Remote Biomonitoring (RBM) for Temperature Surveillance of Mothers and Newborns: Pre-clinical and Clinical Evaluation
Condition: Temperature Change, Body
MeSH terms: Body Temperature Changes
Study type: Interventional

Summary: 
      Based on client needs and technological requirements, a wearable sensor device was designed
      and developed using principles of 'social innovation' design. The device underwent multiple
      iterations in product design and engineering based on user-feedback and then following
      pre-clinical testing, a techno-feasibility study and clinical trial were undertaken in a
      tertiary-care, teaching hospital in Bangalore, India. Clinical trial phases I and IIa
      {studies/pilot studies designed to demonstrate clinical efficacy or biological activity
      ('proof of concept' studies)} for evaluation of safety and efficacy were undertaken in the
      following sequence: first with healthy adult volunteers; then healthy mothers; healthy
      babies; stable babies in the Neonatal intensive care unit (NICU) and then a baby with
      morbidities. Time-stamped skin temperatures obtained at 5-minute intervals over a 1-hour
      period from the device secured on upper arms of mothers and abdomen of neonates were compared
      against readings from thermometers used routinely in clinical practice, radiant warmer and
      multimodal sensor
    

Detailed description: 
      Study setting: St John's Medical College Hospital, Bangalore, a 1300-bedded, tertiary-care
      hospital with 2500 deliveries per annum and a Level-3 nursery that takes care of 1000
      neonates (inborn: outborn ratio = 2:1) in the neonatal care intensive unit (NICU) annually,
      one-third of whom are low birth weight and one-fifth are preterm.

      Choice of site of temperature measurement in adult and newborn: In the adult, the upper arm
      was selected for continuous monitoring. While in the newborn abdominal skin temperature was
      selected. In addition to being close to the liver, a metabolically-active organ facilitating
      a measurement close to the core temperature, it is also a non-invasive method that is steady,
      continuous, easy-to-use and comfortable for the infant.

      Innovation Pathway: The USAID 2006 Innovation Pathway model was adopted and it incorporated
      four steps from research to field implementation - (1) priority-setting phase and product
      design (2) product development and proof-of-concept (3) product introduction and (4) field
      implementation.As part of step 1, the sub-steps of (a) problem identification (epidemiologic/
      technological/ social/ financial, etc), (b) critical review of temperature measurement
      devices and other issues (temperature sensors or thermistors, core body temperature
      measurement issues, etc), and (c) determination of niche of this device vis-à-vis other
      devices through horizon scanning.

      Epidemiologic burden of chief causes of maternal and neonatal mortality and morbidity were
      reviewed as a first step.A technological review revealed that the device to be strapped-on to
      the mother or newborn for vital sign detection had to be a medical-grade device with
      extremely high safety profile. Further, it had to remain functional in situations such as
      soiling or wetting by the newborn, and also continue to work in different areas with varying
      population densities as well as buildings. Several devices such as the ThermoSpot®, a
      temperature sensor tag and remote infrared-based instruments were evaluated. Social review
      revealed that a sensor being continually strapped on to the body for long periods was not
      dissimilar to that of talismans strapped around the arms of adults or around the necks/waists
      of children and might therefore not be too disagreeable to families. A financial review
      revealed that for the device to be used widely, especially by low-income populations, it
      would have to be a low-cost device. Implementation review focused on possible uptake and
      utilization of such a device in rural, urban and slum communities.

      Conceptual framework: The conceptual framework for remote monitoring consisted of five
      components: (1) a low-cost, wearable sensor tag; (2) a gateway device acting as an
      ultra-low-power 'real-time' communication link; (3) piggy-backing on a commercial cellular
      communication network; (4) smart data analytics system; and (5) feedback loop to the
      care-giver or frontline health worker. This framework was to be ideated, designed, prototyped
      and developed into a Class A medical device with lowest risk level as per Medical Device
      Regulatory Authority of India bearing in mind that the end-product should enable tenets of
      good Quality of Care (QoC) namely effectiveness, timeliness, safety, people-centeredness and
      equity.

      Requirements for components Two key requirements for the 'on-body' sensor were safety and
      accuracy. Given the fragility of the newborn skin, the device had to be hypoallergenic,
      burst/leak proof, cause minimal infections, and dissipate minimal heat or ultra-low power,
      non-ionizing electromagnetic radiation. nThe adhesive used to secure the device to the skin
      should similarly cause minimal 'medical adhesive-related skin injury' (MARSI), allergy or
      infections. Device accuracy was targeted to be +/-0.2°C in in-vitro conditions and +/-0.5°C
      in actual clinical practice. Other mechanical requirements for the device were: long
      battery-life up to 28 days (with sampling frequency of 5 minutes); robustness (without any
      malfunction on coming into contact with body fluids like sweat, blood, urine, faeces, etc);at
      least 'ingress protection class 67' (dust-proof and water-proof); human-centric and aesthetic
      design for non-intrusiveness over prolonged use; and ability to withstand mild shock or
      vibration; and that the device should not get re-set accidentally. There was also a
      requirement for the device to store data locally and communicate with a gateway device for
      onward transmission of data via the configured cellular network.

      Product design and engineering: Based on the clinical requirements, a preliminary design was
      constituted and subsequent design choices underwent multiple iterations driven by
      technological capabilities and user reviews. The wearable sensor enclosures were
      pebble-shaped or coin-stack shaped with all the electronics embedded inside. A battery of
      tests (both mechanical and electrical) were undertaken to confirm device performance,
      robustness, and reliability. After several rounds of pre-testing, design optimization was
      achieved.

      Prototype and Implementation: The details of the prototype sensor device are given elsewhere.
      Briefly, the sensor hardware platform, developed using a multi-layer printed circuit board,
      consisted of a microcontroller (MCU) with integrated Bluetooth 4.0 Low Energy (BLE), a 12-bit
      ADC {Analog to Digital Converter} (CC2540 from Texas Instruments), a NICU-grade temperature
      sensor with its analog front-end circuit, status LEDs {Light Emitting Diode}, power supply
      and RF {Radio-Frequency} balun {a electrical device that converts between a balanced and
      imbalanced signal} transmits filter and antenna for wireless communication over 2.4 GHz
      {gigahertz} ISM {Industrial Scientific and Medical} band. High-precision MF51E NTC {high
      precision negative temperature coefficient} thermistors were used for extremely accurate
      temperature measurements. An embedded Inverted F-antenna (IFA) with higher efficiency, longer
      range and a wider bandwidth than a chip antenna was used. It also had a very low tolerance
      resistor enabling a low power consumption during both active (150μA) as well as sleep (1μA)
      modes. The sensor hardware was programmable as per requirements. A 3-volt coin battery
      powered the device. A baby-friendly enclosure was made from medical-grade hypoallergenic
      plastics.

      The sensor communicated with a gateway device (a smartphone or a Raspberry pi) that could
      subsequently relay the temperature data over a secured internet backbone provided by GPRS
      {General Packet Radio Service}/Wi-fi on to a centralized database for storage (web figure 3).

      Phases of device testing: The planned phases of device testing were pre-clinical testing (in
      June 2013) and clinical trial phases I& IIa {studies/pilot studies designed to demonstrate
      clinical efficacy or biological activity ('proof of concept' studies)} for evaluation of
      safety and efficacy in the following sequence: healthy adult volunteers (May 2014); healthy
      mothers (Jan-Feb 2015); healthy babies (Feb 2015); stable babies in the NICU (Feb-Mar 2015)
      and babies with morbidities such as hypoxic ischemic encephalopathy (Mar 2015). The results
      of the pre-clinical testing in the laboratory setting were published earlier. Briefly, the
      response time of the sensor device to attain thermal equilibrium with the surroundings was 4
      minutes compared to 3 minutes observed with a precision-grade digital thermometer used as a
      reference standard. In terms of accuracy, the error was calculated to be within 0.1°C of the
      reference standard while using water-baths in the temperature range of 25°C to 40°C. The
      details of the clinical phase of testing are outlined below.

      Seven free-living healthy adult volunteers (males = 2; females = 5), with no known
      morbidities, were the first phase participants over a 7-day period. All of them had the
      devices strapped with an arm band secured with Velcro® tape on to their left upper arms and
      were invited to contribute at least a minimum of 24 hours of observations accumulated from
      over one or more days and report any adverse events or side-effects they experienced. In
      parallel, they also noted down timed axillary temperature readings (at least 5 times in a
      24-hour window) using a digital thermometer for paired comparisons.

      Testing in healthy postnatal mothers (n=11) was first carried out amongst those with well
      babies in the postnatal ward and then amongst mothers (n=7) with neonates admitted in the
      NICU. The devices were secured on to their upper arms with arm band secured with Velcro®
      tape. Paired readings taken every 5 minutes over a 1-hour period with an axillary digital
      thermometer were compared against the readings of the sensor with its time stamp.

      Testing among neonates was carried out in three different phases in all of which the devices
      were secured with cotton and micropore adhesive to the upper epigastrium. In the first phase,
      well-babies (n=3) in their early neonatal periods in the postnatal ward had their axillary
      temperature readings taken every 5 minutes over a 1-hour period with a digital thermometer
      and compared against the sensor readings. In the second phase, sick but stable neonates
      (n=10) from the NICU were recruited. They were under the radiant warmer with the temperature
      probe fixed on to the upper abdomen beside the sensor device and so the readings taken every
      5 minutes over a 1-hour period from the warmer panel were compared against the sensor
      readings. But since all these babies had their temperatures maintained within a narrow normal
      range under the radiant warmer, we included one sick infant with hypoxic ischemic
      encephalopathy (HIE) due to birth asphyxia and who was on treatment with therapeutic
      whole-body cooling. This facilitated comparison of readings in the range of 33° to 34°C
      during the cooling and re-warming phases of the treatment. The radiant warmer probe readings
      taken every 5 minutes over a 1-hour period from the warmer panel were compared against the
      sensor readings.

      Definitions Safety: An adverse event reporting and resolution protocol for the wearable
      sensor devices was instituted. This enabled capture of the number and severity of adverse
      events as well as the individual clinical management as also feedback for changes into device
      design. Adverse events to be recorded were: dermatitis, infection, thermal injury, radiation
      injury, device leak/burst and others.

      Accuracy: Of the device was estimated by comparing temperatures recorded by the device
      against other measurements routinely used in clinical practice. For mothers and well-babies
      in postnatal wards, the comparisons were between the device temperatures versus axillary
      temperatures read from a digital thermometer (once readings stabilized after the beep -
      usually after 3 minutes); for newborns in NICU, the comparisons were between the time-stamped
      device temperatures versus skin probe temperatures obtained from the control panels of
      calibrated radiant warmers (Phoenix Medical Systems Private Limited, Chennai, India or Zeal
      Medical Ltd, Mumbai, India).

      Statistical Analysis: Mean [+/-Standard deviation (S.D.)] was calculated for the paired sets
      of readings noted in mothers and newborns and the mean differences were obtained. Paired
      t-test was used for testing of significance between two different methods.

      Ethics: Ethics approval for the study was obtained from the St John's Institutional Ethics
      Review Board (IERB #59/2011 dated 15 Mar 2011&# 125/2014 dated 16 Aug 2014). The clinical
      trial was registered with the Clinical Trials Registry of India (CTRI/2015/05/005779).
      Informed consent was obtained from all participants/care-givers.
    

Intervention name(s): Remote biomonitoring sensor device
Intervention type(s): Device
Intervention description(s): Same as described in arm descriptions. Safety was ensured by getting radiant warmer and multichannel probe examined and services by the biomedical engineering department; calibration certificates were obtained and these were used routinely in care of other neonates. An adverse event reporting and resolution protocol for the wearable sensor devices to capture number and severity of adverse events; individual clinical management and feedback for changes into device design. Adverse events recorded were: dermatitis, infection, thermal injury, radiation injury, device leak/burst and others.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Newborns; Biomonitoring; Sensor; Device; Remote