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For peer review onlyBiomarkers of sympathetic-parasympathetic balance for predicting psychological distress and recovery following

road traffic injuries: protocol for a prospective cohort study.

Journal: BMJ Open

Manuscript ID bmjopen-2018-024391

Article Type: Protocol

Date Submitted by the Author: 24-May-2018

Complete List of Authors: Pozzato, Ilaria; University of Sydney, Sydney Medical School - Northern, John Walsh Centre for Rehabilitation ResearchCraig, Ashley; University of Sydney, Northern Clinical School; Gopinath, Bamini; University of Sydney, Centre for Vision Research; University of Sydney, Sydney Medical School - Northern, John Walsh Centre for Rehabilitation ResearchTran, Yvonne; University of Sydney, Sydney Medical School - Northern, John Walsh Centre for Rehabilitation ResearchDinh, Michael; Royal Prince Alfred Hospital, Emergency DepartmentGillett, Mark; Royal North Shore Hospital, Emergency DepartmentCameron, Ian; University of Sydney, Sydney Medical School - Northern, John Walsh Centre for Rehabilitation Research

Keywords:MENTAL HEALTH, Neurophysiology < NEUROLOGY, ACCIDENT & EMERGENCY MEDICINE, TRAUMA MANAGEMENT, REHABILITATION MEDICINE

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open

For peer review only

1

Biomarkers of sympathetic-parasympathetic balance for predicting psychological

distress and recovery following road traffic injuries: protocol for a prospective cohort

study.

Ilaria Pozzato1

Ashley Craig1

Bamini Gopinath1

Yvonne Tran1

Michael Dinh2

Mark Gillett 3

Ian D Cameron1

1 John Walsh Centre for Rehabilitation Research, Sydney Medical School - Northern, Kolling

Institute of Medical Research, University of Sydney, Sydney, Australia.

2 Emergency Department, Royal Prince Alfred Hospital, Sydney, Australia.

3 Emergency Department, Royal North Shore Hospital, Sydney, Australia.

Correspondence to:

Ashley Craig

John Walsh Centre for Rehabilitation Research, Sydney Medical School - Northern,

University of Sydney, Kolling Institute of Medical Research, Royal North Shore Hospital

Corner Reserve Road & Westbourne Street, St Leonards, NSW 2065, Australia

Telephone: 61 2 9926 4925 Mobile: 0417 290 521 Fax: 61 2 9926 4045

Email: [email protected]

[Word count (excluding title page, abstract, references, figures and tables): 2823/4000]

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ABSTRACT

Introduction: Psychological distress is a prevalent condition often overlooked following a

motor vehicle crash (MVC), particularly when injuries are not severe. The aim of this study

is to detect risk of elevated psychological distress and poor functional recovery early after a

MVC, using autonomic biomarkers within a biopsychosocial framework, and clarify links

between mental and physical health outcomes.

Methods and analysis: This is a controlled longitudinal cohort study, with follow-up

occurring at 3, 6 and 12 months. Participants include up to 120 mild to moderately injured

MVC survivors who consecutively present to the Emergency Departments (ED) of two

hospitals in Sydney and who agree to participate, and a group of up to 120 non-MVC

controls, recruited with matched demographic characteristics, for comparison. The WHO

International Classification of Functioning is used as the framework for study assessment.

The primary outcomes are the development of psychological distress and autonomic

biomarkers. Secondary outcomes include quality of life, return to functioning, participation

and physical health indicators. For each outcome, risk will be described by the frequency of

occurrence over the 12 months, and pathways determined via latent class mixture growth

modelling. Regression models will be used to identify best predictors/biomarkers and to

study associations between mental and physical health.

Ethics and dissemination: Ethical approvals were obtained from the Sydney Local Health

District and the research sites Ethics Committees. Study findings will be disseminated to

health professionals, related policy makers and the community through peer-reviewed

journals, conference presentations, and health forums.

Registration details: ANZCTR, 17 October 2016 (ACTRN12616001445460, IMPRINT

study).

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Strengths and limitations of this study

• This study will comprehensively describe the risk of developing psychological distress

and poor functional recovery in people involved in a motor vehicle crash and sustaining

mild to moderate injuries.

• Identifying biomarkers of mental health risk and recovery adds novelty to this field. The

analysis of autonomic nervous system responses holds promise in preventing serious

mental disorders, reducing the stigma around mental health diagnosis and improving

outcomes among crash survivors.

• The use of the ICF standard framework for a comprehensive risk prediction model, will

assure an in-depth analysis of all domains involved in a person’s functioning, which are

often studied in isolation, and will promote comparability with other research.

• Findings may be useful to acute health clinicians in the early detection of at-risk

individuals, for a better management of mental health and a more integrated form of care.

• The purpose of the study is to determine prognostic markers, not casual factors involved

in the development of psychological distress and poor recovery following a motor vehicle

crash.

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INTRODUCTION

Around 50 million people worldwide are injured annually in non–fatal motor vehicle crashes

(MVC).[1] Surviving a crash can lead to a number of physical and psychological

consequences, and many individuals develop long-term disability. While improved outcomes

are shown for severe injuries,[2] evidence suggests that minor to moderate injuries are a

challenge, accounting for 46% of injury-related disability,[3] with traffic injuries remaining

the 10th leading cause of Disability Adjusted Life Years (DALYs) in 2010.[4] Therefore,

consequences and costs of non-severe traffic injuries such as whiplash, mild traumatic brain

injury and musculoskeletal injury are serious public health concerns.[5] In Australia, it is

estimated that around $1b is spent each year on traffic injuries admitted to hospital for less

than 24 hours, with an average cost by casualty of $14,183.[6] Nevertheless, when

psychological problems are involved, care costs have been shown to escalate alarmingly and

time to recovery to increase fourfold.[7]

Psychological distress is prevalent in people surviving a MVC and has been

demonstrated to be a substantial contributor to long-lasting morbidity and disability,[8 ,9]

affecting up to one in two MVC survivors, according to a recent meta-analysis.[10] Although

there is some variability in estimates, the proportion of MVC survivors (up to 50%) who

experience psychological problems appears to be many times greater than the proportion of

people with mental health in the Australian community (20%)[11] and global population

(25%),[12] often resulting in serious mental disorders, such as post-traumatic stress disorder

(PTSD), major depressive disorder (MDD), driving phobias and other anxiety disorders.[13]

Unlike physical problems, that ideally receive appropriate and timely medical care

following a MVC, early clinical management of psychological symptoms associated with

mild to moderate physical injury rarely occur since, for example, these are often normalised

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as a common response to the trauma. Hence, it is not surprising that mental health-related

quality of life of MVC survivors is more resistant to improvement over time than physical

outcomes, as for instance demonstrated by Kenardy et al.[8] This is pertinent given failure to

address psychological distress will have a significant detrimental impact on functional

recovery,[14] supporting the hypothesis that there is ‘no health without mental health’.[12]

Some underlying circumstances may lead to delayed recognition of psychological

distress. First, a clear diagnostic framework is lacking for detecting psychological distress

symptoms that include clinically elevated anxiety and depressive mood and high levels of

arousal,[10] and which often co-occur following a MVC. Previous studies on MVC survivors

typically focused on a single mental disorder, particularly post-traumatic stress disorder

(PTSD). The second and more significant fact is the absence of empirical evidence for

reliable biomarkers of vulnerability for psychological distress following a MVC. Individual

vulnerability to psychological distress and poor recovery has been linked to a number of

biological (e.g. pre-injury health, injury severity), psychological (e.g. prior traumatic

experiences, perceptions) and environmental factors (e.g. social support, compensation),[15]

however biological responses, in particular autonomic responses, to physical threat remain an

under-investigated area in traffic injury recovery.

Biological responses to threat involve activation of neural substrates such as the stress

response systems. The autonomic nervous system (ANS) is the first to respond to stressors by

a transitory withdrawal of the parasympathetic ‘brake’, for a rapid control of body functions

critical for survival, i.e. increased heart rate, blood pressure and breathing rate, and later re-

engagement of this system during recovery, by inhibition of sympathetic control. The

integrity of this ANS response can be reliably studied using an index of arousal and

relaxation, that is, heart rate variability (HRV), the variation in the beat-to-beat interval,

reflecting innervation of the heart by the ANS sympathetic/parasympathetic divisions.

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Different theoretical models[16-18] have linked HRV to individual differences in

adaptation to external and internal stressors, suggesting ANS imbalance is an indicator of

poor self-regulatory capacity in managing stress levels, that can in turn affect psychological

health,[19 ,20] physical health,[21 ,22] cognitive performance,[17 ,22] and social

functioning.[16 ,20] Thus, ANS imbalance, measured early after a MVC, is regarded as a

promising biomarker of vulnerability to develop dysfunctional responses, such as elevated

psychological distress and stress-related disorders that can affect a person's capacity to

recover following traffic injury.

There is substantial evidence that supports the co-occurrence of psychological and

physical conditions among MVC survivors, for example anxiety, depression, chronic pain,

fatigue, sleep disturbance, and other somatic conditions,[15 ,23] for which physical evidence

is often missing, hinting at the possibility of shared psychological and biological processes

being involved in stress vulnerability.[24 ,25] However, the majority of evidence for this

comes from cross-sectional studies, especially from the relationship between chronic pain and

PTSD in whiplash injuries. Therefore, prospective research is now needed to investigate links

between mental and physical health in the recovery phase following a MVC.

In the current study, the WHO International Classification of Functioning (ICF)[26]

will be employed as the biopsychosocial framework to assess outcomes following MVC-

related injury, and to build a comprehensive prognostic model for identification of the at-risk

cohort. Within this framework, potential autonomic biomarkers will be novel, and so the use

of ICF as a multidimensional approach to assess recovery from non-severe MVC injuries.

Early detection is crucial for preventing disease and progression to chronicity, therefore this

study has the potential to improve the health and quality of life of thousands of MVC

survivors in Australia annually. Providing ‘biological evidence’ for psychopathology may

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also contribute to removing the stigma around mental health disorder and patient-related

barriers to mental health care.[27]

Study Aims

The study objectives are:

1) To determine prevalence estimates and trajectories of psychological distress and recovery

post-MVC;

2) To determine the efficacy of autonomic biomarkers, alone or in combination with other

biopsychosocial factors, in predicting mental health and poor recovery following injury

sustained in a MVC;

3) To investigate associations and shared predictors/biomarkers, between mental and physical

health outcomes post-MVC.

METHODS AND ANALYSIS

Conceptual framework

The conceptual study framework, drawing on the WHO ICF model,[26] is outlined in Figure

1. Mental health and recovery are investigated through the interaction between biological,

personal and environmental factors, with autonomic regulation playing a pivotal role in the

maintenance of the overall person’s functioning.

Design

A controlled longitudinal cohort design will be undertaken to assess risk of psychological

distress and poor recovery among mildly to moderately injured MVC survivors. Baseline

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assessment will occur within 1 month (3 to 6 weeks) of their injury, with follow-up

assessments occurring at 3, 6 and 12 months post-injury. Results will be compared to a

control group who have not sustained a MVC or severe injuries in the past 5 years, and who

will be assessed at the same time periods.

Participants’ eligibility and identification

The study inclusion and exclusion criteria for MVC survivors and control participants are

presented in Table 1. The identification of MVC survivors will begin following their

presentation to the emergency departments (ED) of one of two metropolitan hospitals in

Sydney, Australia: Royal North Shore Hospital (RNSH) and Royal Prince of Alfred Hospital

(RPAH). Participants will be consecutively identified and assessed for eligibility by a

research nurse from the information management system, FirstNet.

The non-MVC control group, matched by sex, age (± 5 years) and education (up to

Secondary school, Senior Secondary school, Technical or further education, University

Undergraduate or University Post-graduate) to the MVC sample on a case by case basis, will

be recruited through advertising or by using convenience sampling.

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Table 1. Inclusion and exclusion criteria of MVC participants and Non-MVC controls.

MVC participants Non-MVC controls

Inclusion

criteria • Age ≥18 years • Age ≥18 years

• Sustained, in last 6 weeks, a minor to moderate injury due to MVC in NSW, Australia

• No history of MVC, serious injury or traumatic event (i.e. w/ perceived threat of injury to self or others) in the previous 5 years

• Sufficient English proficiency • A driver, motorbike rider, passenger, pillion

passengers, pedestrian and bicyclist (only collision involving a motorised vehicle)

• Presented to RNSH or RPAH Emergency Departments, Sydney, Australia

• Sufficient English proficiency

Exclusion

criteria

• Catastrophic injury as defined by NSW icare lifetime care, i.e. a very severe traumatic brain injury, a spinal cord injury, extensive burns to the body (>60%), major amputation or blindness

• Chronic disease such as severe heart disease, stroke, cancer, chronic respiratory diseases, obesity and advanced complicated diabetes.

• Serious Injury (Injury Severity Score[28] >15)

• Dementia or cognitive impairment affecting ability to consent

• Localised, superficial soft tissue injuries • Severe mental health condition • Death of a family member in the MVC • Severe brain injury • MVC due to intentional self-harm • Degenerative neurologic disease • Dementia or cognitive impairment affecting

ability to consent

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Recruitment process and timeframe

Eligible survivors will be invited to participate by: i) being approached at the time of ED

presentation, or ii) receiving an invitation letter to their postal address from the ED treating

clinician. After written consent is obtained (opt-in approach), participants will be requested to

complete the baseline interview-based assessment by accessing an online secure website, and

otherwise by completing a paper-based or phone interview. As part of their enrollment,

within 6 weeks of their accident, participants will also be asked to attend a 30-minute hospital

visit for collection of autonomic biomarkers (HRV assessment). An overall reimbursement up

to $100 in vouchers will be provided to cover participant travel cost and time.

The first participant was recruited on 16 June 2017, and both sites are actively

contributing towards the recruitment target. It is anticipated that the recruitment will last until

the end of January 2019, thus data collection is expected to be completed by early 2020.

Sample size

A sample size of up to 120 MVC participants and an equivalent number of non-MVC

controls will be employed to test the study aims. Assuming a loss to follow-up of 20-30%, a

moderate effect size of 0.2 (eta-squared or η2) at α=0.05, 2 groups and 4 time periods,

statistical power using repeated measures analyses was calculated to be 83%.[29] For the

logistic regression, assuming an α=0.05, 10 predictors, a moderate effect size of 0.2 (eta-

squared or η2), the power to measure the strength of relationship was calculated to be

90%.[29]

Assessments and outcome measures

Assessment time points and details of the validated measures used within each ICF domain

are provided in Table 2.

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Table 2. IMPRINT study: Measures and Assessment Points, within each ICF Domain.

ICF MODEL STUDY ASSESSMENTS AND MEASUREMENTS

Domain Category Measures Assessment points

Baseline (within 6 weeks)

3 months

6 & 12 months

BODY

FUNCTIONS &

STRUCTURES

Injury Injury type; Injury severity (Abbreviated Injury Severity[28], Glasgow Coma Score[30]); Hospital admission, Length of hospital stay, Surgery.

X

Autonomic functioning *Biomarkers

Post-crash vital signs; HRV; Heart rate; Respiration; Galvanic Skin Response; Peripheral body temperature; Blood volume pulse.

X

Pain Pain Intensity (NRS[31]); Risk of persistent pain and disability (OMPQ, short form[32]).

X X X

Fatigue Fatigue Intensity (VAFS[33]). X X X Physical health Stress-related physical symptoms (sleep disturbance, loss of sex drive, frequent

infections, upset stomach, constipation); Lifestyle habits (physical activity, smoking, alcohol use); Medications; Referral to physiotherapist; Post-crash new clinical diagnoses.

X X X

Mental health Depressive mood and Anxiety (DASS21[34]); PTSD symptoms (IES-R[35]); Driving Phobia (MINI[36]); Adjustment Disorder (MINI[36]); Referral to psychologist/psychiatrist.

X X X

Emotional functioning Emotional balance (PANAS[37]); Valence and Arousal dimension of emotions (Self-Assessment Manikin scale[38]).

X X X

Cognitive functioning Perceived cognitive functioning (WHODAS II - Domain 1[39]); Stroop test[40]. X X X ACTIVITIES Quality of life Health-related physical and mental quality of life (SF-12[41]). X X X PARTICIPATION Disability Return to work and activities; Social participation (WHODAS II - Domain 6[39]). X X X PERSONAL

FACTORS

Socio-demographic Sex; Age; Primary language; Education; Marital status. X Traumas and stressors Prior and post-crash Stressors. Traumatic events following the crash (MINI[36]). X

Physical health history

Past clinical and medication history; Body composition (BMI); Past chronic pain or fatigue diagnosis; Pre-health care utilisation.

X

Mental health history Prior trauma (MINI[36]); Previous mental health problems and mental health treatment.

X

Coping Skills Coping responses (COPE Inventory[42]). X X X Perceptions Perceived life threat; Perceived helplessness; Blame vs self or others; Perceived

injustice; Perceived resilience; Perceived sense of safety and life balance. X X X

Cognitive bias Pain catastrophizing, Rumination, Magnification (PCS[43]); Self-efficacy beliefs X X X

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(GSE[44]); Expectations to return to work (OMPQ[32]) and expectations to recover.

ENVIRONMENTAL

FACTORS

Crash circumstances Role in the accident. X Health care quality Care satisfaction. X X X Socioeconomic status Index of Relative Socioeconomic Disadvantage; Financial issues pre and post-

crash. X

Employment Pre-injury employment status; Job satisfaction. X X X Social life Satisfaction with pre-social relationships and pre-social activities. Perceived social

support. X X X

Compensation status Claim lodged, Claim type, Claim finalisation, Legal representation, Disputes, Claims satisfaction. Previous claims.

X

DASS21: Depression, Anxiety and Stress Scale; IES-R: Impact of Events Scale; MINI: Mini International Neuropsychiatric Interview Version;

PANAS: Positive and Negative Affect Schedule; WHODAS: World Health Organisation Disability Assessment Schedule; NRS: Numeric Rating

Scale; OMPQ: Orebro Musculoskeletal Pain Question; PCS: Pain Catastrophising Scale; VAFS: Visual Analogue Fatigue Scale; GSE (General

Self-Efficacy Scale); BMI: Body Mass Index.

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Primary outcomes

The primary outcome is the development of psychological distress up to 12 months following

the MVC. Psychological distress is defined as any psychological discomfort that interferes

with daily living functioning, evaluated using a mixture of validated psychometric

assessments for depressive mood and anxiety (Depression, Anxiety and Stress Scale)[34] and

PTSD symptoms (Impact of Events Scale),[35] and diagnostic interview (Mini International

Neuropsychiatric Interview based on DSM V)[36] for driving phobia and adjustment

disorder. Another key outcome is autonomic functioning using HRV.

Secondary outcomes

Secondary outcomes include indicators of physical health (e.g. pain, fatigue and somatic

symptoms and/or new clinical diagnosis) and recovery as any psychosocial difficulty

experienced (e.g. health-related quality of life, social participation, return to functioning) up

12 months post-MVC. Other secondary measures include a comprehensive regimen of

biological factors (injury details), personal factors (socio-demographic, pre-injury health,

psychological reaction to the accident, perceptions) and environmental factors (crash

circumstances, economic factors, compensation, health care utilisation and satisfaction), that

may influence study outcomes.

Autonomic assessment

Measures and procedures: Autonomic measures include vital signs on the day of the accident

(at the scene and ED triage)[45] and autonomic biomarkers within 1 month (3-6 weeks) of

the injury, acquired using a BiosemiTM Active-Two System at a 2480 Hz native sampling

rate. Electrophysiology assessment will include respiration (sensitive band around chest),

electrodermal activity (surface electrodes on hand), peripheral body temperature (clip-on

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sensors on hand), blood volume pulse (finger light sensor), heart rate and HRV (ECG

recording).[46] For the ECG recording, three Ag/AgCl electrodes will be placed in modified

Einthoven I and II configurations (beneath the right and left clavicles, and on the 4th

intercostal space on the left side of the sternum).

Experimental design and structure: The chosen design allows examination of within

and between subject changes between phases. On the morning prior to the electrophysiology

assessment, participants will be asked to follow a normal sleep routine and to abstain from

eating, drinking caffeinated and alcoholic beverages, smoking and intense physical activity.

Recording will be conducted under constant conditions, between 8am-1pm to control

circadian influences.[47] Participants will sit in a relaxed position with eyes open. The

protocol includes four phases: i) 5-minute baseline, after a two minute acclimatisation; ii) 5-

minute response inhibition task, using the validated Stroop Color-Word test[40]; iii) 5-minute

recovery; iv) 2-minute slow paced breathing (6 breaths/min). Before every phase change,

participants will be asked to rate pain and fatigue intensity, and their emotional state (Self-

Assessment Manikin scale).[38]

Data manipulation: After appropriate data cleaning and re-sampling (512 Hz sampling

rate), analysis of phasic and tonic signals will be performed using Kubios (Version 2.0 beta 2,

Department of Applied Physics, University of Kuopio, Finland)[48] and other Analysis

Software. For HRV, time-domain, frequency-domain (LF: 0.04–0.15 Hz; HF: 0.15–0.4 Hz)

and non-linear indices will be analysed.

Hypothesis and Data analysis

All data analyses will be performed using SPSS software V.22. Descriptive statistics will

define socio-demographic characteristics and other variables of interest of the study. First,

risk will be calculated separately for each outcome by the frequency of occurrence and

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percentage over the 12 month post-MVC period, while latent class mixture growth modelling

will determine outcome class pathways. In addition, repeated measures linear mixed models

will analyse differences between and within groups over time.

To identify biomarkers/predictors at 3, 6 and 12 months post MVC, multiple regression

analyses will be conducted for each outcome of interest, after appropriate selection

procedures (e.g. univariate analysis, bootstrap), whereas adjustment for confounders will not

be considered as priority given the non-aetiologic nature of the study.[49]

Sensitivity/specificity analyses and constructing receiver operating character (ROC) plots

will determine discriminative performance.

Further, subgroup analyses and multiple regression will study differences and shared

predictors/biomarkers between mental and physical health outcomes following the MVC.

Clinical significance of autonomic biomarkers will be also tested using cluster analysis. The

same analyses will be conducted with control data, to describe differences in psychological

distress, psychosocial difficulties and autonomic balance within the group of MVC survivors.

Bias

To reduce selective bias, the study will adopt the following strategies: consecutive

recruitment from hospitals with different catchment areas, a 6-week inception period,

participant cost reimbursement, and adequate statistical power.

To minimise loss-to-follow-up, multiple options will be given on assessment modality

(online, paper-based on phone interview) and date/time to schedule the hospital visit. Follow-

up reminders via emails and phone calls will also increase adherence through the study.

Though experienced research staff will ensure quality and completeness of assessment,

missing data are expected to occur. Imputation techniques will be used for missing values,

considering comparison with non-missing cases. The study will also aim to assess a wide

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range of possible prognostic markers on their ability to identify people with poor outcomes,

for ease of use when translating the research findings to clinical practice.[49]

ETHICS AND DISSEMINATION

Approvals

Ethical approval was obtained from the Sydney Local Health District Ethics, Australia

(HREC/ 15/RPAH/423), and Site Specific approvals obtained for each site

(SSA/16/HAWKE/505; RESP/16/349). The study has been prospectively registered with the

Australia New Zealand Clinical trial registry on 17 October 2016 (Registration number:

ACTRN 12616001445460, IMPRINT study). STROBE guidelines have been followed for

this protocol.

Data storage and sharing

Eligible participants’ information will be stored on the local health server at the site, until

informed consent is obtained. Signed consent forms will be stored in lockable cabinets. Data

from consenting participants will be then entered and stored on a secure online platform

(REDCap) at The University of Sydney, to which only designated research team will have

access. Methodology details and de-identified data will be available on request once analyses

have been completed, provided there is no breach of participant confidentiality.

Confidentiality and safety aspects

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Written informed consent will be sought from participants and for publication of de-identified

study findings. Participants will be reminded their information will remain confidential and

that consent can be withdrawn at any time, without interference with their usual care.

To minimise and manage any distress or anxiety they may experience completing

assessments, the expertise of the principal investigators and follow-up care calls will be

employed to identify potential critical situations and provide guidance or referral to further

care.

Dissemination

Findings from this study will be disseminated through peer-reviewed publications and

conference presentations to communicate results and clinical implications to health

professionals and health policy makers. Presentations on research findings at local

community forums will also occur.

Authors’ contributions: All authors - IP, BG, YT, MD, MG, IDC, AC - provided inputs in

study design. IP, YT, and AC are involved in data analysis and data acquisition. IP, AC, BG,

IDC are responsible for publication writing. All authors reviewed and approved the final

version of this manuscript.

Funding: This study has received research grant support by the NSW State Insurance

Regulatory Authority (grant: MAA 14/1433) and the Australian Rotary Health (Ian Scott

Mental Health PhD Scholarship).

Acknowledgements: The authors would like to acknowledge the support of Emergency

Department staff at each of the study sites.

Competing interests: None declared.

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REFERENCES

1. World Health Organisation. Global status report on road safety 2015. WHO 2015.

2. Gabbe BJ, Lyons RA, Fitzgerald MC, et al. Reduced population burden of road transport–

related major trauma after introduction of an inclusive trauma system. Ann Surg

2015;261(3):565.

3. Polinder S, Haagsma J, Bos N, et al. Burden of road traffic injuries: Disability-adjusted life

years in relation to hospitalization and the maximum abbreviated injury scale. Accid

Anal Prev 2015;80:193-200.

4. Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291

diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global

Burden of Disease Study 2010. Lancet 2012;380(9859):2197-223.

5. Gopinath B, Jagnoor J, Elbers N, et al. Overview of findings from a 2-year study of

claimants who had sustained a mild or moderate injury in a road traffic crash:

prospective study. BMC Res Notes 2017;10(1):76.

6. Connelly LB, Supangan R. The economic costs of road traffic crashes: Australia, states and

territories. Accid Anal Prev 2006;38(6):1087-93.

7. Guest R, Tran Y, Gopinath B, et al. Psychological distress following a motor vehicle crash:

evidence from a statewide retrospective study examining settlement times and costs of

compensation claims. BMJ Open 2017;7(9):e017515.

8. Kenardy J, Heron-Delaney M, Warren J, et al. Effect of mental health on long-term

disability after a road traffic crash: results from the UQ SuPPORT study. Arch Phys

Med Rehabil 2015;96(3):410-17.

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9. Jacoby SF, Shults J, Richmond TS. The effect of early psychological symptom severity on

long-term functional recovery: A secondary analysis of data from a cohort study of

minor injury patients. Int J Nurs Stud 2017;65:54-61.

10. Craig A, Tran Y, Guest R, et al. Psychological impact of injuries sustained in motor

vehicle crashes: systematic review and meta-analysis. BMJ Open 2016;6(9):e011993.

11. Australian Bureau of Statistics. Australia National Survey of Mental Health and

Wellbeing 2016. Canberra, Australia: ABS 2016.

12. World Health Organization. Promoting mental health: Concepts, emerging evidence,

practice: Summary report. WHO 2004.

13. Smith B, Mackenzie-Ross S, Scragg P. Prevalence of poor psychological morbidity

following a minor road traffic accident (RTA): The clinical implications of a

prospective longitudinal study. Couns Psychol Q 2007;20(2):149-55.

14. Gopinath B, Jagnoor J, Harris IA, et al. Prognostic indicators of social outcomes in

persons who sustained an injury in a road traffic crash. Injury 2015;46(5):909-17.

15. Duckworth MP, Iezzi T. Physical injuries, pain, and psychological trauma: Pathways to

disability. Psychol Inj Law 2010;3(3):241-53.

16. Porges SW. The polyvagal theory: new insights into adaptive reactions of the autonomic

nervous system. Cleve Clin J Med 2009;76(Suppl 2):S86.

17. Thayer JF, Hansen AL, Saus-Rose E, et al. Heart rate variability, prefrontal neural

function, and cognitive performance: the neurovisceral integration perspective on self-

regulation, adaptation, and health. Ann Behav Med 2009;37(2):141-53.

18. McCraty R, Shaffer F. Heart rate variability: new perspectives on physiological

mechanisms, assessment of self-regulatory capacity, and health risk. Glob Adv Health

Med 2015;4(1):46-61.

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19. Balzarotti S, Biassoni F, Colombo B, et al. Cardiac Vagal Control as a Marker of

Emotion Regulation in Healthy Adults: A Review. Biol Psychol 2017.

20. Kok BE, Fredrickson BL. Upward spirals of the heart: Autonomic flexibility, as indexed

by vagal tone, reciprocally and prospectively predicts positive emotions and social

connectedness. Biol Psychol 2010;85(3):432-36.

21. Lu W-C, Tzeng N-S, Kao Y-C, et al. Correlation between health-related quality of life in

the physical domain and heart rate variability in asymptomatic adults. Health Qual

Life Outcomes 2016;14(1):149.

22. Beaumont A, Burton AR, Lemon J, et al. Reduced cardiac vagal modulation impacts on

cognitive performance in chronic fatigue syndrome. PloS One 2012;7(11):e49518.

23. Giummarra MJ, Casey SL, Devlin A, et al. Co-occurrence of posttraumatic stress

symptoms, pain, and disability 12 months after traumatic injury. Pain Rep

2017;2(5):e622.

24. Kemp AH, Quintana DS. The relationship between mental and physical health: insights

from the study of heart rate variability. Int J Psychophysiol 2013;89(3):288-96.

25. Sharp TJ, Harvey AG. Chronic pain and posttraumatic stress disorder: mutual

maintenance? Clin Psychol Rev 2001;21(6):857-77.

26. World Health Organization. International Classification of Functioning, Disability and

Health: ICF. WHO 2001.

27. Craig A, Tran Y, Craig M. Stereotypes towards stuttering for those who have never had

direct contact with people who stutter: A randomized and stratified study. Percept

Mot Skills 2003;97(1):235-45.

28. Greenspan L, McLELLAN BA, Greig H. Abbreviated Injury Scale and Injury Severity

Score: a scoring chart. J Trauma 1985;25(1):60-64.

29. Faul F. G* Power Version 3.1. 9.2 Universitat Kiel, Germany 2014.

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30. Teasdale G, Jennett B. Assessment of coma and impaired consciousness: a practical scale.

Lancet 1974;304(7872):81-84.

31. Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J

Clin Nurs 2005;14(7):798-804.

32. Linton SJ, Nicholas M, MacDonald S. Development of a short form of the Örebro

Musculoskeletal Pain Screening Questionnaire. Spine (Phila Pa 1976)

2011;36(22):1891-95.

33. Wewers ME, Lowe NK. A critical review of visual analogue scales in the measurement of

clinical phenomena. Res Nurs Health 1990;13(4):227-36.

34. Henry JD, Crawford JR. The short‐form version of the Depression Anxiety Stress Scales

(DASS‐21): Construct validity and normative data in a large non‐clinical sample. Br J

Clin Psychol 2005;44(2):227-39.

35. Weiss DS. The impact of event scale: revised. Springer 2007.

36. Association AP. Diagnostic and statistical manual of mental disorders (DSM-5®).

American Psychiatric Pub 2013.

37. Crawford JR, Henry JD. The Positive and Negative Affect Schedule (PANAS): Construct

validity, measurement properties and normative data in a large non‐clinical sample.

Br J Clin Psychol 2004;43(3):245-65.

38. Bradley MM, Lang PJ. Measuring emotion: the self-assessment manikin and the semantic

differential. J Behav Ther Exp Psychiatry 1994;25(1):49-59.

39. World Health Organisation. World Health Organization disabilty assessment schedule:

WHODAS II. Phase 2 field trials Health services research 2000.

40. Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol Gen

1935;121(1):15.

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41. Ware JE, Kosinski M, Turner-Bowker DM, et al. How to score version 2 of the SF-12

health survey (with a supplement documenting version 1). QualityMetric Incorporated

Lincoln, RI 2005.

42. Carver CS, Scheier MF, Weintraub JK. Assessing coping strategies: a theoretically based

approach. J Pers Soc Psychol 1989;56(2):267.

43. Sullivan MJ, Bishop SR, Pivik J. The pain catastrophizing scale: development and

validation. Psychol Assess 1995;7(4):524.

44. Luszczynska A, Scholz U, Schwarzer R. The general self-efficacy scale: multicultural

validation studies. J Psychol 2005;139(5):439-57.

45. Coronas R, Gallardo O, Moreno M, et al. Heart rate measured in the acute aftermath of

trauma can predict post-traumatic stress disorder: A prospective study in motor

vehicle accident survivors. Eur Psychiatry 2011;26(8):508-12.

46. Laborde S, Mosley E, Thayer JF. Heart rate variability and cardiac vagal tone in

psychophysiological research–recommendations for experiment planning, data

analysis, and data reporting. Front Psychol 2017;8:213.

47. Tran Y, Wijesuriya N, Tarvainen M, et al. The relationship between spectral changes in

heart rate variability and fatigue. J Psychophysiol 2009;23(3):143-51.

48. Tarvainen MP, Niskanen J-P, Lipponen JA, et al. Kubios HRV–heart rate variability

analysis software. Comput Methods Programs Biomed 2014;113(1):210-20.

49. Herbert RD. Cohort studies of aetiology and prognosis: they’re different. J Physiother

2014;60(4):241-44.

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Figure 1. ICF-based IMPRINT study framework: the biopsychosocial assessment of mental health and recovery post traffic injuries.

PERSONAL

FACTORS

Demographic

Mental health history

Physical history

Coping skills

Perceptions

Cognitive bias

Stressors

MVC

PHYSICAL HEALTH

Injury

Pain and Fatigue

Physical functioning

MENTAL HEALTH

Psychological Distress

Emotional functioning

Cognitive functioning

BODY FUNCTIONS

AND STRUCTURES

AUTONOMIC

FUNCTIONING

ENVIRONMENTAL

FACTORS

Socioeconomic status

Social life

Crash circumstances

Employment

Health care quality

Compensation

RECOVERY

QoL

Disability

ACTIVITIES AND

PARTICIPATION

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Table S1. STROBE Checklist of items that should be included in reports of case-control

studies.

Item

No Recommendation

Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or

the abstract

�

(b) Provide in the abstract an informative and balanced summary of

what was done and what was found

�

Introduction

Background/rationale 2 Explain the scientific background and rationale for the investigation

being reported

�

Objectives 3 State specific objectives, including any prespecified hypotheses �

Methods

Study design 4 Present key elements of study design early in the paper �

Setting 5 Describe the setting, locations, and relevant dates, including periods of

recruitment, treatment, follow-up, and data collection �

Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and

methods of selection of participants. Describe methods of follow-up

Case-control study—Give the eligibility criteria, and the sources and

methods of case ascertainment and control selection. Give the rationale

for the choice of cases and controls

Cross-sectional study—Give the eligibility criteria, and the sources and

methods of selection of participants

�

(b) Cohort study—For matched studies, give matching criteria and

number of treated and untreated

Case-control study—For matched studies, give matching criteria and

the number of controls per case

�

Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers

potentially eligible, examined for eligibility, confirmed eligible,

included in the study, completing follow-up, and analysed

N/A

(b) Give reasons for non-participation at each stage N/A

Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical,

social) and information on other treatments and potential confounders

N/A

(b) Indicate number of participants with missing data for each variable

of interest

N/A

(c) Cohort study—Summarise follow-up time (eg, average and total

amount)

N/A

Variables 7 Clearly define all outcomes, treatments, predictors, potential

confounders, and effect modifiers. Give diagnostic criteria, if applicable

�

Data sources/

measurement

8* For each variable of interest, give sources of data and details of methods

of assessment (measurement). Describe comparability of assessment

methods if there is more than one group.

�

Bias 9 Describe any efforts to address potential sources of bias �

Study size 10 Explain how the study size was arrived at �

Quantitative

variables

11 Explain how quantitative variables were handled in the analyses. If

applicable, describe which groupings were chosen and why

�

Statistical methods 12 (a) Describe all statistical methods, including those used to control for

confounding

�

(b) Describe any methods used to examine subgroups and interactions �

(c) Explain how missing data were addressed �

(d) Cohort study—If applicable, explain how loss to follow-up was

addressed

Case-control study—If applicable, explain how matching of cases and

controls was addressed

Cross-sectional study—If applicable, describe analytical methods

�

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taking account of sampling strategy

(e) Describe any sensitivity analyses �

*Give information separately for cases and controls.

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For peer review onlyBiomarkers of sympathetic-parasympathetic balance for predicting psychological distress and recovery following

road traffic injuries: protocol for a prospective cohort study.

Journal: BMJ Open

Manuscript ID bmjopen-2018-024391.R1


Date Submitted by the Author: 04-Oct-2018


<b>Primary Subject Heading</b>: Mental health

Secondary Subject Heading: Rehabilitation medicine



BMJ Open


1

Biomarkers of sympathetic-parasympathetic balance for predicting psychological

distress and recovery following road traffic injuries: protocol for a prospective cohort

study.

Ilaria Pozzato1

Ashley Craig1

Bamini Gopinath1

Yvonne Tran1

Michael Dinh2

Mark Gillett 3

Ian D Cameron1





Correspondence to:

Ashley Craig







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ABSTRACT



is to examine whether autonomic biomarkers alone or in combination with other factors

assessed shortly after MVC, could predict risk of elevated psychological distress and poor

functional recovery in the long term, and clarify links between mental and physical health

outcomes.







The primary outcomes are the development of psychological distress and autonomic

biomarkers. Secondary outcomes include quality of life, return to functioning, participation

and physical health indicators. For each outcome, risk will be described by the frequency of

occurrence over the 12 months, and pathways determined via latent class mixture growth

modelling. Regression models will be used to identify best predictors/biomarkers and to

study associations between mental and physical health.






study).

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• This study will comprehensively describe the risk of developing psychological distress


mild to moderate injuries.

• Identifying biomarkers of mental health risk and recovery adds novelty to this field. Easy-

to-measure markers of autonomic balance hold promise in preventing serious mental

disorders, reducing patient-related barriers to mental health care and improving recovery

among crash survivors.

• The use of the ICF standard framework will assure an in-depth analysis of all domains

involved in a person’s functioning, which are often studied in isolation, and will promote

comparability with other research.

• Findings may be useful to general and acute care clinicians in the early detection of at-

risk individuals, for a better management of mental health and a more integrated form of

care.

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INTRODUCTION



consequences, and many individuals develop long-term disability.[2-4] While improved

outcomes are shown for severe injuries,[5] evidence suggests that minor-to-moderate injuries

are a challenge.[6, 7] With traffic injuries remaining the 10th leading cause of Disability

Adjusted Life Years (DALYs) in 2010,[8] non-severe injuries (i.e. Maximum Abbreviated

Injury Score of less than 3) account for 46% of injury-related disability.[3] Therefore,

consequences and costs of non-severe traffic injuries such as whiplash, mild traumatic brain

injury and musculoskeletal injury are serious public health concerns.[6]

A recent longitudinal study from Europe reported that non-severe (MAIS <3) traffic

injuries hospitalised for more than 24 hours result in higher average costs, both direct and

indirect, compared to severe injuries.[9] On the other hand, in Australia it is estimated that

around $1b is spent each year only on traffic injuries admitted to hospital for less than 24

hours, with an average cost by casualty of $14,183.[10] Furthermore, when psychological

problems are involved, care costs have been shown to escalate alarmingly and time to

recovery to increase fourfold.[11]

Psychological distress is prevalent in people surviving a MVC and has been

demonstrated to be a substantial contributor to long-lasting morbidity and disability,[7, 12,

13] affecting up to one in two MVC survivors, according to a recent meta-analysis.[14]

Although there is some variability in estimates, the proportion of MVC survivors (up to 50%)

who experience psychological problems appears to be many times greater than the proportion

of people with mental health in the Australian community (20%)[15] and global population


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(PTSD), major depressive disorder (MDD), driving phobias and other anxiety disorders.[17,

18]

Unlike physical problems that ideally receive appropriate and timely medical care

following a MVC, early clinical management of psychological symptoms associated with

mild to moderate physical injury rarely occur since, for example, these are often normalised

as a common response to the trauma. Hence, it is not surprising that mental health-related

quality of life of MVC survivors is more resistant to improvement over time than physical

outcomes, as for instance demonstrated by Kenardy et al.[12] This is pertinent given failure

to address psychological distress will have a significant detrimental impact on functional

recovery,[19] supporting the hypothesis that there is ‘no health without mental health’.[16]




arousal,[14] and which often co-occur following a MVC.[18] It is argued that these

symptoms may be all manifestations of one construct of general distress.[20] However,

previous studies on MVC survivors typically focused on a single mental disorder, particularly

post-traumatic stress disorder (PTSD). The second and more significant fact is the absence of

empirical evidence for reliable biomarkers of vulnerability to psychological distress

following a MVC.

Vulnerability to psychological distress and poor recovery draws on the broader concept

of psychological resilience as the unique ability of an individual to adapt to adversity, which

develops throughout the lifespan.[21] Following an MVC, individual vulnerability to poor

adjustment, i.e. persistence of psychological distress and physical symptoms and poor

functioning, has been linked to a number of biological (e.g. pre-injury health, injury severity),

psychological (e.g. prior traumatic experiences, perceptions) and environmental factors (e.g.

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social support, compensation),[4, 19, 22] however biological responses, in particular

autonomic responses, to traffic injury remain an under-investigated area.

Unlike other traumatic or pathological conditions, there have been very few studies

examining the predictive value of autonomic biomarkers, such as traditional vital signs[23-

28] measured early after a MVC, to investigate long-term outcomes, and only one study, to

our knowledge, has attempted to use heart rate variability (HRV).[29] The main focus of

these studies was the association between heart rate at the scene or during hospitalisation and

the development of PTSD following a MVC. However, there was lack of consistency

between findings, highlighting differences in methodology and confirming that substantial

inter-individual variability exists in psychobiological responses to physical threat.

Biological responses to potential threats involve activation of neural substrates such as

the stress response system. The autonomic nervous system (ANS) is the first to respond to

stressors by a transitory withdrawal of the parasympathetic ‘brake’ and modulation of

sympathetic activity for a rapid control of body functions critical for survival, i.e. changes in

heart rate, blood pressure and breathing rate, and later re-engagement of the parasympathetic

system during recovery, by inhibition of sympathetic control.

Studying the sympathetic-parasympathetic balance is rather complex, and one marker is

often not enough to convey the complexity of stress regulatory processes.[30] Therefore,

more research is needed to assess autonomic resting level, reactivity and recovery[31] in a

comprehensive manner, by using several markers to increase predictive ability[21, 32] and

investigating their relationship with other psychological, social and biological factors. There

is emerging evidence of associations between negative affect, perseverative cognition and

physiological over-reactivity to stress [21, 33], as introduced for example, by the

perseverative cognition hypothesis.[34] The most common autonomic markers include vital

signs (i.e. heart rate, respiratory rate, blood pressure, peripheral skin temperature), skin

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conductance, peripheral blood circulation and heart rate variability. While skin conductance

and peripheral skin temperature have been widely used as an index of sympathetic activity,

heart rate variability (HRV), the variation in the beat-to-beat interval, is recommended as a

reliable, noninvasive index for assessing cardiac vagal tone. Higher levels of vagally-

mediated resting-state HRV [33] and faster cardiovascular recovery [21], have been shown to

be associated with better self-regulatory capacity to environmental demands.

Different theoretical models[35-37] have linked vagally-mediated HRV to individual

differences in adaptation to external and internal stressors, suggesting ANS imbalance is an

indicator of poor self-regulatory capacity in managing stress levels, that can be associated

with poor psychological health,[38, 39] physical health,[40, 41] cognitive performance,[36,

41] and social functioning.[35, 39] Thus, ANS imbalance, measured early after a MVC, is

regarded as a promising biomarker of vulnerability to develop dysfunctional responses, such

as elevated psychological distress and stress-related disorders that can affect a person's

capacity to recover following traffic injury.[42]


physical conditions among MVC survivors, for example anxiety, depression, chronic pain,

fatigue, sleep disturbance, and other somatic conditions,[22, 43] for which physical evidence

is often missing, hinting at the possibility of shared psychological and biological factors in

stress vulnerability.[44-46] However, the majority of evidence for these associations comes

from cross-sectional studies, especially from the relationship between chronic pain and PTSD

in whiplash injuries. Therefore, prospective research is now needed to investigate links

between mental and physical health in recovery from traffic injuries.

In the current study, the WHO International Classification of Functioning (ICF)[47]

will be employed as the biopsychosocial framework to assess mental health and recovery

outcomes following MVC-related injury, and to build a comprehensive prognostic model for

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identification of the at-risk cohort. Within this model, the use of autonomic biomarkers will

be novel, and so the use of ICF as a multidimensional approach to assess recovery from non-

severe MVC injuries. Early detection is crucial for preventing disease and progression to

chronicity, therefore this study has the potential to prevent the development of serious mental

health conditions and improve recovery of thousands of MVC survivors in Australia

annually. Employing easy-to-measure ‘biological markers’ for early detection of risk of

mental health disorders may facilitate timely access to care and help reduce patient-related

barriers to mental health care.[48]

Study Aims


1) To determine prevalence estimates and trajectories of psychological distress and recovery

post-MVC;

2) To determine the efficacy of autonomic biomarkers, alone or in combination with other

biopsychosocial factors, in predicting mental health and poor recovery following injury

sustained in a MVC;

3) To investigate associations and shared predictors/biomarkers, between mental and physical

health outcomes post-MVC.




1. The WHO International Classification of Functioning Disability and Health (ICF) model is

widely recognised as the most recent and comprehensive framework for assessing health and

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disability. Therefore, it provides an effective framework for describing consequences of road

traffic injuries, such as psychological distress and poor recovery. Potential predictors will be

biological, personal and environmental factors, with a particular focus on testing the

predictive ability of autonomic biomarkers, which are simple and easy-to-measure. This is a

prognostic study where event prediction will follow a data-driven approach and careful

consideration will be given to the issue of over-fitting.[49] There are also plans of exploring

causal effects that will come as a separate proposal.

Design


distress and poor recovery among mildly to moderately injured MVC survivors (Injury

Severity Score [ISS][50] ≤ 15)[51-53]. Baseline assessment will occur around 1 month (3 to

6 weeks) of their injury, with follow-up assessments occurring at 3, 6 and 12 months post-

injury. Results will be compared to a control group who have not sustained a MVC or severe

injuries in the past 5 years, and who will be assessed at the same time periods.

Setting

The Emergency Departments of two of the seven adult major trauma services in NSW,

Australia, were involved in recruitment of MVC survivors: Royal North Shore Hospital

(RNSH) and Royal Prince of Alfred Hospital (RPAH). These are large public hospitals

located in Sydney metropolitan area, providing care to trauma patients across the whole

spectrum of severity.


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presented in Table 1. These include exposure status (i.e. injury vs non-injury) and factors

related to the outcomes being studied (i.e. mental health, autonomic function, disability and

physical health). At the time of their enrolment both cohorts will be free of severe mental

health disorders or major disabling conditions due to very severe injury like spinal cord

injury. The non-injured cohort will include normally healthy individuals with no active

medical concern or serious comorbid conditions (i.e. chronic disease, degenerative neurologic

disease). Medications or other factors that could potentially influence autonomic function/

outcomes investigated, as well as differences between the two cohorts, will be adjusted for in

the analysis.

The identification of MVC survivors will begin following their presentation to the

emergency departments (ED) of the two hospitals. Participants will be consecutively

identified and assessed for eligibility by a research nurse from the information management

system, FirstNet.

The non-MVC control group, matched by sex and age (± 5 years) to the MVC sample

on a case by case basis, will be recruited through advertising. Study eligibility will be

assessed using an online self-reported screening interview.

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MVC participants Non-MVC controls

Inclusion

criteria • Age ≥18 years • Age ≥18 years

• Sustained in last 6 weeks, a minor to moderate injury due to MVC in NSW, Australia

• No history of MVC, serious injury or traumatic event (i.e. w/ perceived threat of injury to self or others) in the previous 5 years

• A driver, motorbike rider, passenger, pillion passenger, pedestrian and bicyclist (only collision involving a motorised vehicle)


• Presented to RNSH or RPAH Emergency Departments, Sydney, Australia


Exclusion

criteria

• Catastrophic injury as defined by NSW icare lifetime care, i.e. a very severe traumatic brain injury, a spinal cord injury, extensive burns to the body (>60%), major amputation or blindness

• Catastrophic injury: severe brain injury, spinal cord injury, extensive burns to the body, major amputation or blindness

• Serious Injury (ISS[50] >15)[51] • Severe mental health condition • Localised, superficial soft tissue injuries • Dementia or cognitive impairment

affecting ability to consent • MVC due to intentional self-harm or MVC

survivors with severe mental health condition • Chronic disease such as severe heart

disease, stroke, cancer, chronic respiratory diseases, obesity and advanced complicated diabetes.

• Death of a family member in the MVC • Degenerative neurologic disease • Dementia or cognitive impairment affecting

ability to consent

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Recruitment process and timeframe

Eligible survivors will be invited to participate by: i) being approached at the time of ED

presentation, or ii) receiving an invitation letter to their postal address from the ED treating

clinician. After written consent is obtained (opt-in approach), participants will be requested to

complete the baseline interview-based assessment by accessing an online secure website, and

otherwise by completing a paper-based or phone interview. As part of their enrollment,

within 6 weeks of their accident, participants will also be asked to attend a 30-minute hospital

visit for collection of autonomic biomarkers (autonomic assessment). An overall

reimbursement up to $100 in vouchers will be provided to cover participant travel cost and

time.

The first participant was recruited on 16 June 2017, and both sites are actively

contributing towards the recruitment target. It is anticipated that the recruitment will last until

the end of January 2019, thus data collection is expected to be completed by early 2020.

Participants’ recruitment flowchart is illustrated in Figure 2.

Sample size







90%.[54]


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Assessment time points and details of the validated measures used within each ICF domain

are provided in Table 2.

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Table 2. IMPRINT study: Measures and Assessment Points, within each ICF Domain.

ICF MODEL STUDY ASSESSMENTS AND MEASUREMENTS

Domain Category Measures Assessment points


3 months

6 & 12 months

BODY

FUNCTIONS &

STRUCTURES


X

Autonomic functioning *Biomarkers

Post-crash vital signs; HRV; Heart rate; Respiration rate; Skin conductance; Peripheral body temperature; Blood volume pulse.

X

Pain Pain Intensity (NRS[56]); Risk of persistent pain and disability (OMPQ, short form[57]).

X X X

Fatigue Fatigue Intensity (VAFS[58]). X X X Physical health Stress-related physical symptoms (sleep disturbance, loss of sex drive, frequent

infections, upset stomach, constipation); Lifestyle habits (physical activity, smoking, alcohol use); Medications; Referral to physiotherapist; Post-crash new clinical diagnoses.

X X X

Mental health Depressive mood and Anxiety (DASS21[59]); PTSD symptoms (IES-R[60]); Driving Phobia (MINI[61]); Adjustment Disorder (MINI[61]); Referral to psychologist/psychiatrist.

X X X

Emotional functioning Emotional balance (PANAS[62]); Valence and Arousal dimension of emotions (Self-Assessment Manikin scale[63]).

X X X

Cognitive functioning Perceived cognitive functioning (WHODAS II - Domain 1[64]); Stroop test[65]. X X X ACTIVITIES Quality of life Health-related physical and mental quality of life (SF-12[66]). X X X PARTICIPATION Disability Return to work and activities; Social participation (WHODAS II - Domain 6[64]). X X X PERSONAL

FACTORS

Socio-demographic Sex; Age; Primary language; Education; Marital status. X Traumas and stressors Prior and post-crash Stressors. Traumatic events following the crash (MINI[61]). X

Physical health history

Past clinical and medication history; Body composition (BMI); Past chronic pain or fatigue diagnosis; Pre-health care utilisation.

X


X

Coping Skills Coping responses (COPE Inventory[67]). X X X Perceptions Perceived life threat; Perceived helplessness; Blame vs self or others; Perceived

injustice; Perceived resilience; Perceived sense of safety and life balance. X X X

Cognitive bias Pain catastrophizing, Rumination, Magnification (PCS[68]); Self-efficacy beliefs X X X

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(GSE[69]); Expectations to return to work (OMPQ[57]) and expectations to recover.

ENVIRONMENTAL

FACTORS

Crash circumstances Role in the accident. X Health care quality Care satisfaction. X X X Socioeconomic status Index of Relative Socioeconomic Disadvantage; Financial issues pre- and post-

crash. X

Employment Pre-injury employment status; Job satisfaction. X X X Social life Satisfaction with pre-social relationships and pre-social activities. Perceived social

support. X X X

Compensation status Claim lodged, Claim type, Claim finalisation, Legal representation, Disputes, Claims satisfaction. Previous claims.

X

DASS21: Depression, Anxiety and Stress Scale; IES-R: Impact of Events Scale; MINI: Mini International Neuropsychiatric Interview Version;

PANAS: Positive and Negative Affect Schedule; WHODAS: World Health Organisation Disability Assessment Schedule; NRS: Numeric Rating

Scale; OMPQ: Orebro Musculoskeletal Pain Question; PCS: Pain Catastrophizing Scale; VAFS: Visual Analogue Fatigue Scale; GSE (General

Self-Efficacy Scale); BMI: Body Mass Index.

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Primary outcomes

The primary outcome is the development of psychological distress as any psychological

discomfort that interferes with daily living functioning following the MVC. Psychological

distress is defined as the presence of at least one of the following psychological symptoms

over the 12 months after the MVC, including elevated depressive mood and anxiety

(Depression, Anxiety and Stress Scale)[59] and PTSD symptoms (Impact of Events

Scale),[60] evaluated using these two validated psychometric assessments, as well as the

presence of driving phobia and adjustment disorder using diagnostic interview (Mini

International Neuropsychiatric Interview based on DSM V)[61] . Another key outcome is

autonomic functioning by means of HRV and other autonomic measures of sympathetic-

parasympathetic balance as described below.

Secondary outcomes

Secondary outcomes include indicators of physical health (e.g. pain, fatigue and somatic

symptoms and/or new clinical diagnosis) and recovery as any psychosocial difficulty

experienced (e.g. health-related quality of life, social participation, return to functioning) up

12 months post-MVC. Other secondary measures include a comprehensive regimen of

biological factors (injury details), personal factors (socio-demographic, pre-injury health,

psychological reaction to the accident, perceptions) and environmental factors (crash

circumstances, economic factors, compensation, health care utilisation and satisfaction), that

may influence study outcomes.

Autonomic assessment

Measures and procedures: Autonomic measures consist of vital signs (heart rate,

respiratory rate, blood pressure) on the day of the accident (at the scene and ED triage)[23]

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and autonomic biomarkers around 1 month (3-6 weeks) of the injury, non-invasively and

simultaneously acquired using a BiosemiTM Active-Two System at a 2480 Hz native

sampling rate. Electrophysiology assessment will include respiration rate (sensitive band

around chest), skin conductance (SC) level and responsiveness, i.e. absolute SC and

number/amplitude of non-specific SC fluctuations (surface electrodes on second and fourth

fingers of non-dominant hand), peripheral body temperature (clip-on sensor on fifth finger of

non-dominant hand), blood volume pulse amplitude (light sensor on third finger of non-

dominant hand), heart rate and HRV (ECG recording).[70] For the ECG recording, three

Ag/AgCl electrodes will be placed in modified Einthoven I and II configurations (beneath the

right and left clavicles, and on the 4th intercostal space on the left side of the sternum).


and between subject changes between phases. For an in-depth investigation of autonomic

regulatory processes, a 3-R protocol[33] will be employed that allows examination of tonic

resting level (baseline) and phasic autonomic control, including autonomic reactivity (change

between baseline and task) and recovery (change between task and post-task, percentage/time

of return to baseline).

On the morning prior to the electrophysiology assessment, participants will be asked to

follow a normal sleep routine and to abstain from eating, drinking caffeinated and alcoholic

beverages, smoking and intense physical activity. Recording will be conducted under

constant conditions, between 8am-1pm to control circadian influences.[71] Participants will

sit in a relaxed position with eyes open. The protocol includes four phases, throughout which

autonomic biomarkers will be measured continuously: i) 5-minute resting baseline, after a

two-minute acclimatisation; ii) 5-minute response inhibition task, using the validated Stroop

Color-Word test[65]; iii) 5-minute resting post-task; iv) 2-minute slow paced breathing (6

breaths/min), using a breath pacer application providing visual feedback for breathing cycle

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control. Before every phase change, participants will be asked to rate pain and fatigue

intensity, and their emotional state (Self-Assessment Manikin scale).[63]

Data manipulation: After appropriate data cleaning to remove noise and artifacts and

re-sampling (512 Hz sampling rate), biosignals analysis will be performed using Kubios

(Version 2.0 beta 2, Department of Applied Physics, University of Kuopio, Finland)[72] and

other Analysis Software. For HRV, time-domain, frequency-domain (LF: 0.04–0.15 Hz; HF:

0.15–0.4 Hz) and non-linear indices will be analysed.

Hypothesis and Data analysis

It is first hypothesised that among MVC survivors disrupted autonomic functioning, alone or

in association with other personal and environmental factors, would be a strong predictor for

the risk of elevated psychological distress and poorer recovery following a MVC.




percentage over the 12-month post-MVC period, while latent class mixture growth modelling


will be used to analyse differences between and within groups over time.







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Further, it is hypothesised that shared trajectories and predictors/biomarkers may exist

for vulnerability to mental and physical health disorders in recovery from a MVC. Subgroup

analyses and multiple regression will study differences and shared predictors/biomarkers

between mental and physical health outcomes following the MVC. Clinical significance of

autonomic biomarkers will be also tested using cluster analysis and other exploratory

analyses.

Finally, it is hypothesised that MVC survivors compared to the non-injured group, would

have greater disruption of autonomic functioning, be in worse physical and mental shape and

have higher disability. The same analyses will be conducted with control data, to describe

differences in psychological distress, psychosocial difficulties and autonomic balance within

the group of MVC survivors.

Bias

To reduce selective bias, the study will adopt the following strategies: a 6-week inception

period, participant cost reimbursement, adequate statistical power, as well as consecutive

recruitment from two hospitals with major catchments for traumatic MVC injury in Sydney

that will provide a wide variety across ethnicity, culture, socioeconomic status and education

levels.







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Patient and Public Involvement

Research question and outcome measures were developed with knowledge from our ongoing

research into patient feedback, expectations and concerns following traumatic injury.

However, the present study is not a clinical trial, therefore participants were not directly

involved in study design, conduct or assessment of intervention. Nevertheless, findings from

this study, i.e. peer-reviewed publications, will be shared with study participants via email

communication.


Approvals


(HREC/ 15/RPAH/423), and Site-Specific approvals obtained for each site




this protocol.




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care.

Dissemination









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REFERENCES

1. World Health Organisation. Global status report on road safety 2015. Geneva,

Switzerland: WHO 2015.

2. Alghnam S, Palta M, Remington PL, et al. The association between motor vehicle

injuries and health-related quality of life: a longitudinal study of a population-based sample

in the United States. Qual Life Res 2014;23(1):119-27.

3. Polinder S, Haagsma J, Bos N, et al. Burden of road traffic injuries: Disability-

adjusted life years in relation to hospitalization and the maximum abbreviated injury scale.

Accid Anal Prev 2015;80:193-200.

4. Nhac-Vu H-T, Hours M, Chossegros L, et al. Prognosis of outcome in adult survivors

of road accidents in France: one-year follow-Up in the ESPARR cohort. Traffic Inj Prev

2014;15(2):138-47.

5. Gabbe BJ, Lyons RA, Fitzgerald MC, et al. Reduced population burden of road

transport–related major trauma after introduction of an inclusive trauma system. Ann Surg

2015;261(3):565.

Page 22 of 34


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


23


claimants who had sustained a mild or moderate injury in a road traffic crash: prospective

study. BMC Res Notes 2017;10(1):76.

7. Haagsma J, van Beeck E, Toet H, et al. Posttraumatic Stress Disorder Following

Injury: Trajectories and Impact on Health-Related Quality of Life. J Depress Anxiety

2013;14:1242-49.


diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden

of Disease Study 2010. Lancet 2012;380(9859):2197-223.

9. Papadakaki M, Stamouli M-A, Ferraro OE, et al. Hospitalization costs and estimates

of direct and indirect economic losses due to injury sustained in road traffic crashes: results

from a one-year cohort study in three European countries (the REHABILAID project).

Trauma 2017;19(4):264-76.

10. Connelly LB, Supangan R. The economic costs of road traffic crashes: Australia,

states and territories. Accid Anal Prev 2006;38(6):1087-93.

11. Guest R, Tran Y, Gopinath B, et al. Psychological distress following a motor vehicle

crash: evidence from a statewide retrospective study examining settlement times and costs of

compensation claims. BMJ Open 2017;7(9):e017515.


disability after a road traffic crash: results from the UQ SuPPORT study. Arch Phys Med

Rehabil 2015;96(3):410-7.

13. Jacoby SF, Shults J, Richmond TS. The effect of early psychological symptom

severity on long-term functional recovery: A secondary analysis of data from a cohort study

of minor injury patients. Int J Nurs Stud 2017;65:54-61.

Page 23 of 34


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


24


vehicle crashes: systematic review and meta-analysis. BMJ Open 2016;6(9):e011993.




practice: Summary report. Geneva, Switzerland: WHO 2004.


following a minor road traffic accident (RTA): The clinical implications of a prospective

longitudinal study. Couns Psychol Q 2007;20(2):149-55.

18. Kenardy J, Edmed SL, Shourie S, et al. Changing patterns in the prevalence of

posttraumatic stress disorder, major depressive episode and generalized anxiety disorder over

24 months following a road traffic crash: Results from the UQ SuPPORT study. J Affect

Disord 2018;236:172-9.


persons who sustained an injury in a road traffic crash. Injury 2015;46(5):909-17.

20. Grant DM, Beck JG, Marques L, et al. The structure of distress following trauma:

Posttraumatic stress disorder, major depressive disorder, and generalized anxiety disorder. J

Abnorm Psychol 2008;117(3):662.

21. Walker FR, Pfingst K, Carnevali L, et al. In the search for integrative biomarker of

resilience to psychological stress. Neurosci Biobehav Rev 2017;74:310-20.

22. Duckworth MP, Iezzi T. Physical injuries, pain, and psychological trauma: Pathways

to disability. Psychol Inj Law 2010;3(3):241-53.

23. Coronas R, Gallardo O, Moreno M, et al. Heart rate measured in the acute aftermath

of trauma can predict post-traumatic stress disorder: A prospective study in motor vehicle

accident survivors. Eur Psychiatry 2011;26(8):508-12.

Page 24 of 34


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


25

24. Kuhn E, Blanchard EB, Fuse T, et al. Heart rate of motor vehicle accident survivors in

the emergency department, peritraumatic psychological reactions, ASD, and PTSD severity:

A 6‐month prospective study. J Trauma Stress 2006;19(5):735-40.

25. Blanchard EB, Hickling EJ, Galovski T, et al. Emergency room vital signs and PTSD

in a treatment seeking sample of motor vehicle accident survivors. J Trauma Stress

2002;15(3):199-204.

26. Veazey CH, Blanchard EB, Hickling EJ, et al. Physiological responsiveness of motor

vehicle accident survivors with chronic posttraumatic stress disorder. Appl Psychophysiol

Biofeedback 2004;29(1):51-62.

27. Bryant RA, Harvey AG, Guthrie RM, et al. Acute psychophysiological arousal and

posttraumatic stress disorder: a two-year prospective study. J Trauma Stress 2003;16(5):439-

43.

28. Zatzick DF, Russo J, Pitman RK, et al. Reevaluating the association between

emergency department heart rate and the development of posttraumatic stress disorder: A

public health approach. Biol Psychiatry 2005;57(1):91-5.

29. Guédon-Moreau L, Ducrocq F, Molenda S, et al. Temporal analysis of heart rate

variability as a predictor of post traumatic stress disorder in road traffic accidents survivors. J

Psychiatr Res 2012;46(6):790-6.

30. Berna G, Ott L, Nandrino J-L. Effects of emotion regulation difficulties on the tonic

and phasic cardiac autonomic response. PloS One 2014;9(7):e102971.

31. Laborde S, Mosley E, Mertgen A. Vagal tank theory: the 3 Rs of cardiac vagal control

functioning–Resting, Reactivity, and Recovery. Front Neurosci 2018;12:458.

32. Prinsloo GE, Rauch HL, Derman WE. A brief review and clinical application of heart

rate variability biofeedback in sports, exercise, and rehabilitation medicine. Phys Sportsmed

2014;42(2):88-99.

Page 25 of 34


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


26

33. Laborde S, Mosley E, Mertgen A. Vagal tank theory: the three rs of cardiac vagal

control functioning–resting, reactivity, and recovery. Front Neurosci 2018;12.

34. Brosschot JF, Gerin W, Thayer JF. The perseverative cognition hypothesis: A review

of worry, prolonged stress-related physiological activation, and health. J Psychosom Res

2006;60(2):113-24.

35. Porges SW. The polyvagal theory: new insights into adaptive reactions of the

autonomic nervous system. Cleve Clin J Med 2009;76(Suppl 2):S86.



regulation, adaptation, and health. Ann Behav Med 2009;37(2):141-53.


mechanisms, assessment of self-regulatory capacity, and health risk. Glob Adv Health Med

2015;4(1):46-61.


Emotion Regulation in Healthy Adults: A Review. Biol Psychol 2017.

39. Kok BE, Fredrickson BL. Upward spirals of the heart: Autonomic flexibility, as

indexed by vagal tone, reciprocally and prospectively predicts positive emotions and social

connectedness. Biol Psychol 2010;85(3):432-6.

40. Lu W-C, Tzeng N-S, Kao Y-C, et al. Correlation between health-related quality of life

in the physical domain and heart rate variability in asymptomatic adults. Health Qual Life

Outcomes 2016;14(1):149.

41. Beaumont A, Burton AR, Lemon J, et al. Reduced cardiac vagal modulation impacts

on cognitive performance in chronic fatigue syndrome. PloS One 2012;7(11):e49518.

42. Carnevali L, Koenig J, Sgoifo A, et al. Autonomic and Brain Morphological

Predictors of Stress Resilience. Front Neurosci 2018;12:228.

Page 26 of 34


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


27


symptoms, pain, and disability 12 months after traumatic injury. Pain Rep 2017;2(5):e622.

44. Kemp AH, Quintana DS. The relationship between mental and physical health:

insights from the study of heart rate variability. Int J Psychophysiol 2013;89(3):288-96.


maintenance? Clin Psychol Rev 2001;21(6):857-77.

46. McLean SA, Clauw DJ, Abelson JL, et al. The development of persistent pain and

psychological morbidity after motor vehicle collision: integrating the potential role of stress

response systems into a biopsychosocial model. Psychosom Med 2005;67(5):783-90.


Health: ICF. Geneva, Switzerland: WHO 2001.

48. Craig A, Tran Y, Craig M. Stereotypes towards stuttering for those who have never

had direct contact with people who stutter: A randomized and stratified study. Percept Mot

Skills 2003;97(1):235-45.


2014;60(4):241-4.

50. Greenspan L, McLELLAN BA, Greig H. Abbreviated Injury Scale and Injury

Severity Score: a scoring chart. J Trauma 1985;25(1):60-4.

51. New South Wales Institute of Trauma and Injury Management. The NSW Trauma

Registry profile of serious to critical injuries. Sydney: NSW Health 2009.

52. Mitchell RJ, Chong SS. Injury trends and mortality in adult patients with major

trauma in New South Wales. Med J Aust 2012;197(4):233-7.

53. Cameron PA, Gabbe BJ, Cooper DJ, et al. A statewide system of trauma care in

Victoria: effect on patient survival. Med J Aust 2008;189(10):546.

54. Faul F. G* Power Version 3.1. 9.2. Kiel: Universitat Kiel, Germany; 2014.

Page 27 of 34


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


28

55. Teasdale G, Jennett B. Assessment of coma and impaired consciousness: a practical

scale. Lancet 1974;304(7872):81-4.

56. Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales.

J Clin Nurs 2005;14(7):798-804.


Musculoskeletal Pain Screening Questionnaire. Spine (Phila Pa 1976) 2011;36(22):1891-5.

58. Wewers ME, Lowe NK. A critical review of visual analogue scales in the

measurement of clinical phenomena. Res Nurs Health 1990;13(4):227-36.

59. Henry JD, Crawford JR. The short‐form version of the Depression Anxiety Stress

Scales (DASS‐21): Construct validity and normative data in a large non‐clinical sample. Br

J Clin Psychol 2005;44(2):227-39.

60. Weiss DS, Marmar CR. The Impact of Event Scale-Revised. In: Wilson JP, Keane

TM, eds. Assessing psychological trauma and PTSD: a practitioner's handbook. Guilford

1997:399–411.

61. Diagnostic and statistical manual of mental disorders (DSM-5®). Arlington:

American Psychiatric Association 2013.

62. Crawford JR, Henry JD. The Positive and Negative Affect Schedule (PANAS):

Construct validity, measurement properties and normative data in a large non‐clinical

sample. Br J Clin Psychol 2004;43(3):245-65.

63. Bradley MM, Lang PJ. Measuring emotion: the self-assessment manikin and the

semantic differential. J Behav Ther Exp Psychiatry 1994;25(1):49-59.

64. World Health Organisation. World Health Organization disabilty assessment

schedule: WHODAS II. Phase 2 field trials. Health services research. Geneva, Switzerland:

WHO 2000.

Page 28 of 34


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29


1935;121(1):15.

66. Ware JE, Kosinski M, Turner-Bowker DM, et al. How to Score Version 2 of the SF-

12 Health Survey (with a Supplement Documenting Version 1); Lincoln, R.I., Ed.;

QualityMetric Inc.; Health Assessment Lab.: Boston, MA, USA 2005.

67. Carver CS, Scheier MF, Weintraub JK. Assessing coping strategies: a theoretically

based approach. J Pers Soc Psychol 1989;56(2):267.


validation. Psychol Assess 1995;7(4):524.


validation studies. J Psychol 2005;139(5):439-57.


psychophysiological research–recommendations for experiment planning, data analysis, and

data reporting. Front Psychol 2017;8:213.

71. Tran Y, Wijesuriya N, Tarvainen M, et al. The relationship between spectral changes

in heart rate variability and fatigue. J Psychophysiol 2009;23(3):143-51.


analysis software. Comput Methods Programs Biomed 2014;113(1):210-20.

FIGURES

Figure 1. ICF-based IMPRINT study framework: the biopsychosocial assessment of mental

health and recovery post traffic injuries.

Figure 2. IMPRINT study Participants Recruitment Flowchart.

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Figure 1. ICF-based IMPRINT study framework: the biopsychosocial assessment of mental health and recovery post traffic injuries.

846x461mm (96 x 96 DPI)

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Figure 2. IMPRINT study Participants Recruitment Flowchart

870x491mm (96 x 96 DPI)

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For peer review onlyBiomarkers of autonomic regulation for predicting

psychological distress and functional recovery following road traffic injuries: protocol for a prospective cohort study.

Journal: BMJ Open

Manuscript ID bmjopen-2018-024391.R2


Date Submitted by the Author: 14-Jan-2019


<b>Primary Subject Heading</b>: Mental health

Secondary Subject Heading: Rehabilitation medicine



BMJ Open


1

Biomarkers of autonomic regulation for predicting psychological distress and functional

recovery following road traffic injuries: protocol for a prospective cohort study.

Ilaria Pozzato1

Ashley Craig1

Bamini Gopinath1

Yvonne Tran1

Michael Dinh2

Mark Gillett 3

Ian D Cameron1





Correspondence to:

Ashley Craig







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mailto:[email protected]


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ABSTRACT



is to examine whether biomarkers of autonomic regulation alone or in combination with other

factors assessed shortly after MVC, could predict risk of elevated psychological distress and

poor functional recovery in the long term, and clarify links between mental and physical

health consequences of traffic injury.







The primary outcomes are the development of psychological distress (depressive mood and

anxiety, post-traumatic stress symptoms, driving phobia, adjustment disorder) and biomarkers

of autonomic regulation. Secondary outcomes include indicators of physical health (presence

of pain/fatigue, physical functioning) and functional recovery (quality of life, return to

function, participation) as well as measures of emotional and cognitive functioning. For each

outcome, risk will be described by the frequency of occurrence over the 12 months, and

pathways determined via latent class mixture growth modelling. Regression models will be

used to identify best predictors/biomarkers and to study associations between mental and

physical health.



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study).


This study will comprehensively describe the risk of developing psychological distress


mild-to-moderate injuries.

Identifying biomarkers of mental health risk and poor functional recovery adds novelty to

this field. Easy-to-measure biomarkers of autonomic regulation hold promise in

preventing serious mental disorders, reducing patient-related barriers to mental health

care and improving recovery rates among crash survivors.

The use of the ICF standard framework and validated measures will assure an in-depth

analysis of complex needs of the injured person, which are often studied in isolation, and

will promote comparability with other research.

Findings may be useful to primary care clinicians in the early diagnosis and referral of at-

risk individuals for a better management of mental health and a more integrated form of

care.

Findings may also assist changes in compensation processes and policies towards a more

holistic approach to injury recovery.

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INTRODUCTION



consequences, and many individuals develop long-term disability.[2-4] While improved

outcomes are shown for severe injuries,[5] evidence suggests that minor-to-moderate injuries

are a challenge.[6, 7] With traffic injuries remaining the 10th leading cause of Disability

Adjusted Life Years (DALYs) in 2010,[8] minor-to-moderate injuries (i.e. Maximum

Abbreviated Injury Score of less than 3) account for 46% of injury-related disability.[3]

Therefore, consequences and costs of minor-to-moderate traffic injuries such as whiplash,

mild traumatic brain injury and musculoskeletal injury are serious public health concerns.[6]

A recent longitudinal study from Europe reported that minor-to-moderate (MAIS <3)

traffic injuries hospitalized for more than 24 hours result in higher average costs, both direct

and indirect, compared to severe injuries.[9] On the other hand, in Australia it is estimated

that around $1b is spent each year only on traffic injuries admitted to hospital for less than 24

hours, with an average cost by casualty of $14,183.[10] Furthermore, when psychological

problems are involved, care costs have been shown to escalate alarmingly and time to

recovery to increase fourfold.[11]

Psychological distress is prevalent in people surviving a MVC [11-16] and has been

demonstrated to be a substantial contributor to long-lasting morbidity and disability,[7, 17,

18] affecting up to one in two MVC survivors, according to a recent meta-analysis.[19]

Although there is some variability in estimates, the proportion of MVC survivors (up to 50%)

who experience psychological problems appears to be many times greater than the proportion

of people with mental health in the Australian community (20%)[20] and global population


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(PTSD), major depressive disorder (MDD), driving phobias and other anxiety disorders.[13,

14]

Unlike physical consequences that ideally receive appropriate and timely medical care

following a MVC, early clinical management of psychological consequences associated with

mild-to-moderate physical injury rarely occurs since, for example, psychological distress is

often normalized as a common response to the trauma. Hence, it is not surprising that mental

health-related quality of life of MVC survivors is more resistant to improvement over time

than physical-related outcomes, as for instance demonstrated by Kenardy et al.[17] This is

pertinent given failure to address psychological distress will have a significant detrimental

impact on functional recovery,[22] supporting the hypothesis that there is ‘no health without

mental health’.[21]




arousal,[19] and which often co-occur following a MVC.[14] It is argued that these

symptoms may be all manifestations of one construct of general distress.[23] However,

previous studies on MVC survivors typically focused on a single mental disorder, particularly

post-traumatic stress disorder (PTSD). The second and more significant fact is the absence of

empirical evidence for reliable biomarkers of vulnerability to psychological distress

following a MVC.

Vulnerability to psychological distress and poor functional recovery draws on the

broader concept of psychological resilience as the unique ability of an individual to adapt to

adversity, which develops throughout the lifespan.[24] Following an MVC, individual

vulnerability to poor psychological adjustment and functional recovery, has been linked to a

number of biological (e.g. pre-injury health, injury severity), psychological (e.g. prior

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traumatic experiences, perceptions) and environmental factors (e.g. social support,

compensation),[4, 22, 25] however biological responses, in particular autonomic responses, to

traffic injury remain an under-investigated area.

Unlike other traumatic or pathological conditions, there have been very few studies

examining the predictive value of biomarkers of autonomic regulation, such as traditional

vital signs[26-31] measured early after a MVC, to investigate long-term outcomes, and only

one study, to our knowledge, has attempted to use heart rate variability (HRV).[32] The main

focus of these studies was the association between heart rate at the scene or during

hospitalization and the development of PTSD following a MVC. However, there was lack of

consistency between findings, highlighting differences in methodology and confirming that

substantial inter-individual variability exists in psychobiological responses to physical threat.

Biological responses to potential threats involve activation of neural substrates such as

the stress response system. The autonomic nervous system (ANS) is the first to respond to

stressors by a transitory withdrawal of the parasympathetic ‘brake’ and modulation of

sympathetic activity for a rapid control of body functions critical for survival, i.e. changes in

heart rate, blood pressure and breathing rate, and later re-engagement of the parasympathetic

system during recovery, by inhibition of sympathetic control.

Studying the sympathetic-parasympathetic balance is rather complex, and one marker is

often not enough to convey the complexity of stress regulatory processes.[33] Therefore,

more research is needed to assess autonomic resting level, reactivity and recovery[34] in a

comprehensive manner, by using several markers to increase predictive ability[24, 35] and

investigating their relationship with other psychological, social and biological factors. There

is emerging evidence of associations between negative affect, perseverative cognition and

physiological over-reactivity to stress [24, 34], as introduced for example, by the

perseverative cognition hypothesis.[36] The most common autonomic markers include vital

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signs (i.e. heart rate, respiratory rate, blood pressure, peripheral skin temperature), skin

conductance, peripheral blood circulation and heart rate variability. While skin conductance

and peripheral skin temperature have been widely used as an index of sympathetic activity,

heart rate variability (HRV), the variation in the beat-to-beat interval, is recommended as a

reliable, noninvasive index for assessing cardiac vagal tone. Higher levels of vagally-

mediated resting-state HRV[34] and faster cardiovascular recovery [24], have been shown to

be associated with better self-regulatory capacity to environmental demands.

Different theoretical models[37-39] have linked vagally-mediated HRV to individual

differences in adaptation to external and internal stressors, suggesting poor autonomic

regulationis an indicator of poor self-regulatory capacity in managing stress levels, that can

be associated with poor psychological health,[40, 41] physical health,[42, 43] cognitive

performance,[38, 43] and social functioning.[37, 41] Thus, sympathetic-parasympathetic

balance, measured early after a MVC, is regarded as a promising biomarker of vulnerability

to develop dysfunctional responses, such as elevated psychological distress and stress-related

disorders that can affect a person's capacity to recover following traffic injury.[44]


physical consequences post-MVC, for example anxiety, depression, chronic pain, fatigue,

sleep disturbance, and other somatic conditions,[25, 45] for which physical evidence is often

missing, hinting at the possibility of shared psychological and biological factors in stress

vulnerability.[46-48] However, the majority of evidence for these associations comes from

cross-sectional studies, especially from the relationship between chronic pain and PTSD in

whiplash injuries. Therefore, prospective research is now needed to investigate links between

mental and physical health in recovery from traffic injuries.

Full functional recovery is a combination of a person's physical and mental wellbeing,

often measured as health-related quality of life, and social functioning, such as resumption of

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work/usual level of activities and social participation.[49] In the current study, the WHO

International Classification of Functioning (ICF)[50] will be employed as the bio-

psychosocial framework to assess mental health and functional recovery outcomes following

MVC-related injury, and to build comprehensive prognostic models for identification of the

at-risk cohort. Early detection is crucial for preventing disease and progression to chronicity,

therefore this study has the potential to prevent the development of serious mental health

conditions and disability among thousands of MVC survivors in Australia and worldwide

annually.

Study Aims


1) To determine prevalence estimates and trajectories of psychological distress (i.e.

depressive mood and anxiety, PTSD symptoms, driving phobia, adjustment disorder) and

functional recovery (i.e. health-related quality of life, return to work/activities, social

participation) post-MVC;

2) To determine the efficacy of autonomic biomarkers (i.e. post-MVC vital signs and

autonomic measures 1-month post-injury), alone or in combination with other bio-

psychosocial factors, in predicting psychological distress and poor functional recovery post-

MVC;

3) To investigate associations and shared bio-psychosocial predictors/biomarkers, between

mental health (i.e. psychological distress, emotional and cognitive functioning) and physical

health (i.e. pain, fatigue, physical functioning) consequences post-MVC.


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1. The WHO International Classification of Functioning Disability and Health (ICF) model is

widely recognized as the most recent and comprehensive framework for assessing health and

disability. Therefore, it provides an effective framework for describing consequences of road

traffic injuries, such as psychological distress and poor functional recovery. Potential

predictors will be biological, personal and environmental factors, with a focus on testing the

predictive ability of autonomic biomarkers, which are simple and easy-to-measure. This is a

prognostic study where event prediction will follow a data-driven approach and careful

consideration will be given to the issue of over-fitting.[51] There are also plans of exploring

causal effects that will come as a separate proposal.

Design


distress and poor functional recovery among mildly to moderately injured MVC survivors

(Injury Severity Score [ISS][52] ≤ 15)[53-55]. Baseline assessment will occur around 1

month (3 to 6 weeks) of their injury, with follow-up assessments occurring at 3, 6 and 12

months post-injury. Results will be compared to a control group who have not sustained a

MVC or severe injuries in the past 5 years, and who will be assessed at the same time

periods.

Setting

The Emergency Departments of two of the seven adult major trauma services in NSW,

Australia, will be involved in recruitment of MVC survivors: Royal North Shore Hospital

(RNSH) and Royal Prince of Alfred Hospital (RPAH).[56] These are large public hospitals

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located in Sydney metropolitan area, providing care to trauma patients across the whole

spectrum of severity.



presented in Table 1. These include exposure status (i.e. injury vs non-injury) and factors

related to the outcomes being studied (i.e. mental health, autonomic function, disability and

physical health). At the time of their enrolment both cohorts will be free of severe mental

health disorders or major disabling conditions due to very severe injury like spinal cord

injury. The non-injured cohort will include normally healthy individuals with no active

medical concern or serious comorbid conditions (i.e. chronic disease, degenerative neurologic

disease). Medications or other factors that could potentially influence autonomic

function/outcomes investigated, as well as differences between the two cohorts, will be

adjusted for in the analysis.

The identification of MVC survivors will begin following their presentation to the

emergency departments (ED) of the two hospitals. Participants will be consecutively

identified and assessed for eligibility by a research nurse from the information management

system, FirstNet.

The non-MVC control group, matched by sex and age (± 5 years) to the MVC sample

on a case by case basis, will be recruited through advertising. Study eligibility will be

assessed using an online self-reported screening interview.

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MVC participants Non-MVC controls Age ≥18 years Age ≥18 years

Sustained in last 6 weeks, a minor to moderate injury due to MVC in NSW, Australia

No history of MVC, serious injury or traumatic event (i.e. w/ perceived threat of injury to self or others) in the previous 5 years

A driver, motorbike rider, passenger, pillion passenger, pedestrian and bicyclist (only collision involving a motorised vehicle)

Sufficient English proficiency

Presented to RNSH or RPAH Emergency Departments, Sydney, Australia

Inclusion criteria

Sufficient English proficiency

Catastrophic injury as defined by NSW icare lifetime care, i.e. a very severe traumatic brain injury, a spinal cord injury, extensive burns to the body (>60%), major amputation or blindness

Catastrophic injury: severe brain injury, spinal cord injury, extensive burns to the body, major amputation or blindness

Serious Injury (ISS[52] >15)[53] Severe mental health condition Localised, superficial soft tissue injuries Dementia or cognitive impairment

affecting ability to consent MVC due to intentional self-harm or MVC

survivors with severe mental health condition

Chronic disease such as severe heart disease, stroke, cancer, chronic respiratory diseases, obesity and advanced complicated diabetes.

Death of a family member in the MVC Degenerative neurologic disease

Exclusion criteria

Dementia or cognitive impairment affecting ability to consent

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Recruitment process

Participants’ recruitment flowchart is illustrated in Figure 2. Eligible survivors will be invited

to participate by: i) being approached at the time of ED presentation, or ii) receiving an

invitation letter to their postal address from the ED treating clinician. After written consent is

obtained (opt-in approach), participants will be requested to complete the baseline interview-

based assessment by accessing an online secure website, and otherwise by completing a

paper-based or phone interview. As part of their enrollment, within 6 weeks of their accident,

participants will also be asked to attend a 30-minute hospital visit for collection of autonomic

biomarkers. An overall reimbursement up to $100 in vouchers will be provided to cover

participant travel cost and time.

Sample size







90%.[57]


Assessment time points, study outcomes and details of the validated measures used within

each ICF domain are provided in Table 2.

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Table 2. IMPRINT study: Outcome Measures and Assessment Points, within each ICF Domain.

ICF MODEL STUDY ASSESSMENTS AND OUTCOME MEASURESAssessment pointsDomain Outcome Category Outcome Measures


3 months

6 & 12 months

*Psychological distress[Mental health]

Depressive mood and Anxiety (DASS21[58]); PTSD symptoms (IES-R[59]); Driving Phobia (MINI[60]); Adjustment Disorder (MINI[60]);

X X X

**Emotional functioning[Mental health]

Emotional balance (PANAS[61]); self-reported Valence and Arousal dimension of emotions (Self-Assessment Manikin scale[62]).

X X X

**Cognitive functioning[Mental health]

Perceived cognitive health (WHODAS II - Domain 1[63]); selective attention and processing speed ability (Stroop test[64]).

X X X

*Autonomic regulation[Biomarkers]

Sympathetic-parasympathetic balance (Post-crash vital signs; HRV; Heart rate; Respiration rate; Skin conductance; Peripheral body temperature; Blood volume pulse).

X

**Pain[Physical health]

Pain Intensity (NRS[65]); Risk of persistent pain and disability (OMPQ, short form[66]).

X X X

**Fatigue[Physical health]

Fatigue Intensity (VAFS[67]). X X X

**Physical functioning [Physical health]

Stress-related physical symptoms (sleep disturbance, loss of sex drive, frequent infections, upset stomach, constipation); Lifestyle habits (physical activity, smoking, alcohol use); Medications; Post-crash new clinical diagnoses.

X X X

Body Functions &Structures


X

Activities **Quality of life[Functional recovery]

Health-related physical and mental quality of life (SF-12[69]). X X X

Participation **Social functioning [Functional recovery]

Return to work and activities; Social participation (WHODAS II - Domain 6[63]). X X X

Demographic Sex; Age; Primary language; Education; Marital status. XTrauma and stressors Prior and post-crash Stressors. Traumatic events following the crash (MINI[60]). X

Personal Factors

Physical health history Past clinical and medication history; Body composition (BMI); Past chronic pain or fatigue diagnosis; Pre-health care utilisation.

X

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X

Coping Skills Coping responses (COPE Inventory[70]). X X XPerceptions Perceived life threat; Perceived helplessness; Blame vs self or others; Perceived

injustice; Perceived resilience; Perceived sense of safety and life balance.X X X

Cognitive bias Pain catastrophizing, Rumination, Magnification (PCS[71]); Self-efficacy beliefs (GSE[72]); Expectations to return to work (OMPQ[66]) and expectations to recover.

X X X

Socioeconomic status Index of Relative Socioeconomic Disadvantage; Financial issues pre- and post-crash. XSocial life Satisfaction with pre-social relationships and pre-social activities. Perceived social

support.X X X

Crash circumstances Role in the accident. XHealth care use/quality Referral to psychologist/psychiatrist; Referral to physiotherapist; Care satisfaction. X X X

Employment Pre-injury employment status; Job satisfaction. X X X

Environmental Factors

Compensation status Claim lodged, Claim type, Claim finalization, Legal representation, Disputes, Claims satisfaction. Previous claims.

X

DASS21: Depression, Anxiety and Stress Scale; IES-R: Impact of Events Scale; MINI: Mini International Neuropsychiatric Interview Version; PANAS: Positive and Negative Affect Schedule; WHODAS: World Health Organisation Disability Assessment Schedule; NRS: Numeric Rating Scale; OMPQ: Orebro Musculoskeletal Pain Question; PCS: Pain Catastrophizing Scale; VAFS: Visual Analogue Fatigue Scale; GSE (General Self-Efficacy Scale); BMI: Body Mass Index.

Note: Outcome categories marked in bold are primary (*) and secondary (**) study outcomes. The remaining measures are bio-psychosocial predictors.

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Primary outcomes

The primary outcome is the development of psychological distress as any psychological

discomfort that interferes with daily living functioning following the MVC. Psychological

distress is defined as the presence of at least one of the following psychological symptoms

over the 12 months after the MVC, including elevated depressive mood and anxiety

(Depression, Anxiety and Stress Scale)[58] and PTSD symptoms (Impact of Events

Scale),[59] evaluated using these two validated psychometric assessments, as well as the

presence of driving phobia and adjustment disorder using diagnostic interview (Mini

International Neuropsychiatric Interview based on DSM V)[60] . Another key outcome are

biomarkers of autonomic regulation by means of HRV and other autonomic measures of

sympathetic-parasympathetic balance as described below.

Secondary outcomes

Secondary outcomes include indicators of physical health (i.e. pain, fatigue and physical

functioning measures such as somatic symptoms and/or new clinical diagnosis) and

functional recovery (i.e. health-related quality of life, return to work/usual activities, social

participation) up 12 months post-MVC. Other outcomes of interest are measures of emotional

(i.e. emotional balance, self-reported valence and arousal of affect) and cognitive functioning

(i.e. perceived cognitive health, selective attention and processing speed ability).

Predictors

Bio-psychosocial predictors include a comprehensive regimen of biological (e.g. injury

details), personal (e.g. demographic, health history, perceptions/reaction to the

injury/expectations, coping skills, self-efficacy, cognitive styles) and environmental factors

(e.g. crash circumstances, economic factors, social life, compensation, health care use and

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satisfaction) that may predict risk of elevated psychological distress and poor recovery, in

association with autonomic biomarkers.

Biomarkers of autonomic regulation

Measures and procedures: Biomarkers of autonomic regulation consist of vital signs (heart

rate, respiratory rate, blood pressure) on the day of the accident (at the scene and ED

triage)[26] and autonomic measures around 1 month (3-6 weeks) of the injury, non-

invasively and simultaneously acquired using a BiosemiTM Active-Two System at a 2480 Hz

native sampling rate. Autonomic assessment will include respiration rate (sensitive band

around chest), skin conductance (SC) level and responsiveness, i.e. absolute SC and

number/amplitude of non-specific SC fluctuations (surface electrodes on second and fourth

fingers of non-dominant hand), peripheral body temperature (clip-on sensor on fifth finger of

non-dominant hand), blood volume pulse amplitude (light sensor on third finger of non-

dominant hand), heart rate and HRV (ECG recording).[73] For the ECG recording, three

Ag/AgCl electrodes will be placed in modified Einthoven I and II configurations (beneath the

right and left clavicles, and on the 4th intercostal space on the left side of the sternum).


and between subject changes between phases. For an in-depth investigation of autonomic

regulatory processes, a 3-R protocol[34] will be employed that allows examination of tonic

resting level (baseline) and phasic autonomic control, including autonomic reactivity (change

between baseline and task) and recovery (change between task and post-task, percentage/time

of return to baseline).

On the morning prior to the autonomic assessment, participants will be asked to follow

a normal sleep routine and to abstain from eating, drinking caffeinated and alcoholic

beverages, smoking and intense physical activity. Recording will be conducted under

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constant conditions, between 8am-1pm to control circadian influences.[74] Participants will

sit in a relaxed position with eyes open. The protocol includes four phases, throughout which

autonomic biomarkers will be measured continuously: i) 5-minute resting baseline, after a

two-minute acclimatization; ii) 5-minute response inhibition task, using the validated Stroop

Color-Word test[64]; iii) 5-minute resting post-task; iv) 2-minute slow paced breathing (6

breaths/min), using a breath pacer application providing visual feedback for breathing cycle

control. Before every phase change, participants will be asked to rate pain and fatigue

intensity, and their emotional state (Self-Assessment Manikin scale).[62]

Data manipulation: After appropriate data cleaning to remove noise and artifacts and

re-sampling (512 Hz sampling rate), biosignals analysis will be performed using Kubios

(Version 2.0 beta 2, Department of Applied Physics, University of Kuopio, Finland)[75] and

other Analysis Software. For HRV, time-domain, frequency-domain (LF: 0.04–0.15 Hz; HF:

0.15–0.4 Hz) and non-linear indices will be analyzed.

Hypotheses and Data analysis

It is hypothezised that:

(a) People sustaining mild-to-moderate injuries in an MVC will continue to suffer high

rates of psychological distress, poor physical health (e.g. high levels of pain and

fatigue, poor physical functioning) and poor functional recovery (e.g. poor quality of

life, limited work/activities resumption and low social participation) 6 to12 months

post-injury, though improvements in all outcomes are expected to occur over time

compared to 1-3 months post-injury;

(b) Compared to non-MVC controls, MCV survivors will have significantly poorer

autonomic regulation (i.e. lower sympathetic-parasympathetic balance) at 1 month

follow-up, and will exhibit poorer mental health (e.g. higher psychological distress,

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poorer emotional and cognitive functioning), poorer physical health (e.g. higher levels

of pain and fatigue, lower physical functioning), and poorer social outcomes (e.g.

poorer health-related quality of life and social functioning) over the follow-up period,

though to a lesser extent at long-term (6 and 12 months) compared to short-term (1-3

months) post-injury;

(c) Among MVC survivors, those with sustained elevated psychological distress over the

first-year post-injury will be less likely to recover and have significantly lower

autonomic regulation early after the crash (i.e. higher heart rate and respiratory rate on

the day of the accident; poorer sympathetic-parasympathetic balance 1 month -post-

injury) compared to those without psychological distress who will be more likely to

recover;

(d) Specific biological factors (e.g. higher injury severity, longer hospital stay), personal

factors (e.g. older age, being female, poor pre-injury health, poor coping skills,

negative perceptions/reactions to the injury, catastrophic thinking, low self-efficacy,

poor recovery expectations) and environmental factors (e.g. pre-injury

unemployment, poor socio-economic background, protected road-users, poor social

support, poor health care use and satisfaction, involvement in compensation) will

predict increased risk of elevated psychological distress and poorer functional

recovery in those injured in an MVC;

(e) There will be similarities in factors predicting mental and physical health

consequences of a traffic injury. Shared predictors/biomarkers will include

biomarkers of poor autonomic regulation, and psychological/personal factors like pre-

injury health, psychological distress, thinking styles, coping skills and self-efficacy;

(f) In both groups, there will be high correlations between states of low sympathetic-

parasympathetic balance, reactivity to stress, and negative emotions/perceptions.

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Those with balanced autonomic regulation will be more likely to exhibit better health

(i.e. both mental and physical health) and social outcomes (quality of life, social

functioning).




percentage over the 12-month post-MVC period, while latent class mixture growth modelling


will be used to analyse differences between and within groups over time.







Subgroup analyses and multiple regression will study differences and shared

predictors/biomarkers between mental and physical health outcomes following the MVC.

Clinical significance of autonomic biomarkers will be also tested using cluster analysis and

other exploratory analyses.

The same analyses will be conducted with control data, to describe differences in

outcomes with the group of MVC survivors.

Bias

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To reduce selective bias, the study will adopt the following strategies: a 6-week inception

period, participant cost reimbursement, adequate statistical power, as well as consecutive

recruitment from two hospitals with major catchments for traumatic MVC injury in Sydney

that will provide a wide variety across ethnicity, culture, socioeconomic status and education

levels.









Patient and Public Involvement

Research question and outcome measures are developed with knowledge from our ongoing

research into patient feedback, expectations and concerns following traumatic injury.

However, the present study is not a clinical trial, therefore participants are not directly

involved in study design, conduct or assessment of intervention. Nevertheless, findings from

this study, i.e. peer-reviewed publications, will be shared with study participants via email

communication.


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Approvals, progress and timeframe


(HREC/ 15/RPAH/423), and Site-Specific approvals obtained for each site




this protocol.

The first participant was recruited on 16 June 2017, and both sites are actively contributing

towards the recruitment target. It is anticipated that the recruitment will last until the end of

March 2019, thus data collection is expected to be completed by early 2020.














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care.

Dissemination





DISCUSSION

This study intends to raise awareness about the risk of psychological distress and poor

functional recovery following minor-to-moderate traffic injuries, and to develop processes for

the early detection of at-risk individuals, the aim being to prevent disability in the long-term.

This study, for the first time, will use biomarkers of autonomic balance, to detect this

risk. If results of this study are positive, a non-invasive screening tool like HRV holds

promise for providing a means of preventing serious mental health disorders and disability

through detection and early treatment, as well as clarifying links between mental and physical

health consequences post-MVC.

It is expected that general and acute care clinicians would have a crucial role in early

diagnosis and referral of at-risk individuals. Employing easy-to-measure ‘biological markers’

for those at risk of mental health disorders may facilitate timely access to care and help

reduce patient-related barriers to mental health care. [76]

Adopting the ICF framework to assess consequences of minor-to-moderate injuries also

represents a real shift in this field. For example, compared to severe injuries, recovery from

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these injuries is rarely accepted as a complex multidimensional experience and management

often follows a biomedical care model. By contrast, the comprehensive study assessment

using standardized measured will clarify the complex needs of people sustaining minor-to-

moderate traffic injuries, assist compensation processes and policy changes towards a more

holistic approach to injury recovery, and promote comparability with other research.











REFERENCES

1. World Health Organisation. Global status report on road safety 2015. Geneva,

Switzerland: WHO 2015.

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2. Alghnam S, Palta M, Remington PL, et al. The association between motor vehicle

injuries and health-related quality of life: a longitudinal study of a population-based sample

in the United States. Qual Life Res 2014;23:119-27.

3. Polinder S, Haagsma J, Bos N, et al. Burden of road traffic injuries: Disability-

adjusted life years in relation to hospitalization and the maximum abbreviated injury scale.

Accid Anal Prev 2015;80:193-200.

4. Nhac-Vu H-T, Hours M, Chossegros L, et al. Prognosis of outcome in adult survivors

of road accidents in France: one-year follow-Up in the ESPARR cohort. Traffic Inj Prev

2014;15:138-47.

5. Gabbe BJ, Lyons RA, Fitzgerald MC, et al. Reduced population burden of road

transport–related major trauma after introduction of an inclusive trauma system. Ann Surg

2015;261:565.


claimants who had sustained a mild or moderate injury in a road traffic crash: prospective

study. BMC Res Notes 2017;10:76.

7. Haagsma J, van Beeck E, Toet H, et al. Posttraumatic Stress Disorder Following

Injury: Trajectories and Impact on Health-Related Quality of Life. J Depress Anxiety

2013;14:1242-49.


diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden

of Disease Study 2010. Lancet 2012;380:2197-223.

9. Papadakaki M, Stamouli M-A, Ferraro OE, et al. Hospitalization costs and estimates

of direct and indirect economic losses due to injury sustained in road traffic crashes: results

from a one-year cohort study in three European countries (the REHABILAID project).

Trauma 2017;19:264-76.

Page 24 of 36


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


25

10. Connelly LB, Supangan R. The economic costs of road traffic crashes: Australia,

states and territories. Accid Anal Prev 2006;38:1087-93.

11. Guest R, Tran Y, Gopinath B, et al. Psychological distress following a motor vehicle

crash: evidence from a statewide retrospective study examining settlement times and costs of

compensation claims. BMJ Open 2017;7:e017515.

12. Papadakaki M, Ferraro OE, Orsi C, et al. Psychological distress and physical

disability in patients sustaining severe injuries in road traffic crashes: Results from a one-year

cohort study from three European countries. Injury 2017;48:297-306.


following a minor road traffic accident (RTA): The clinical implications of a prospective

longitudinal study. Couns Psychol Q 2007;20:149-55.

14. Kenardy J, Edmed SL, Shourie S, et al. Changing patterns in the prevalence of

posttraumatic stress disorder, major depressive episode and generalized anxiety disorder over

24 months following a road traffic crash: Results from the UQ SuPPORT study. J Affect

Disord 2018;236:172-9.

15. Mayou R, Bryant B. Outcome 3 years after a road traffic accident. Psychol Med

2002;32:671-5.

16. Blanchard EB, Hickling EJ, Taylor AE, et al. Psychiatric morbidity associated with

motor vehicle accidents. J Nerv and Ment Dis 1995;183(8):495-504.


disability after a road traffic crash: results from the UQ SuPPORT study. Arch Phys Med

Rehabil 2015;96:410-7.

18. Jacoby SF, Shults J, Richmond TS. The effect of early psychological symptom

severity on long-term functional recovery: A secondary analysis of data from a cohort study

of minor injury patients. Int J Nurs Stud 2017;65:54-61.

Page 25 of 36


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


26


vehicle crashes: systematic review and meta-analysis. BMJ Open 2016;6:e011993.




practice: Summary report. Geneva, Switzerland: WHO 2004.


persons who sustained an injury in a road traffic crash. Injury 2015;46:909-17.

23. Grant DM, Beck JG, Marques L, et al. The structure of distress following trauma:

Posttraumatic stress disorder, major depressive disorder, and generalized anxiety disorder. J

Abnorm Psychol 2008;117:662-72.

24. Walker FR, Pfingst K, Carnevali L, et al. In the search for integrative biomarker of

resilience to psychological stress. Neurosci Biobehav Rev 2017;74:310-20.

25. Duckworth MP, Iezzi T. Physical injuries, pain, and psychological trauma: Pathways

to disability. Psychol Inj Law 2010;3:241-53.

26. Coronas R, Gallardo O, Moreno M, et al. Heart rate measured in the acute aftermath

of trauma can predict post-traumatic stress disorder: A prospective study in motor vehicle

accident survivors. Eur Psychiatry 2011;26:508-12.

27. Kuhn E, Blanchard EB, Fuse T, et al. Heart rate of motor vehicle accident survivors in

the emergency department, peritraumatic psychological reactions, ASD, and PTSD severity:

A 6‐month prospective study. J Trauma Stress 2006;19:735-40.

28. Blanchard EB, Hickling EJ, Galovski T, et al. Emergency room vital signs and PTSD

in a treatment seeking sample of motor vehicle accident survivors. J Trauma Stress

2002;15:199-204.

Page 26 of 36


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


27

29. Veazey CH, Blanchard EB, Hickling EJ, et al. Physiological responsiveness of motor

vehicle accident survivors with chronic posttraumatic stress disorder. Appl Psychophysiol

Biofeedback 2004;29:51-62.

30. Bryant RA, Harvey AG, Guthrie RM, et al. Acute psychophysiological arousal and

posttraumatic stress disorder: a two-year prospective study. J Trauma Stress 2003;16:439-43.

31. Zatzick DF, Russo J, Pitman RK, et al. Reevaluating the association between

emergency department heart rate and the development of posttraumatic stress disorder: A

public health approach. Biol Psychiatry 2005;57:91-5.

32. Guédon-Moreau L, Ducrocq F, Molenda S, et al. Temporal analysis of heart rate

variability as a predictor of post traumatic stress disorder in road traffic accidents survivors. J

Psychiatr Res 2012;46:790-6.

33. Berna G, Ott L, Nandrino J-L. Effects of emotion regulation difficulties on the tonic

and phasic cardiac autonomic response. PloS One 2014;9:e102971.

34. Laborde S, Mosley E, Mertgen A. Vagal tank theory: the three rs of cardiac vagal

control functioning–resting, reactivity, and recovery. Front Neurosci 2018;12:458.

35. Prinsloo GE, Rauch HL, Derman WE. A brief review and clinical application of heart

rate variability biofeedback in sports, exercise, and rehabilitation medicine. Phys Sportsmed

2014;42:88-99.

36. Brosschot JF, Gerin W, Thayer JF. The perseverative cognition hypothesis: A review

of worry, prolonged stress-related physiological activation, and health. J Psychosom Res

2006;60:113-24.

37. Porges SW. The polyvagal theory: new insights into adaptive reactions of the

autonomic nervous system. Cleve Clin J Med 2009;76:S86-90.

Page 27 of 36


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


28



regulation, adaptation, and health. Ann Behav Med 2009;37:141-53.


mechanisms, assessment of self-regulatory capacity, and health risk. Glob Adv Health Med

2015;4:46-61.


Emotion Regulation in Healthy Adults: A Review. Biol Psychol 2017;130:54-66.

41. Kok BE, Fredrickson BL. Upward spirals of the heart: Autonomic flexibility, as

indexed by vagal tone, reciprocally and prospectively predicts positive emotions and social

connectedness. Biol Psychol 2010;85:432-6.

42. Lu WC, Tzeng NS, Kao YC, et al. Correlation between health-related quality of life in

the physical domain and heart rate variability in asymptomatic adults. Health Qual Life

Outcomes 2016;14:149.

43. Beaumont A, Burton AR, Lemon J, et al. Reduced cardiac vagal modulation impacts

on cognitive performance in chronic fatigue syndrome. PloS One 2012;7:e49518.

44. Carnevali L, Koenig J, Sgoifo A, et al. Autonomic and Brain Morphological

Predictors of Stress Resilience. Front Neurosci 2018;12:228.


symptoms, pain, and disability 12 months after traumatic injury. Pain Rep 2017;2:e622.

46. Kemp AH, Quintana DS. The relationship between mental and physical health:

insights from the study of heart rate variability. Int J Psychophysiol 2013;89:288-96.


maintenance? Clin Psychol Rev 2001;21:857-77.

Page 28 of 36


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


29

48. McLean SA, Clauw DJ, Abelson JL, et al. The development of persistent pain and

psychological morbidity after motor vehicle collision: integrating the potential role of stress

response systems into a biopsychosocial model. Psychosom Med 2005;67:783-90.

49. Lahera G, Gálvez JL, Sánchez P, et al. Functional recovery in patients with

schizophrenia: recommendations from a panel of experts. BMC psychiatry 2018;18:176.


Health: ICF. Geneva, Switzerland: WHO 2001.


2014;60:241-4.

52. Greenspan L, McLellan BA, Greig H. Abbreviated Injury Scale and Injury Severity

Score: a scoring chart. J Trauma 1985;25:60-4.

53. New South Wales Institute of Trauma and Injury Management. The NSW Trauma

Registry profile of serious to critical injuries: 2009. Sydney: NSW Health 2012.

54. Mitchell RJ, Chong SS. Injury trends and mortality in adult patients with major

trauma in New South Wales. Med J Aust 2012;197:233-7.

55. Cameron PA, Gabbe BJ, Cooper DJ, et al. A statewide system of trauma care in

Victoria: effect on patient survival. Med J Aust 2008;189:546-50.

56. Jagnoor J, Blyth F, Gabbe B, et al. Factors influencing social and health outcomes

after motor vehicle crash injury: an inception cohort study protocol. BMC Public Health

2014;14:199.

57. Faul F. G* Power Version 3.1. 9.2. Kiel: Universitat Kiel, Germany 2014.

58. Henry JD, Crawford JR. The short‐form version of the Depression Anxiety Stress

Scales (DASS‐21): Construct validity and normative data in a large non‐clinical sample. Br J

Clin Psychol 2005;44:227-39.

Page 29 of 36


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


30

59. Weiss DS, Marmar CR. The Impact of Event Scale-Revised. In: Wilson JP, Keane

TM, eds. Assessing psychological trauma and PTSD: a practitioner's handbook. Guilford

1997:399–411.

60. Diagnostic and statistical manual of mental disorders (DSM-5®). Arlington:

American Psychiatric Association 2013.

61. Crawford JR, Henry JD. The Positive and Negative Affect Schedule (PANAS):

Construct validity, measurement properties and normative data in a large non‐clinical sample.

Br J Clin Psychol 2004;43:245-65.

62. Bradley MM, Lang PJ. Measuring emotion: the self-assessment manikin and the

semantic differential. J Behav Ther Exp Psychiatry 1994;25:49-59.

63. World Health Organisation. World Health Organization disabilty assessment

schedule: WHODAS II. Phase 2 field trials. Health services research. Geneva, Switzerland:

WHO 2000.


1935;121:15-23.

65. Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales.

J Clin Nurs 2005;14:798-804.


Musculoskeletal Pain Screening Questionnaire. Spine (Phila Pa 1976) 2011;36:1891-5.

67. Wewers ME, Lowe NK. A critical review of visual analogue scales in the

measurement of clinical phenomena. Res Nurs Health 1990;13:227-36.

68. Teasdale G, Jennett B. Assessment of coma and impaired consciousness: a practical

scale. Lancet 1974;304:81-4.

Page 30 of 36


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


31

69. Ware JE, Kosinski M, Turner-Bowker DM, et al. How to Score Version 2 of the SF-

12 Health Survey (with a Supplement Documenting Version 1); Lincoln, R.I., Ed.;

QualityMetric Inc.; Health Assessment Lab.: Boston, MA, USA 2005.

70. Carver CS, Scheier MF, Weintraub JK. Assessing coping strategies: a theoretically

based approach. J Pers Soc Psychol 1989;56:267-83.


validation. Psychol Assess 1995;7:524-532.


validation studies. J Psychol 2005;139:439-57.


psychophysiological research–recommendations for experiment planning, data analysis, and

data reporting. Front Psychol 2017;8:213.

74. Tran Y, Wijesuriya N, Tarvainen M, et al. The relationship between spectral changes

in heart rate variability and fatigue. J Psychophysiol 2009;23:143-51.


analysis software. Comput Methods Programs Biomed 2014;113:210-20.

76. Craig A, Tran Y, Craig M. Stereotypes towards stuttering for those who have never

had direct contact with people who stutter: A randomized and stratified study. Percept Mot

Skills 2003;97:235-45.

FIGURES

Figure 1. ICF-based IMPRINT study bio-psychosocial assessment framework (Primary outcomes*; Secondary outcomes**).

Figure 2. IMPRINT study Participants Recruitment Flowchart.

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Figure 1. ICF-based IMPRINT study bio-psychosocial assessment framework (Primary outcomes*; Secondary outcomes**).

847x479mm (96 x 96 DPI)

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Figure 2. IMPRINT study Participants Recruitment Flowchart

870x491mm (96 x 96 DPI)

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