Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT05515640 |
| Other study ID # |
2019-5610 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
August 1, 2019 |
| Est. completion date |
June 2024 |
Study information
| Verified date |
March 2024 |
| Source |
Karolinska University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Following brain injury, complex interactions between the nervous system and other organs are
frequently encountered. Systemic effects may be induced by dysregulation of the
hypothalamic-pituitary-adrenal axis and the autonomic nervous system. This observational
study will investigate the link between clinical, physiological and biochemical expressions
of dysautonomic reactions and physiological stress, and their relations to sympathetic
activation in traumatic brain injury patients treated in the neurointensive care unit.
Description:
Following traumatic brain injury (TBI) complex interactions between the nervous system and
other organs are frequently encountered. Systemic reactions may be induced by dys-regulation
of the hypothalamic-pituitary adrenal (HPA) axis and the autonomic nervous system.
Neuro-endocrine disturbances are common and up to 50 % of brain injured Neuro-intensive care
(NICU) patients may exhibit a period of relative adreno-cortico insufficiency in the early
phase of TBI, which in part may be centrally mediated. Catecholamine surge is thought
responsible for cardio pulmonary reactions such as myocardial stunning, and may be an
instrumental part of neurogenic pulmonary edema. An imbalance between the parasympathetic and
sympathetic nervous system has been identified, and may even effect outcome, but is poorly
understood. This is seen both in early and chronic stages of brain injury. Heart rate
variability has been implicated as an indicator of dys-autonomic parasympathetic dysfunction,
and has in small studies been related to TBI outcome. Recently a clinical definition of
Paroxysmal Sympathetic Hyper-activation (PSH) has been suggested and identities as related to
patient outcome.
Thus, in TBI the picture of a triad of dysautonomic and hypothalamic-pituitary dysregulation
and injury driven inflammation, with a potential of bi-directional cross-talk between central
and peripheral immuno- modulators, is emerging. This study will aim to explore and integrate
indicators of these three components as to define phenotypes. It will investigate the utility
of medically approved (CE) Skin Conductance Algesimeter (Med-Storm ®) in relation to other
parameters of physiological stress including, heart rate variability (HRV), intra-cranial
pressure reactivity index (PrX), and products of the HPA axis such as, ACTH, adrenaline and
nor-adrenaline including break down products, markers of brain trauma driven neuro and
systemic inflammation.
The investigators hypothesize that a limited number of composite patterns will emerge and may
describe patient phenotypes with differing trajectories.
CRF:
Electronic case report form (eCRF) with pseudo anonymized data via a globally unique personal
identifier (GUPI) to secure eCRF platform.
Patient Key kept locally and GDPR compliant.
Variables:
Baseline variables including IMPACT calculator variables for co-variate adjustment and trauma
time, including predictors from the from Karolinska Traumatic Brain injury Database.
Additional parameters of injury severity assessment and outcome predictors: Intracranial
injury severity scoring on computed tomography (CT) scan by abbreviated injury severity
score, Marshall CT classification, Rotterdam CT score, Helsinki CT score and Stockholm CT
score.
Severity scoring on magnetic resonance imaging (MRI) (if available) focusing on the presence
of diffuse axonal injury (DAI), burden and region of DAI.
Concomitant drugs of interest, such as analgesics, sedation, alpha II agonists, betablockers,
vasopressor support.
Daily injury severity scores. Daily symptom assessment of paroxysmal sympathetic
hyperactivity (PSH) in relation to guideline definition.
Daily Therapy Intensity level (TIL) and individual components. Daily Pain assessment scores.
Available relevant clinical lab data in hospital system such as S100B, ProBNP, Troponins
TSH,T3,T4.
High resolution physiological data, physiological monitoring during ICU stay. Physiological
monitoring via ICM+ including intracranial pressure (ICP), Brain tissue oxygenation (PbtO2),
ECG waveform and heart rate variability (HRV), Central Temperature (Temp) , Saturation
(SaO2). Pulse reactivity Index (PrX).
Med-Storm Skin Conductance Algesimeter measure of sympathetic activity. ICM + ® annotation
tool: Time-stamped changes in sedation and potentially painful and stressful clinical
interventions.
Bio-sampling:
Biomaterial bio-banked for analyses Collection of plasma (from 4 ml whole blood sample)
Daily, day 1-7, sampled from arterial line when available clinically.
Cerebral Microdialysis: hourly when clinically available, pooled. Cerebral spinal fluid(CSF):
Daily (2 ml), when clinically available from EVD catheter, day 1-7.
Urine: Daily mixed aliquot (20 ml) of a 6 hour measured collection, day 1-7. Samples
centrifuged 20G-15min: Aliquots of 200 μl and frozen with sample to freezer time recorded.
Outcome Follow-up:
Extended Glasgow Outcome Scale (GOSE) questionnaire and/or interview at 3, 6 and 12 months.
Extraction from Karolinska Traumatic Brain injury Database.
Death Date.
Planned analyses:
Wet-lab Proteomics: protein profiling of brain enriched and inflammatory proteins from serum,
CSF and cerebral microdialysis.
Microparticles/ exosomes, microRNA of central origin in CSF, microdialysate and plasma.
HPA axis parameters and breakdown products including cortisol, catecholamines, metanephrines.
Specific parameters of inflammatory crosstalk periphery/brain including choline acetyl
transferase, HMGB1 as well as peripheral and central modulators of levels of T and B cell
subgroup and glial activation.
Analytics:
Signal decomposition of physiological variables: ECG derived metrics including decreased
baroreflex sensitivity (BRS), low frequency (LF), high frequency (HF) and total power (TP).
Entropy. HRV. Signal analysis including FFT and wavelet.
ICP derived metrics including PrX. Dimensionality reduction techniques such as principle
component analysis (PCA) and non-supervised clustering techniques.
Time series analyses: Cross-correlations and Trajectory analyses, Deep learning
