 ml;

- Glasgow Coma Score ≤ 13;

- Abnormal pupillary reaction onsite.

OR

Patients with one of the following clinically suspicious diagnoses:

- flail chest, open chest or multiple rib fractures;

- severe abdominal injury;

- pelvic fracture;

- unstable vertebral fractures/spinal cord compression;

- fractures from at least two long bones.

OR

Patients with one of the following injury mechanisms:

- fall from height (> 3 m/> 10 ft);

- ejection from the vehicle;

- death occupant in same vehicle;

- severely injured patient in same vehicle;

- wedged or trapped chest/abdomen.

Exclusion Criteria

Trauma patients with one of the following characteristics will be excluded:

- known age < 18 years;

- known pregnancy;

- referred from another hospital;

- clearly low-energy trauma with blunt injury mechanism;

- penetrating injury in 1 body region (except gun shot wounds) as the clearly isolated injury;

- any patient who is judged to be too unstable to undergo a CT scan and requires (cardiopulmonary) resuscitation or immediate operation because death is imminent according to the trauma team leader in mutual agreement with the other leading care givers.

Endpoints

The primary outcome criterion for this trial is in-hospital mortality.

As secondary parameters for the trial focus on additional clinical consequences for the patients and cost-effectiveness and cost-utility:

- mortality (24-h, 30-day and 1-year mortality);

- morbidity (complications and total number of (re-)interventions and re-admissions up to 6 months post trauma; transfusion requirements, length of ICU stay and number of ventilation days);

- several time intervals during initial evaluation (time of arrival, time to CT, scanning time, time to diagnosis and time in the ED);

- radiation exposure;

- quality of life 6 and 12 months after the trauma as recorded by completing the EuroQol-6D;

- general health 6 and 12 months after the trauma as recorded by completing the HUI-3;

Economic parameters/endpoints:

- total costs of imaging during the initial/index hospital stay;

- total direct and indirect medical and non-medical costs during the first half year posttrauma;

- quality adjusted life-years (QALY's).

Randomization

If a patient is eligible for the trial the diagnostic imaging pathway for initial assessment in the trauma resuscitation room will be determined by randomization. The randomization will be performed immediately after inclusion at computers located in the trauma room of the participating hospitals. Randomization will be performed using a 'one-click' computer program on a 1:1 basis per hospital with varying block sizes of 2, 4, 6, 8, 10 and 12. The trauma team will be directly informed on the outcome of the randomization so that imaging can be started. A standardized case record from (CRF) will be used. This CRF is totally web-based via a secured internet module.

Sample Size Calculation and Data Analysis

A previous study reported a reduction in mortality from 15% to 8.6% with total-body CT scanning as the single diagnostic procedure during trauma evaluation as compared to historical control data.[29] Analysis on the large German polytrauma registration database performed by Huber-Wagner et al. showed a significant reduction in the 24-h mortality in patient who underwent immediate total-body CT compared to the conventional group (10% vs. 12%, P = 0.038).[25] Historical AMC data show a mortality rate of 12% for trauma patients matching the current trial inclusion criteria. Based on the combination of the AMC data and the participation of the other trauma centers with comparable trauma populations, it is expected to find a reduction in mortality from 12% to 7%. The detection of such a difference requires 539 patients per group using a power of 80% and a two-sided alpha of 5%. Based on the historical and estimated data of the participating centers the inclusion period will take about 1,5 years and the follow-up period will take an additional year.

The main analyses of primary and secondary outcomes will be conducted for all randomized patients according to the result of the randomization (intention-to-treat). Data are expressed as percentages for categorical data, as mean and standard deviation (SD) for normally distributed numerical data and as median, range, and, where appropriate, inter-quartile range (IQR = 25 to 75%) for non-normally distributed numerical data.

The following subgroups will be used for subgroup analysis:

- multitrauma patients (defined as Injury Severity Score (ISS) >/=16);

- severe traumatic brain injury patients (defined as admission Glasgow Coma; Scale (GCS) ≤ 8 and an Abbreviated Injury Score (AIS)-head of ≥ 3);

- penetrating versus blunt trauma.

A p-value less than 0.05 is considered statistically significant. If appropriate, predictive values between variables are calculated. Predictive values in continuous outcome variables are assessed using a multivariate regression model, and binary outcome measures are assessed using a multivariate logistic regression model. In case of binary outcome measures, predictive values are expressed as Odds Ratio's (OR) with 95% Confidence Intervals (CI). Data are analyzed using the Statistical Package for the Social Sciences (SPSS) version 18.0 SPSS Inc., Chicago, IL.

Economic Evaluation and Cost Analysis

Total-body CT scanning will be evaluated economically from a societal perspective against a conventional diagnostic strategy consisting of X-ray, FAST and selective CT scanning according to the ATLS guidelines. Cost-effectiveness analyses will be performed with the costs per patient alive and costs per patient alive without serious morbidity as outcome measures. Additionally, a cost-utility analysis will be done with the cost per QALY as outcome measure. Incremental cost-effectiveness ratios will be calculated, expressing the extra costs per (i) extra patients alive, (ii) extra patients alive and without serious morbidity, and (iii) additional QALY. Sampling variability will be accounted for by (bias-corrected and accelerated) non-parametric bootstrapping. Sensitivity analyses will be directed at applied QALY algorithms (generic, country-specific; uniform, linear, curvilinear interpolations between measurements), unit costs of major cost components, and the (country-specific) friction period in case of production loss. Subgroup analyses will be performed by the predefined subgroups. The time horizon for the cost-effectiveness analysis will be six months following trauma. Because of this time horizon, no discounting will take place.

The economic evaluation will take all direct and indirect medical and non-medical costs into account. The direct and indirect medical costs include the costs of initial trauma care, ICU-care and care at the general ward during the index admission - including all diagnostic and therapeutic procedures - as well as the costs of repeat hospital admissions, other intramural care like rehabilitation and extramural care during the first 6 months post trauma. Direct and indirect non-medical costs of, respectively, out-of-pocket expenses and production loss during the first 6 months will also be estimated. Volume data will be collected by case report form, institutional administrative databases and by patient questionnaires at 3 and 6 months, depending on the cost category. The patient questionnaire will be derived from the Dutch Health and Labour Questionnaire and adapted for international use. Unit costing will be based on activity based costing and hospital ledger data concerning the major diagnostic procedures in this trial. Unit costing of other health care components will be based on available national guidelines. In case of absence of national guidelines in specific countries, available unit costs from abroad will be recalculated using Organisation for Economic Co-operation and Development (OECD) purchasing power parities. Out-of-pocket expenses will be estimated as supplied by the patients. Indirect costs of production loss will be calculated according to the Dutch perspective by following the friction cost method, while applying the most recent friction cost period known at the time of analysis. Costs will be calculated for the base year 2012. Unit costs of other base years will be price-indexed.

Safety Monitoring

An independent Data and Safety Monitoring Board (DSMB), consisting of three members (2 physicians and 1 clinical epidemiologist), is installed for this trial. On regular intervals, this committee will review accumulating trial data and provide advice on the conduct of the trial to the trial leader and Steering Committee. The DSMB will focus both on safety and effectiveness data. Standard Operating Procedures (SOP) will be used with respect to the schedule and format of DSMB meetings and with respect to the format and timing of presenting data. The DSMB can recommend the Steering Committee to terminate the trial when there is clear and substantial evidence of harm.

Safety and Efficacy Monitoring

The role of the DSMB is to perform an interim review of the trial's progress including updated figures on main outcomes and safety data. This review would include, but not be restricted to, the following:

• monitor compliance with the protocol by participants and investigators;

• monitor evidence for treatment differences in the main efficacy outcome measures;

• monitor evidence for treatment harm (e.g. SAEs, deaths);

• decide whether to recommend that the trial continues to recruit participants or whether recruitment should be terminated either for everyone or for some treatment groups and/or some participant subgroups;

• suggest additional data analyses;

• monitor compliance with previous DSMB recommendations;

• consider the ethical implications of any recommendations made by the DSMB;

• assess the impact and relevance of external evidence as supplied by the Chief Investigator.

The DSMB will evaluate these safety and efficacy parameters at regular intervals. After 275 (25%), 550 (50%) and 700 (65%) included patients, non-blinded interim-analyses for evaluation of safety rules will be performed. No formal stopping rules based on statistical criteria alone will be used. The DSMB decides after evaluation of all necessary interim data whether the trial will be continued or terminated. Other investigators, designated by the Board of Direct of the AMC to control the trial will have the authority to gain insight in all the confidential data relevant for the trial as well.

Ethics

This trial is conducted in accordance with the principles of the Declaration of Helsinki,[30] the Medical Research Involving Human Subjects Act (WMO) and 'Good Clinical Practice' guidelines. The Medical Ethical Committee of the Academic Medical Center in Amsterdam has approved the protocol on January 6 2011. The Ethical Committees of the participating centers approved for local feasibility.

To participate in a research project the subjects must be volunteers and informed participants according to ethical principles stated in the Declaration of Helsinki. However, the acute life-threatening situation of severely injured trauma patients hinders a considered decision. Neither a legal guardian nor a legal representative of the patient can make a decision because of the time pressure or because they simply do not arrive in time. A temporary waiver of informed consent during randomization and the consecutive diagnostic phase during trauma survey was approved by the Medical Ethical Committee of the Academic Medical Center in Amsterdam. In all cases informed consent will be asked afterwards from the patient or the legal guardian/representative of the patient, as soon as reasonably possible.

processing....