<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02993549</url>
  </required_header>
  <id_info>
    <org_study_id>A094233</org_study_id>
    <nct_id>NCT02993549</nct_id>
  </id_info>
  <brief_title>TBI Multimodal Monitoring Study</brief_title>
  <acronym>monTBI</acronym>
  <official_title>Multimodality Monitoring Directed Management of Patients Suffering From Traumatic Brain Injury</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Cambridge</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Cambridge University Hospitals NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Cambridge</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Head injury is a common and devastating condition that can affect people at any stage of&#xD;
      their lives. The treatment of severe head injury takes place in intensive care where&#xD;
      interventions are designed to protect the brain from further injury and provide the best&#xD;
      environment for recovery. A number of different monitors are used after head injury,&#xD;
      including a monitor called microdialysis, to measure how the brain is generating energy.&#xD;
      Abnormalities in these monitors guide doctors to the right treatments when the brain is at&#xD;
      risk of further injury. There are lots of ways that the brain can be injured further after&#xD;
      head injury such as raised pressure in the skull from brain swelling, low oxygen levels and&#xD;
      low glucose levels. In this study we aim to combine information from all of these monitors to&#xD;
      figure out what the underlying problem is and choose the right intervention to treat the&#xD;
      problem that is affecting the patient at the time and compare this with previous treatment&#xD;
      protocols to see if it improved outcome.&#xD;
&#xD;
      Aim:&#xD;
&#xD;
      To establish and validate a protocol to treat abnormalities in a microdialysis measure called&#xD;
      lactate/pyruvate ratio (LPR) that reflects how cells are generating energy, and compare it&#xD;
      with patient cohorts not being monitored using the current protocol.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      Traumatic brain injury (TBI, &quot;head injury) is a major cause of morbidity and mortality&#xD;
      worldwide (Hyder et al., 2007). During the first four decades of life, trauma is the leading&#xD;
      cause of death and TBI is involved in at least half the number of cases (Jennett, 1996). In&#xD;
      the UK, 1,500 per 100,000 of the population (total 1 million) attend Accident and Emergency&#xD;
      Departments with a head injury per year. Of these, around 135,000 people are admitted each&#xD;
      year and there are an estimated 500,000 people (aged 16 - 74) with long term disabilities as&#xD;
      a direct result of TBI (Headway, 2016). Approximately 10 per 100,000 per year die from head&#xD;
      injury (Jennett and MacMillan, 1981, Hutchinson et al., 1998).&#xD;
&#xD;
      The major determinant of outcome from TBI is the severity of the primary injury, which is&#xD;
      irreversible. However, primary injury invariably leads to the activation of cellular and&#xD;
      molecular cascades which mediate further secondary injury that evolve over the ensuing hours&#xD;
      and days (Masel and DeWitt, 2010) and are therefore amenable to therapeutic intervention.&#xD;
      These molecular cascades can lead to brain swelling within the confines of a fixed&#xD;
      intracranial compartment, leading to increased intracranial pressure (ICP) and compromising&#xD;
      cerebral perfusion pressure (CPP) (Werner and Engelhard, 2007). The control of ICP and&#xD;
      maintenance of CPP has been the bedrock of neurointensive care management of TBI for several&#xD;
      decades, however, a recent multicenter randomised clinical trial could not show a long-term&#xD;
      favorable outcome with ICP guided therapy (Carney et al., 2012).&#xD;
&#xD;
      The Neuro Critical Care Unit (NCCU) in Cambridge is a world leader in TBI monitoring and&#xD;
      routinely employs multi-modal monitoring comprising of ICP, brain tissue oxygen and&#xD;
      microdialysis monitoring, in every TBI patient. Conceptually, microdialysis monitoring is an&#xD;
      attractive method of assessing tissue biochemistry as it provides a direct measure of&#xD;
      metabolic substrates at the cellular level at which energy failure occurs. Specifically, the&#xD;
      microdialysis derived measure Lactate/Pyruvate Ratio (LPR) is a measure of cellular redox&#xD;
      state and therefore the balance between aerobic and anaerobic metabolism. To date, studies in&#xD;
      the literature have focused on demonstrating that individual monitoring parameters e.g.&#xD;
      microdialysis derived LPR&gt;25 correlate with an unfavorable outcome in multivariate analyses&#xD;
      (Sarrafzadeh et al., 2000, Timofeev et al., 2011).&#xD;
&#xD;
      One reason that an ICP monitoring trial has not been proven to deliver improved outcome is&#xD;
      that there are several alternative routes to neuronal injury include insufficient oxygen&#xD;
      delivery (Nortje and Gupta, 2006), diffusion barrier within tissues (Smielewski et al.,&#xD;
      2002), tissue hypoglycaemia (Vespa et al., 2003) and mitochondrial dysfunction (Verweij et&#xD;
      al., 2000). Our understanding of these pathophysiological mechanisms has been greatly&#xD;
      advanced by the use of multi-modality monitoring including direct measurement of brain tissue&#xD;
      oxygen and cerebral microdialysis. In theory, these pathophysiological states could be&#xD;
      treated using treatment of ICP lowering therapy, augmenting cerebral perfusion pressure&#xD;
      (CPP), increasing oxygen delivery and augmenting glucose delivery. Though, we currently don't&#xD;
      know the best way to combine these treatments and they are often used together making&#xD;
      independent analysis difficult. Moreover, there is currently no approved therapy for&#xD;
      mitochondrial dysfunction, and while some claim that mitochondrial dysfunction is imminent in&#xD;
      increased LPR (Nordstrom et al., 2016), the reality is more complex as there will be&#xD;
      conditions that are treatable with an increased LPR, but these states need to be better&#xD;
      established for clinicians in order to accurately guide treatment (Lazaridis and Robertson,&#xD;
      2016). Previous implementations of guidelines in TBI have shown to improve care and reduce&#xD;
      health related cost, something we hope to achieve with our established clinical protocol&#xD;
      (Faul et al., 2007).&#xD;
&#xD;
      Overall research design&#xD;
&#xD;
      We propose a treatment algorithm exploring how a standardised clinical protocol that&#xD;
      incorporates multi-modality monitoring parameters (intracranial pressure, brain tissue oxygen&#xD;
      and microdialysis parameters) can be systematically and rigorously applied in a traumatic&#xD;
      brain injury (TBI) patient cohort with deranged brain chemistry (LPR &gt;25).&#xD;
&#xD;
      Our principal outcome metric is the ability for the protocol to improve the LPR, as well as&#xD;
      to see how many patients that may be stratified into any of the suggest treatment categories&#xD;
      (see below).&#xD;
&#xD;
      Interventions and assessments&#xD;
&#xD;
      Following inclusion, patients will be monitored using the standard clinical monitoring for&#xD;
      sedated and ventilated TBI patients which includes an Intracranial Pressure (ICP) monitor&#xD;
      device, a brain tissue oxygen monitor (PbO2) and microdialysis to assess brain biochemistry&#xD;
      (Le Roux et al., 2014, Hutchinson et al., 2015). While ICP and PbO2 are measured continually,&#xD;
      microdialysis samples are measured hourly. If a derangement in LPR is identified (LPR&gt;25),&#xD;
      patients will have an increase in monitoring frequency to every 30 minutes. Our primary&#xD;
      measure of deranged energy generation at the cellular level is a LPR&gt;25. This threshold has&#xD;
      been shown to relate to an unfavourable long-term outcome (Timofeev et al., 2011, Stein et&#xD;
      al., 2012). If the LPR&gt;25 on two consecutive samples (to avoid spurious or transient&#xD;
      derangements) it will trigger specific treatment strategies depending on the other&#xD;
      contemporaneous monitoring modalities. After each intervention, two consecutive microdialysis&#xD;
      samples will be taken to confirm whether LPR has been corrected or whether a further step in&#xD;
      the protocol needs to be taken. The sequence of interventions has been chosen on the basis of&#xD;
      the strength of association of each intervention with LPR in the existing literature&#xD;
      (Hutchinson et al., 2015).&#xD;
&#xD;
      STAGE 1: Correction of Intracranial Hypertension; ICP corrected to &lt;20mmHg Raised ICP&#xD;
      compromises delivery of both substrate and oxygen to the injured brain, by reducing Cerebral&#xD;
      Perfusion Pressure) and is in itself an independent predictor of poor outcome (Marmarou et&#xD;
      al., 1991, Bratton et al., 2007b). In the acute setting we will use hypertonic saline (100ml&#xD;
      5% saline by central venous bolus) as a rapid means of reducing ICP (Marko, 2012). This will&#xD;
      be followed by an escalation of ICP control measures using our established ICP protocol&#xD;
      (Helmy et al., 2007).&#xD;
&#xD;
      STAGE 2: Ensure sufficient Oxygenation; increase PbO2&gt;15mmHg&#xD;
&#xD;
      Increased LPR can reflect ischaemia and in the first instance we will ensure that there is&#xD;
      adequate oxygenation by increasing the PbO2&gt;15mmHg. This threshold of PbO2 has been&#xD;
      recognised as physiological in the literature (van den Brink et al., 2000). There are two&#xD;
      possible limitations to oxygen availability to brain tissue recognised in TBI:&#xD;
&#xD;
        1. Inadequate oxygen delivery (DO2(brain)=Cerebral Blood Flow (CBF) x Oxygen Capacity in&#xD;
           Blood) Firstly, we will ensure adequate haemoglobin concentration (&gt;8g/dl) within the&#xD;
           blood and normovolemia to ensure adequate oxygen carrying capacity. Cerebral perfusion&#xD;
           pressure (CPP) is monitored as a surrogate of CBF and is usually maintained at around&#xD;
           60-80 mmHg using vasopressors in the NCCU. The CPP target will be based on the&#xD;
           autoregulatory parameters of the individual patient utilising ICM+ software. The&#xD;
           pressure reactivity index (PRx), is a measure of the ability of the cerebral vasculature&#xD;
           to autoregulate to differing CPP (Czosnyka et al., 1997). Keeping the patient's CPP in&#xD;
           this autoregulatory range has been show in observational studies to improve outcome&#xD;
           (Aries et al., 2012, Needham et al., 2016). If the PRx is &gt;0.3, we will increase the CPP&#xD;
           by 10-20 mmHg (to a maximum of 80mmHg as per the upper threshold suggested in the BTF&#xD;
           guidelines) (Bratton et al., 2007a).&#xD;
&#xD;
        2. Diffusion Barrier Even with adequate oxygen delivery, microcirculatory collapse at the&#xD;
           capillary level can lead to tissue hypoxia (Menon et al., 2004). In this circumstance,&#xD;
           increasing the partial pressure of oxygen in arterial blood (PaO2) can increase the&#xD;
           gradient between oxygen within the blood and the brain tissue and drive oxygen into the&#xD;
           tissues (Reinert et al., 2003). This will be achieved by increasing the fractional&#xD;
           inspired oxygen (FiO2) by 40% to a maximum FiO2 of 80%.&#xD;
&#xD;
      STAGE 3: Ensure adequate metabolic substrate delivery; increase brain glucose &gt;1.0 mmol/L&#xD;
      Glucose is the primary biochemical substrate in order to generate pyruvate through&#xD;
      glycolysis. Brain tissue hypoglycaemia, measured using microdialysis, has been shown to be&#xD;
      common following TBI, and is correlated with an unfavourable outcome (Stein et al., 2012). If&#xD;
      brain tissue glucose levels falls &lt;1.0 mmol/L, we will increase plasma glucose to 7-10&#xD;
      mmol/L, as lower levels have been shown to correlate to brain tissue hypoglacemia (Oddo et&#xD;
      al., 2008), using 50% dextrose. Glucose manipulation has previously been demonstrated to&#xD;
      improve LPR (Oddo et al., 2008).&#xD;
&#xD;
      STAGE 4: Persistent LPR&gt;25 despite all monitoring modalities normalized; consider&#xD;
      mitochondrial dysfunction The mitochondria are the site of oxidative phosphorylation within&#xD;
      cells generating Adenine-Tri-Phosphate (ATP) in the presence of oxygen and suitable&#xD;
      biochemical substrate (typically pyruvate) in the tricarboxylic acid (TCA) cycle. It has been&#xD;
      empirically demonstrated that following TBI, even in the presence of adequate oxygenation and&#xD;
      glucose the mitochondria are incapable of utilising these substrates for energy&#xD;
      generation(Verweij et al., 2000). In this circumstance, limited amounts of ATP are generated&#xD;
      through anaerobic pathways generating lactate as a byproduct, thus increasing the LPR. In&#xD;
      this case, LP ratio is increased, but with an a normal pyruvate concentration (&gt;70mmol/l). In&#xD;
      this circumstance there are no accepted pharmacological therapies although in the literature&#xD;
      both succinate, a component of the tricarboxcylic acid cycle (Ehinger et al., 2016), and&#xD;
      Cyclosporin A, a calcineurin inhibitor, (Mbye et al., 2009) have shown potential efficacy&#xD;
      against mitochondrial dysfunction, and Cyclosporin A has a proven safety profile in TBI&#xD;
      patients (Mazzeo et al., 2009). It will be up to the treating physician to decide if they&#xD;
      wish to consider novel neuroprotective agents or metabolic substrates that have shown&#xD;
      promising results in the treatment of mitochondrial dysfunction.&#xD;
&#xD;
      Sampling strategies and data collection&#xD;
&#xD;
      Multimodality monitoring parameters are collected in the neuro-critical care unit (NCCU) in&#xD;
      real time, including ICP, CPP (PRx) and PbO2 as well as potential treatments provided.&#xD;
      Microdialysis parameters, including the brain metabolites glucose, pyruvate, lactate,&#xD;
      glycerol and glutamate, will be sampled every 30 minutes by research nurses in the NCCU. When&#xD;
      intracranial monitoring is not deemed necessary anymore, it will be discontinued as per&#xD;
      conventional management. The number of interventions that the patient receives and any&#xD;
      deviation from the protocol will be recorded.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">September 16, 2017</start_date>
  <completion_date type="Anticipated">October 2022</completion_date>
  <primary_completion_date type="Anticipated">January 2022</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>LPR &lt;25</measure>
    <time_frame>During neuro-critical care (the first 10 days following trauma).</time_frame>
    <description>Decrease of lactate:pyruvate ratio to below 25</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Different pathological targets</measure>
    <time_frame>During the neuro-critical care period (first 10 days after trauma)</time_frame>
    <description>How many patients have the different pathological targets, including 1. Intracranial hypertension (LPR corrected if ICP &lt;20mmHg), 2. Delivery failure (if LPR is corrected when PbO2 is improved and CPP increased). 3.Oxygen Diffusion Barrier (LPR is corrected if PbO2 is increased through FiO2 increase). 4. Neuroglycopenia (LPR is corrected if brain glucose is increased) or 5. Mitochondrial dysfunction (LPR remains increased despite all the therapies applied).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Monitoring correlation</measure>
    <time_frame>During the neuro-critical care period (first 10 days after trauma)</time_frame>
    <description>Correlation between Microdialysis parameters (glucose (mmol/L), lactate (mmol/L), pyruvate (mmol/L) and glutamate (µmol/L)) and PbO2 (mmHg), ICP (mmHg) and CPP (mmHg)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional Outcome</measure>
    <time_frame>6 months following injury</time_frame>
    <description>extended Glasgow Outcome Score 6 months following trauma assessed in the outpatient clinic at Addenbrooke's Hospital. Comparison between patients in different pathological targets.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cytokine concentration in MD</measure>
    <time_frame>During the neuro-critical care period (first 10 days after trauma)</time_frame>
    <description>Amount of cytokine concentration in microdialysis sample. Comparison between patients in different pathological targets.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomarker concentration in serum</measure>
    <time_frame>During the neuro-critical care (first 10 days after trauma)</time_frame>
    <description>Amount of S100B concentration (µg/L) through serum samples taken twice daily in the neuro-critical care unit. Comparison between patients in different pathological targets.</description>
  </secondary_outcome>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Traumatic Brain INjury</condition>
  <condition>Microdialysis</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Serum and cerebrospinal fluid if available. Microdialysis samples.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients suffering from traumatic brain injury in need of intracranial monitoring admitted&#xD;
        to the neuro-critical care unit at Addenbrooke's hospital, Cambridge, England.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with head injury requiring ICP monitoring&#xD;
&#xD;
          -  Age 18-65 years&#xD;
&#xD;
          -  Abnormal CT scan&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Bilateral fixed and dilated pupils&#xD;
&#xD;
          -  Bleeding diathesis&#xD;
&#xD;
          -  Thrombocytopenia (platelets &lt; 100)&#xD;
&#xD;
          -  Devastating injuries; patient not expected to survive &gt; 24 hours&#xD;
&#xD;
          -  Brainstem damage&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Involvement in other studies non-observational studies&#xD;
&#xD;
          -  MD catheter located in haemorrhagic lesion&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Adel Helmy, MA MB BChir FRCS PhD</last_name>
    <phone>00441223 336946</phone>
    <email>adelhelmy@doctors.org.uk</email>
  </overall_contact>
  <location>
    <facility>
      <name>Cambridge University Hospital NHS Trust</name>
      <address>
        <city>Cambridge</city>
        <state>Cambridgeshire</state>
        <zip>CB2 0QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Adel Helmy</last_name>
    </contact>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <link>
    <url>https://www.headway.org.uk/about-brain-injury/further-information/statistics/</url>
    <description>Head injury statistics in the UK</description>
  </link>
  <reference>
    <citation>Hyder AA, Wunderlich CA, Puvanachandra P, Gururaj G, Kobusingye OC. The impact of traumatic brain injuries: a global perspective. NeuroRehabilitation. 2007;22(5):341-53.</citation>
    <PMID>18162698</PMID>
  </reference>
  <reference>
    <citation>Jennett B. Epidemiology of head injury. J Neurol Neurosurg Psychiatry. 1996 Apr;60(4):362-9. doi: 10.1136/jnnp.60.4.362. No abstract available.</citation>
    <PMID>8774396</PMID>
  </reference>
  <reference>
    <citation>Jennett B, MacMillan R. Epidemiology of head injury. Br Med J (Clin Res Ed). 1981 Jan 10;282(6258):101-4. doi: 10.1136/bmj.282.6258.101.</citation>
    <PMID>6779889</PMID>
  </reference>
  <reference>
    <citation>Hutchinson PJ, Kirkpatrick PJ, Addison J, Jackson S, Pickard JD. The management of minor traumatic brain injury. J Accid Emerg Med. 1998 Mar;15(2):84-8. doi: 10.1136/emj.15.2.84.</citation>
    <PMID>9570046</PMID>
  </reference>
  <reference>
    <citation>Masel BE, DeWitt DS. Traumatic brain injury: a disease process, not an event. J Neurotrauma. 2010 Aug;27(8):1529-40. doi: 10.1089/neu.2010.1358.</citation>
    <PMID>20504161</PMID>
  </reference>
  <reference>
    <citation>Werner C, Engelhard K. Pathophysiology of traumatic brain injury. Br J Anaesth. 2007 Jul;99(1):4-9. doi: 10.1093/bja/aem131.</citation>
    <PMID>17573392</PMID>
  </reference>
  <reference>
    <citation>Carney N, Lujan S, Dikmen S, Temkin N, Petroni G, Pridgeon J, Barber J, Machamer J, Cherner M, Chaddock K, Hendrix T, Rondina C, Videtta W, Celix JM, Chesnut R. Intracranial pressure monitoring in severe traumatic brain injury in latin america: process and methods for a multi-center randomized controlled trial. J Neurotrauma. 2012 Jul 20;29(11):2022-9. doi: 10.1089/neu.2011.2019. Epub 2012 May 15.</citation>
    <PMID>22435793</PMID>
  </reference>
  <reference>
    <citation>Timofeev I, Carpenter KL, Nortje J, Al-Rawi PG, O'Connell MT, Czosnyka M, Smielewski P, Pickard JD, Menon DK, Kirkpatrick PJ, Gupta AK, Hutchinson PJ. Cerebral extracellular chemistry and outcome following traumatic brain injury: a microdialysis study of 223 patients. Brain. 2011 Feb;134(Pt 2):484-94. doi: 10.1093/brain/awq353. Epub 2011 Jan 18.</citation>
    <PMID>21247930</PMID>
  </reference>
  <reference>
    <citation>Sarrafzadeh AS, Sakowitz OW, Callsen TA, Lanksch WR, Unterberg AW. Bedside microdialysis for early detection of cerebral hypoxia in traumatic brain injury. Neurosurg Focus. 2000 Nov 15;9(5):e2. doi: 10.3171/foc.2000.9.5.2.</citation>
    <PMID>16821754</PMID>
  </reference>
  <reference>
    <citation>Nortje J, Gupta AK. The role of tissue oxygen monitoring in patients with acute brain injury. Br J Anaesth. 2006 Jul;97(1):95-106. doi: 10.1093/bja/ael137. Epub 2006 Jun 3.</citation>
    <PMID>16751641</PMID>
  </reference>
  <reference>
    <citation>Smielewski P, Coles JP, Fryer TD, Minhas PS, Menon DK, Pickard JD. Integrated image analysis solutions for PET datasets in damaged brain. J Clin Monit Comput. 2002 Dec;17(7-8):427-40. doi: 10.1023/a:1026293611455.</citation>
    <PMID>14650638</PMID>
  </reference>
  <reference>
    <citation>Vespa PM, McArthur D, O'Phelan K, Glenn T, Etchepare M, Kelly D, Bergsneider M, Martin NA, Hovda DA. Persistently low extracellular glucose correlates with poor outcome 6 months after human traumatic brain injury despite a lack of increased lactate: a microdialysis study. J Cereb Blood Flow Metab. 2003 Jul;23(7):865-77. doi: 10.1097/01.WCB.0000076701.45782.EF.</citation>
    <PMID>12843790</PMID>
  </reference>
  <reference>
    <citation>Verweij BH, Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP. Impaired cerebral mitochondrial function after traumatic brain injury in humans. J Neurosurg. 2000 Nov;93(5):815-20. doi: 10.3171/jns.2000.93.5.0815.</citation>
    <PMID>11059663</PMID>
  </reference>
  <reference>
    <citation>Nordstrom CH, Nielsen TH, Schalen W, Reinstrup P, Ungerstedt U. Biochemical indications of cerebral ischaemia and mitochondrial dysfunction in severe brain trauma analysed with regard to type of lesion. Acta Neurochir (Wien). 2016 Jul;158(7):1231-40. doi: 10.1007/s00701-016-2835-z. Epub 2016 May 17.</citation>
    <PMID>27188288</PMID>
  </reference>
  <reference>
    <citation>Lazaridis C, Robertson CS. The Role of Multimodal Invasive Monitoring in Acute Traumatic Brain Injury. Neurosurg Clin N Am. 2016 Oct;27(4):509-17. doi: 10.1016/j.nec.2016.05.010.</citation>
    <PMID>27637400</PMID>
  </reference>
  <reference>
    <citation>Faul M, Wald MM, Rutland-Brown W, Sullivent EE, Sattin RW. Using a cost-benefit analysis to estimate outcomes of a clinical treatment guideline: testing theBrain Trauma Foundation guidelines for the treatment of severe traumatic brain injury. J Trauma. 2007 Dec;63(6):1271-8. doi: 10.1097/TA.0b013e3181493080.</citation>
    <PMID>18212649</PMID>
  </reference>
  <reference>
    <citation>Hutchinson PJ, Jalloh I, Helmy A, Carpenter KL, Rostami E, Bellander BM, Boutelle MG, Chen JW, Claassen J, Dahyot-Fizelier C, Enblad P, Gallagher CN, Helbok R, Hillered L, Le Roux PD, Magnoni S, Mangat HS, Menon DK, Nordstrom CH, O'Phelan KH, Oddo M, Perez Barcena J, Robertson C, Ronne-Engstrom E, Sahuquillo J, Smith M, Stocchetti N, Belli A, Carpenter TA, Coles JP, Czosnyka M, Dizdar N, Goodman JC, Gupta AK, Nielsen TH, Marklund N, Montcriol A, O'Connell MT, Poca MA, Sarrafzadeh A, Shannon RJ, Skjoth-Rasmussen J, Smielewski P, Stover JF, Timofeev I, Vespa P, Zavala E, Ungerstedt U. Consensus statement from the 2014 International Microdialysis Forum. Intensive Care Med. 2015 Sep;41(9):1517-28. doi: 10.1007/s00134-015-3930-y.</citation>
    <PMID>26194024</PMID>
  </reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>December 7, 2016</study_first_submitted>
  <study_first_submitted_qc>December 12, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 15, 2016</study_first_posted>
  <last_update_submitted>July 10, 2020</last_update_submitted>
  <last_update_submitted_qc>July 10, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 14, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Cambridge</investigator_affiliation>
    <investigator_full_name>Adel Helmy</investigator_full_name>
    <investigator_title>University Lecturer Neurosurgery</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
  </condition_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 31, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/49/NCT02993549/Prot_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02993549
org study id: A094233
nct id: NCT02993549
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Head injury is a common and devastating condition that can affect people at any stage of
      their lives. The treatment of severe head injury takes place in intensive care where
      interventions are designed to protect the brain from further injury and provide the best
      environment for recovery. A number of different monitors are used after head injury,
      including a monitor called microdialysis, to measure how the brain is generating energy.
      Abnormalities in these monitors guide doctors to the right treatments when the brain is at
      risk of further injury. There are lots of ways that the brain can be injured further after
      head injury such as raised pressure in the skull from brain swelling, low oxygen levels and
      low glucose levels. In this study we aim to combine information from all of these monitors to
      figure out what the underlying problem is and choose the right intervention to treat the
      problem that is affecting the patient at the time and compare this with previous treatment
      protocols to see if it improved outcome.

      Aim:

      To establish and validate a protocol to treat abnormalities in a microdialysis measure called
      lactate/pyruvate ratio (LPR) that reflects how cells are generating energy, and compare it
      with patient cohorts not being monitored using the current protocol.
Background:

      Traumatic brain injury (TBI, "head injury) is a major cause of morbidity and mortality
      worldwide (Hyder et al., 2007). During the first four decades of life, trauma is the leading
      cause of death and TBI is involved in at least half the number of cases (Jennett, 1996). In
      the UK, 1,500 per 100,000 of the population (total 1 million) attend Accident and Emergency
      Departments with a head injury per year. Of these, around 135,000 people are admitted each
      year and there are an estimated 500,000 people (aged 16 - 74) with long term disabilities as
      a direct result of TBI (Headway, 2016). Approximately 10 per 100,000 per year die from head
      injury (Jennett and MacMillan, 1981, Hutchinson et al., 1998).

      The major determinant of outcome from TBI is the severity of the primary injury, which is
      irreversible. However, primary injury invariably leads to the activation of cellular and
      molecular cascades which mediate further secondary injury that evolve over the ensuing hours
      and days (Masel and DeWitt, 2010) and are therefore amenable to therapeutic intervention.
      These molecular cascades can lead to brain swelling within the confines of a fixed
      intracranial compartment, leading to increased intracranial pressure (ICP) and compromising
      cerebral perfusion pressure (CPP) (Werner and Engelhard, 2007). The control of ICP and
      maintenance of CPP has been the bedrock of neurointensive care management of TBI for several
      decades, however, a recent multicenter randomised clinical trial could not show a long-term
      favorable outcome with ICP guided therapy (Carney et al., 2012).

      The Neuro Critical Care Unit (NCCU) in Cambridge is a world leader in TBI monitoring and
      routinely employs multi-modal monitoring comprising of ICP, brain tissue oxygen and
      microdialysis monitoring, in every TBI patient. Conceptually, microdialysis monitoring is an
      attractive method of assessing tissue biochemistry as it provides a direct measure of
      metabolic substrates at the cellular level at which energy failure occurs. Specifically, the
      microdialysis derived measure Lactate/Pyruvate Ratio (LPR) is a measure of cellular redox
      state and therefore the balance between aerobic and anaerobic metabolism. To date, studies in
      the literature have focused on demonstrating that individual monitoring parameters e.g.
      microdialysis derived LPR>25 correlate with an unfavorable outcome in multivariate analyses
      (Sarrafzadeh et al., 2000, Timofeev et al., 2011).

      One reason that an ICP monitoring trial has not been proven to deliver improved outcome is
      that there are several alternative routes to neuronal injury include insufficient oxygen
      delivery (Nortje and Gupta, 2006), diffusion barrier within tissues (Smielewski et al.,
      2002), tissue hypoglycaemia (Vespa et al., 2003) and mitochondrial dysfunction (Verweij et
      al., 2000). Our understanding of these pathophysiological mechanisms has been greatly
      advanced by the use of multi-modality monitoring including direct measurement of brain tissue
      oxygen and cerebral microdialysis. In theory, these pathophysiological states could be
      treated using treatment of ICP lowering therapy, augmenting cerebral perfusion pressure
      (CPP), increasing oxygen delivery and augmenting glucose delivery. Though, we currently don't
      know the best way to combine these treatments and they are often used together making
      independent analysis difficult. Moreover, there is currently no approved therapy for
      mitochondrial dysfunction, and while some claim that mitochondrial dysfunction is imminent in
      increased LPR (Nordstrom et al., 2016), the reality is more complex as there will be
      conditions that are treatable with an increased LPR, but these states need to be better
      established for clinicians in order to accurately guide treatment (Lazaridis and Robertson,
      2016). Previous implementations of guidelines in TBI have shown to improve care and reduce
      health related cost, something we hope to achieve with our established clinical protocol
      (Faul et al., 2007).

      Overall research design

      We propose a treatment algorithm exploring how a standardised clinical protocol that
      incorporates multi-modality monitoring parameters (intracranial pressure, brain tissue oxygen
      and microdialysis parameters) can be systematically and rigorously applied in a traumatic
      brain injury (TBI) patient cohort with deranged brain chemistry (LPR >25).

      Our principal outcome metric is the ability for the protocol to improve the LPR, as well as
      to see how many patients that may be stratified into any of the suggest treatment categories
      (see below).

      Interventions and assessments

      Following inclusion, patients will be monitored using the standard clinical monitoring for
      sedated and ventilated TBI patients which includes an Intracranial Pressure (ICP) monitor
      device, a brain tissue oxygen monitor (PbO2) and microdialysis to assess brain biochemistry
      (Le Roux et al., 2014, Hutchinson et al., 2015). While ICP and PbO2 are measured continually,
      microdialysis samples are measured hourly. If a derangement in LPR is identified (LPR>25),
      patients will have an increase in monitoring frequency to every 30 minutes. Our primary
      measure of deranged energy generation at the cellular level is a LPR>25. This threshold has
      been shown to relate to an unfavourable long-term outcome (Timofeev et al., 2011, Stein et
      al., 2012). If the LPR>25 on two consecutive samples (to avoid spurious or transient
      derangements) it will trigger specific treatment strategies depending on the other
      contemporaneous monitoring modalities. After each intervention, two consecutive microdialysis
      samples will be taken to confirm whether LPR has been corrected or whether a further step in
      the protocol needs to be taken. The sequence of interventions has been chosen on the basis of
      the strength of association of each intervention with LPR in the existing literature
      (Hutchinson et al., 2015).

      STAGE 1: Correction of Intracranial Hypertension; ICP corrected to <20mmHg Raised ICP
      compromises delivery of both substrate and oxygen to the injured brain, by reducing Cerebral
      Perfusion Pressure) and is in itself an independent predictor of poor outcome (Marmarou et
      al., 1991, Bratton et al., 2007b). In the acute setting we will use hypertonic saline (100ml
      5% saline by central venous bolus) as a rapid means of reducing ICP (Marko, 2012). This will
      be followed by an escalation of ICP control measures using our established ICP protocol
      (Helmy et al., 2007).

      STAGE 2: Ensure sufficient Oxygenation; increase PbO2>15mmHg

      Increased LPR can reflect ischaemia and in the first instance we will ensure that there is
      adequate oxygenation by increasing the PbO2>15mmHg. This threshold of PbO2 has been
      recognised as physiological in the literature (van den Brink et al., 2000). There are two
      possible limitations to oxygen availability to brain tissue recognised in TBI:

        1. Inadequate oxygen delivery (DO2(brain)=Cerebral Blood Flow (CBF) x Oxygen Capacity in
           Blood) Firstly, we will ensure adequate haemoglobin concentration (>8g/dl) within the
           blood and normovolemia to ensure adequate oxygen carrying capacity. Cerebral perfusion
           pressure (CPP) is monitored as a surrogate of CBF and is usually maintained at around
           60-80 mmHg using vasopressors in the NCCU. The CPP target will be based on the
           autoregulatory parameters of the individual patient utilising ICM+ software. The
           pressure reactivity index (PRx), is a measure of the ability of the cerebral vasculature
           to autoregulate to differing CPP (Czosnyka et al., 1997). Keeping the patient's CPP in
           this autoregulatory range has been show in observational studies to improve outcome
           (Aries et al., 2012, Needham et al., 2016). If the PRx is >0.3, we will increase the CPP
           by 10-20 mmHg (to a maximum of 80mmHg as per the upper threshold suggested in the BTF
           guidelines) (Bratton et al., 2007a).

        2. Diffusion Barrier Even with adequate oxygen delivery, microcirculatory collapse at the
           capillary level can lead to tissue hypoxia (Menon et al., 2004). In this circumstance,
           increasing the partial pressure of oxygen in arterial blood (PaO2) can increase the
           gradient between oxygen within the blood and the brain tissue and drive oxygen into the
           tissues (Reinert et al., 2003). This will be achieved by increasing the fractional
           inspired oxygen (FiO2) by 40% to a maximum FiO2 of 80%.

      STAGE 3: Ensure adequate metabolic substrate delivery; increase brain glucose >1.0 mmol/L
      Glucose is the primary biochemical substrate in order to generate pyruvate through
      glycolysis. Brain tissue hypoglycaemia, measured using microdialysis, has been shown to be
      common following TBI, and is correlated with an unfavourable outcome (Stein et al., 2012). If
      brain tissue glucose levels falls <1.0 mmol/L, we will increase plasma glucose to 7-10
      mmol/L, as lower levels have been shown to correlate to brain tissue hypoglacemia (Oddo et
      al., 2008), using 50% dextrose. Glucose manipulation has previously been demonstrated to
      improve LPR (Oddo et al., 2008).

      STAGE 4: Persistent LPR>25 despite all monitoring modalities normalized; consider
      mitochondrial dysfunction The mitochondria are the site of oxidative phosphorylation within
      cells generating Adenine-Tri-Phosphate (ATP) in the presence of oxygen and suitable
      biochemical substrate (typically pyruvate) in the tricarboxylic acid (TCA) cycle. It has been
      empirically demonstrated that following TBI, even in the presence of adequate oxygenation and
      glucose the mitochondria are incapable of utilising these substrates for energy
      generation(Verweij et al., 2000). In this circumstance, limited amounts of ATP are generated
      through anaerobic pathways generating lactate as a byproduct, thus increasing the LPR. In
      this case, LP ratio is increased, but with an a normal pyruvate concentration (>70mmol/l). In
      this circumstance there are no accepted pharmacological therapies although in the literature
      both succinate, a component of the tricarboxcylic acid cycle (Ehinger et al., 2016), and
      Cyclosporin A, a calcineurin inhibitor, (Mbye et al., 2009) have shown potential efficacy
      against mitochondrial dysfunction, and Cyclosporin A has a proven safety profile in TBI
      patients (Mazzeo et al., 2009). It will be up to the treating physician to decide if they
      wish to consider novel neuroprotective agents or metabolic substrates that have shown
      promising results in the treatment of mitochondrial dysfunction.

      Sampling strategies and data collection

      Multimodality monitoring parameters are collected in the neuro-critical care unit (NCCU) in
      real time, including ICP, CPP (PRx) and PbO2 as well as potential treatments provided.
      Microdialysis parameters, including the brain metabolites glucose, pyruvate, lactate,
      glycerol and glutamate, will be sampled every 30 minutes by research nurses in the NCCU. When
      intracranial monitoring is not deemed necessary anymore, it will be discontinued as per
      conventional management. The number of interventions that the patient receives and any
      deviation from the protocol will be recorded.
observational model: Cohort
time perspective: Prospective
measure: LPR <25
time frame: During neuro-critical care (the first 10 days following trauma).
description: Decrease of lactate:pyruvate ratio to below 25
measure: Different pathological targets
time frame: During the neuro-critical care period (first 10 days after trauma)
description: How many patients have the different pathological targets, including 1. Intracranial hypertension (LPR corrected if ICP <20mmHg), 2. Delivery failure (if LPR is corrected when PbO2 is improved and CPP increased). 3.Oxygen Diffusion Barrier (LPR is corrected if PbO2 is increased through FiO2 increase). 4. Neuroglycopenia (LPR is corrected if brain glucose is increased) or 5. Mitochondrial dysfunction (LPR remains increased despite all the therapies applied).
measure: Monitoring correlation
time frame: During the neuro-critical care period (first 10 days after trauma)
description: Correlation between Microdialysis parameters (glucose (mmol/L), lactate (mmol/L), pyruvate (mmol/L) and glutamate (µmol/L)) and PbO2 (mmHg), ICP (mmHg) and CPP (mmHg)
measure: Functional Outcome
time frame: 6 months following injury
description: extended Glasgow Outcome Score 6 months following trauma assessed in the outpatient clinic at Addenbrooke's Hospital. Comparison between patients in different pathological targets.
measure: Cytokine concentration in MD
time frame: During the neuro-critical care period (first 10 days after trauma)
description: Amount of cytokine concentration in microdialysis sample. Comparison between patients in different pathological targets.
measure: Biomarker concentration in serum
time frame: During the neuro-critical care (first 10 days after trauma)
description: Amount of S100B concentration (µg/L) through serum samples taken twice daily in the neuro-critical care unit. Comparison between patients in different pathological targets.
Serum and cerebrospinal fluid if available. Microdialysis samples.
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Adel Helmy, MA MB BChir FRCS PhD
phone: 00441223 336946
email: adelhelmy@doctors.org.uk
facility: 
status: Recruiting
contact: 
country: United Kingdom
url: https://www.headway.org.uk/about-brain-injury/further-information/statistics/
description: Head injury statistics in the UK
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PMID: 6779889
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PMID: 9570046
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PMID: 20504161
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PMID: 17573392
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PMID: 22435793
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PMID: 21247930
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PMID: 14650638
citation: Vespa PM, McArthur D, O'Phelan K, Glenn T, Etchepare M, Kelly D, Bergsneider M, Martin NA, Hovda DA. Persistently low extracellular glucose correlates with poor outcome 6 months after human traumatic brain injury despite a lack of increased lactate: a microdialysis study. J Cereb Blood Flow Metab. 2003 Jul;23(7):865-77. doi: 10.1097/01.WCB.0000076701.45782.EF.
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citation: Hutchinson PJ, Jalloh I, Helmy A, Carpenter KL, Rostami E, Bellander BM, Boutelle MG, Chen JW, Claassen J, Dahyot-Fizelier C, Enblad P, Gallagher CN, Helbok R, Hillered L, Le Roux PD, Magnoni S, Mangat HS, Menon DK, Nordstrom CH, O'Phelan KH, Oddo M, Perez Barcena J, Robertson C, Ronne-Engstrom E, Sahuquillo J, Smith M, Stocchetti N, Belli A, Carpenter TA, Coles JP, Czosnyka M, Dizdar N, Goodman JC, Gupta AK, Nielsen TH, Marklund N, Montcriol A, O'Connell MT, Poca MA, Sarrafzadeh A, Shannon RJ, Skjoth-Rasmussen J, Smielewski P, Stover JF, Timofeev I, Vespa P, Zavala E, Ungerstedt U. Consensus statement from the 2014 International Microdialysis Forum. Intensive Care Med. 2015 Sep;41(9):1517-28. doi: 10.1007/s00134-015-3930-y.
PMID: 26194024
responsible party type: Principal Investigator
investigator affiliation: University of Cambridge
investigator full name: Adel Helmy
investigator title: University Lecturer Neurosurgery
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
provided document: 