Severe burn patients are some of the most challenging critically ill patients with an extreme
      and continuous state of physiological stress. Patients tends to stay for a long period of
      time in intensive care unit to treat burns as well as dealing with complications that arises
      from the initial burns injury. Severe burns patients are notoriously known to loose weight.
      The word 'catabolism' is used medically. This theory of catabolism after a trauma was
      hypothesised in 1942 by Professor Curthberston and based on animal models. Since this date,
      despite medical technological advancement, there has been no research that confirms Professor
      Curthberston's theory. Investigators still do not know the exact mechanism by which the body
      changes from conserving energy to becoming catabolic. Furthermore, it remains unclear whether
      this change in catabolism is necessary to heal from burns injury.

      This theoretical catabolism in burns patients is currently treated with nutritional
      supplement, use of medications including beta-blockers (suppresses heart rate and decreases
      blood pressure) and oxandrolone (formula which is similar to testosterone to build up
      muscles).

      There are evidences to suggest that increase in weight loss worsens the outcome in burns
      injury. Both overfeeding or underfeeding patients can be detrimental. In this research, the
      exact changes in metabolic rate will be measured in the first 72 hours of the study using a
      calorimetry machine. In addition to the metabolic rate, the response to the heart, liver,
      kidneys and hormonal levels will be measured. By looking into these dynamic changes the
      investigator will be able to elucidate whether there is a real increase in metabolic rate. If
      there is, the investigator would also be able to tell the response of different organs and
      whether there are any hormones that could be responsible to inflicting the metabolic changes.

Metabolic Rate in Burns

Burns

1. Purpose of the study The purpose of this study is to gain a better understanding of the
           acute physiological and metabolic changes in severe burns injury. Unless clinicians
           understand the physiological effect in burns patients, clinicians are unable to develop
           new therapeutic interventions to halt the hyper metabolic changes in burns patient. This
           research will be looking into the acute resting basal metabolic changes in severe adult
           burns patients by using Quark RMR (indirect calorimetry). This equipment will allow the
           investigator to detect the metabolic switch in severe burns patients.

           In addition to the metabolic changes, 'Estimated cardiac output monitor' will be placed
           in conjunction with calculating the Fick principle. Heart rate and pulse oximeter will
           be monitored continuously. These adjuncts will allow the investigator to conclude
           whether hyper-metabolism is associated with hyper dynamic cardiovascular response to
           burns.

           Splanchnic circulation will be monitored using the LiMON indocyanine green test and
           intermittent intra-abdominal pressure will be monitored to assess whether there is a
           link between the metabolic rate and splanchnic circulation.

        2. Objectives

             1. Primary Objective:

                Identifying the 'Ebb' phase and 'Flow' phase in acute burns injury

             2. Secondary Objectives:

      1. To establish cardiovascular response to burns in the acute phase.

      a. To establish cardiovascular response to hyper-catabolism, using ESCO (estimated cardiac
      output) 2. To asses the relationship between the splanchnic circulation and hyper-catabolism
      3. To assess the feasibility of performing LiMON test and (Bispectral Index) BIS monitoring
      for future (Burns Intensive Care Unit) BICU patients 4. To optimize dietary recommendations
      for patients who are suffering from hyper-catabolic state

      8. Study Design Summary: This is a prospective, observational study with intensive monitoring
      but no experimental intervention

      a) Study Site and Duration: This study will be conducted on the adult Burns Intensive Care
      Unit (BICU), Chelsea and Westminster Foundation Trust, London, United Kingdom (UK). This is a
      tertiary referral hospital serving an area of North West London. The average annual admission
      for severe burns to BICU varies form 10 -15 patients. The study will be conducted from
      December 2015 to December 2019.

      The BICU has facilities for ventilatory support, sedation and surgery of critically ill
      patients, with two-bed intensive care unit. Each bed is isolated with three senior trained
      intensive care nurses covering 24 hours. Critically ill burns participants will be monitored
      continuously by nurses and doctors with the use of non-invasive and invasive monitoring
      depending on their clinical needs as per standard clinical care.

      f) Procedure

      General History and Examination Upon enrolment, full history and examination will be
      performed, including detailed assessment of the respiratory system, extent and depth of
      burns, neurological examination, cardiovascular examination and excluding other potential
      trauma that the participants could have suffered from.

      The results will be recorded on a designated record form. Participants will be re-assessed by
      a physician or nurse for the duration of continuous monitoring to independently assess blood
      pressure, heart rate, respiratory rate, oxygen saturation, cardiac output, Glasgow coma
      scale, sedation score, ventilator requirement, urine output, intra-abdominal pressure,
      splanchnic circulation, BIS, EEG, nitrogen balance, resting metabolic rate and temperature.

      Daily follow up will include assessment for any complications of burns including sepsis,
      infection, inhalational injury, suspected Acute Respiratory Distress Syndrome, and suspected
      respiratory distress of uncertain aetiology. The decision to obtain imaging or other
      investigations to assess such complications will be made by the clinical team and the results
      will be archived as source documents.

      In addition to above, venous blood sample will be taken to establish on the daily basis to
      monitor inflammatory markers, renal, liver, bone marrow function, electrolyte levels. Urinary
      nitrogen levels, plasma hormones including Thyroid stimulating hormone, T3, T4, cortisol
      levels, insulin, glucagon levels are taken daily. These tests will be completed by the
      clinical team.

      Regular arterial line gas sample will be taken as guided by the clinical team.

      Continuous monitoring Participants will undergo standard electrophysiological monitoring,
      cardiovascular monitoring including arterial line blood pressure monitoring, placement of
      estimated cardiac output monitoring and intra-abdominal pressure. These devices will be
      connected to a portable diagnostic recording system to aid the diagnosis of any physiological
      changes that occurs. The system comprises a central device, with a display screen, battery
      pack and memory card. The electrophysiological monitoring device will consists or three
      electrodes and wires which feeds into the central device ports. The electrodes will be
      attached to the participants' forehead; left central and right. The intra-abdominal pressure
      device consists of a transducer which is located in the urinary catheter. The wires which are
      connected to the transducers are then fed into the central device ports. The continuous
      estimated cardiac output monitoring devices consist of three cardiac electrodes, pulse
      oximetry device and wires, which are connected to the central device ports. The cardiac
      electrodes are placed to the participants' thorax and the pulse oximetry device is attached
      to the participants' digit either in the foot or hand.

      The following sensors will be applied:

        -  Electrocardiogram: recording cardiac electrical activity to give three recorded and
           three derived traces

        -  Ventilator: recording airflow inhale and exhalation, flow rate, pressure, tidal volume,
           peep, type of ventilator mode.

        -  Pulse oximeter: recording arterial oxygen saturation and pulse rate The monitoring
           system will be applied to the participant once assent is obtained and after the initial
           management; drug administration, examination and other investigation are performed by
           the clinical team. The sensors will be applied with the goal of recording continuously
           for seventy two hours.

      Intermittent monitoring Participant will undergo indirect calorimetry monitoring and LIMON
      test. Resting metabolic rate will be measured every 12 hourly for 72 hours using indirect
      calorimetry with Quark Resting Metabolic Rate (QUARK RMR) (COSMED, Rome, Italy). This device
      consist of canopy, ventilator tubing, heat and moisture exchange filter, air sample analyzing
      tubes, computer, gas analyzing chamber, calibration gas cylinder, air pump to calibrate the
      flow sensor, fuel cell, spirometry and Windows 8.0 computer which has COSMED Quark RMR
      software installed.

      Participants are either ventilated or awake. Ventilated participants will have a gas
      analyzing tubing attached to the heat and moisture exchange filter which is fed unto the gas
      analyzing chamber. The flow meter is attached at the exhaust port at the back of the
      ventilator.

      The measurement is taken until a steady resting state is achieved. This will normally vary
      from two minutes to 20 minutes. The results are automatically recorded onto the Quark RMR
      software. In order to achieve steady ventilation with little minimum bias flow the
      participants' Bispectral index is maintained between forty and sixty using medications such
      as propofol, fentanyl, midazolam or clonidine.

      Liver and splanchnic circulation will be measured every 6 hourly using LIMON Liver Function
      Monitor (Liver Monitor, PULSION Medical Systems, Munich, Germany) The device consist of
      sensor, wires and monitor to display the instructions and results. The sensor is attached to
      the participants' earlobe, finger tips in the hand or foot. The indocyanine green dye (ICG)
      is injected into a vein. The results will be displayed onto the monitor.

      If the recording is suboptimal due to loss of sensors or insufficient recording, it will be
      repeated.

      All of the above equipments and monitoring system will be cleaned and disinfected according
      to the manufacturing advice and microbiology team. The standard operating procedures for the
      above equipments are described in the appendix.

      Cessation of monitoring The recording system, or individual sensors will be removed
      immediately if it is required for clinical investigations or interventions. However, it is
      anticipated that most investigations and interventions will be able to proceed with the
      sensors in place. The device is expected to remain in place during patient re-positioning,
      airway management, delivery of oxygen, delivery of oral and IV medication and fluids and most
      imaging with the exception of magnetic resonance imaging.

      BIS monitoring will be removed in the event of cardio-respiratory arrest. If study clinician
      is not present at the time of cardio-respiratory arrest, the monitor will detach without
      difficulty and will not impede or delay resuscitation efforts.

      Date collection:

      In addition to above data, the investigator be collecting the patients' demographics
      including apache II scoring, end organ function including liver function, renal function,
      haematological status, ventilator settings, arterial gas, urine output and temperature.

      9. Data Analysis Analysis of recording Data will be exported from the monitoring devices
      after each recording and assessed for adequacy and quality.

      All frontal lobe electroencephalogram will be analysed. If there is any EEG finding that are
      consist with seizures it will be reviewed by neurophysiologist. All resting metabolic rate
      will be plotted against the physiological parameters including splanchnic circulation,
      temperature and intra-abdominal pressure. The ECG will be reviewed to assess heart rate,
      rhythm and conduction. Invasive blood pressure monitoring device will assess the blood
      pressure. Estimated cardiac output monitoring will assess the cardiac output and the trend
      over the seventy two hours. Fick principle will be used to calculate the cardiac output using
      the data (CaO2 and CVO2) obtained from the Quark RMR.

      Any stimulus, airway management, changes in the levels of sedation, return from theatres will
      be noted.

        1. Statistical Consideration In the view of the complexity of data provided by continuous
           monitoring, statistical guidance will be sought at all stages of analysis from the
           "Statistician. For the primary end points, the investigator will draw a graph of time
           again resting metabolic rate. The precise choice of test will be determined once the
           distribution pattern of the data is known. Repeated measure analysis of variance will be
           used followed by regression analysis accounted for repeat measures.

           In comparing patient specific outcome measures (mortality, requirement for ventilation,
           development of complications such as sepsis), participants will be placed into ranked
           groups from most to least difference in trend change in resting metabolic rate and
           nonparametric analysis will be used to assess the relationship between mortality or
           morbidity and resting metabolic rate.

        2. Sample Size Justification Primary determinant is expected number of eligible patients
           presenting in the duration of study.

      Power calculation was completed for the primary outcome measures. In order to conclude to
      show that there is an increase in metabolic rate by 200 kcal per day with a power of 0.8, I
      will need 8 patients to be able to conclude that there increase in metabolic rate.

observational study

In Vivo Cellular and Physiological Response to Severe Burns Injuries

The resting metabolic rate will be measured using Quark Indirect Calorimetry Machine from Cosmed, Italy. The rested metabolic rate will be measured in kilo calories.

Consultant in Anaesthesia and Intensive Care Medicine Honorary Senior Clinical Lecturer Divisional Research Lead for Planned Care Surgery and Clinical Support

The cardiac output will be measured in mls.

splanchnic circulation will be measured by using Limon machine from Maquet. The plasma clearance rate of indocyanine green will be measured in % per ml.

Metabolic Rate in Burns

About this trial

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Placebo

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