WO2017009669A1

WO2017009669A1 - Measurement of capillary refill time

Info

Publication number: WO2017009669A1
Application number: PCT/GB2016/052164
Authority: WO
Inventors: Don SHARKEY; Laurence BLAXTER; John Crowe; Barrie Hayes-Gill; David Morris
Original assignee: University of Nottingham
Current assignee: University of Nottingham
Priority date: 2015-07-15
Filing date: 2016-07-15
Publication date: 2017-01-19
Anticipated expiration: 2018-01-15
Also published as: GB201512374D0

Abstract

A device (10) is attachable to a person and configured to automatically measure the capillary refill time of a said person. The device comprises at least one radiation source (12) and at least one detector (14) for detecting radiation reflected from or transmitted through the person's body. The device further comprises an actuator (58, 58') for applying pressure directly or indirectly to the person's skin. A system comprising the device further comprises a unit remote from said device. The unit comprises one or more of a processor for determining a measurement of capillary refill time and a source of fluid such as air.

Description

Measurement of Capillary Refill Time

Technical Field The present invention relates to a device, system and/or method for measuring capillary refill time.

Background to the Invention It is known that, when a person becomes very ill, their blood pressure drops, they get colder and their skin turns paler. This is because, as their vascular system starts to fail, the blood supply to their skin is reduced as the skin is not considered to be an essential organ. Measurement of the capillary refill time provides an indication of the blood flow, or perfusion, to bodily tissue. A measurement of the skin perfusion can thus provide an indication on the overall health of a person.

Traditionally, this has been achieved by a clinician pressing a person's fingernail or the skin on their hand, say, to blanch it, and observing how long it takes for blood to flow back into the blanched area. Such methods are, however, unreliable, because the determination made by the clinician, even though they may be very experienced, is subjective and depends on a multitude of factors including, for example, the amount of pressure they apply to the patient and for how long, and what they consider to be a reasonable time period for the blood to flow back.

Devices have been developed as a step towards addressing some of these shortcomings. For example, WO201 1/078882 discloses an apparatus for measuring capillary refill time comprising one or more radiation sources and associated detectors. Radiation of a first wavelength that is absorbed substantially equally by oxyhaemoglobin and deoxyhaemoglobin and a second, reference wavelength is detected. A person inserts their finger into a probe, which pneumatically applies pressure to their finger to blanch it and the optical detection assesses the blood oxygen level and, through comparison to a reference signal, provides a measurement of capillary refill time.

US2007/0282182 similarly discloses a pulse oximetry device placeable on a person's finger, and inferring the capillary refill time of the patient from the pulse oximetry measurements.

Such devices, whilst clearly useful, have their limitations. For example, if a young child or a baby becomes extremely ill and their vascular system starts to shut down, but their blood pressure only dips during the final moments of life meaning that blood pressure is not an accurate indicator. Whilst capillary refill time would be a useful measurement, the smallness of a child's or a baby's finger makes it extremely difficult to attach such a device to their finger. Babies and young children are also prone to moving around, meaning that the device may easily be dislodged providing inaccurate measurements or may become detached. Aspects and embodiments of the present invention have been devised with the foregoing in mind.

Summary of the invention According to a first aspect of the present invention there is provided a device for measuring the capillary refill time of a patient as defined in claim 1 . The radiation source(s) and detector(s) constitute optodes that can be used in the CRT measurement.

According to a second aspect of the present invention there is provided a system comprising a device for measuring the capillary refill time of a patient as defined in claim 20.

According to another aspect of the present invention there is provided a method for automatically measuring the capillary refill time of a person, comprising emitting radiation from a radiation source, detecting radiation reflected from or transmitted through the person's body, applying pressure directly or indirectly to the person's skin to blanch it and calculating the capillary refill time based on the time it takes for blood to flow back in to the blanched area. The method may include the further steps as discussed throughout, and in relation to use of the device and system. Aspects of the invention advantageously provide for providing a direct and automated CRT measurement. Automation advantageously enables standardisation of the application pressure. Aspects of the invention further advantageously enable the measurement to be carried out non- invasively anywhere on a person's body, e.g. not restricted to fingertips or earlobes as in the prior art. As such, it may be feasible to maximise the range of refill sites without unduly influencing the refill time measurement.

In an embodiment, the capillary refill time is determined from the photoplethysmogram obtained from the at least one radiation source reflected from the person's skin or transmitted through the skin and bodily tissue to a detector. Most known pulse oximetry devices utilise the transmission mode, since in reflectance mode the signal level is much lower at the most effective wavelengths. Embodiments of the present invention advantageously enable both modes to be used.

The device may be adapted for attachment to a person's skin. In an embodiment, the device is disposable. The device may comprise one or more connectors for connecting to a computing and/or display device and/or to a source of fluid such as air. In an embodiment, the device "head" is integrally formed with and/or sealed to the connector. Here, the integral device and connector is disposable. Alternatively, the device is attachable to and detachable from the connector such that the device and/or the connector is disposable. The device may be further configured for wireless communication. Aspects and embodiments of the invention thus provide a disposable, low cost sensor for use with and/or in conjunction with a larger, base unit that balances requirements stipulated by hygiene and practicality.

The at least one radiation source may be configured to emit radiation within the near infrared and visible light spectrum. In an embodiment, the at least one radiation source is configured to emit red, infrared or green light. In an embodiment, green light of a wavelength of approximately 520nm, red light with a wavelength of approximately 640nm and/or infra-red light with a wavelength of approximately 950nm is used. Green light (i.e. with a wavelength between approximately 500nm and 600nm, and e.g. approximately 520nm) is advantageous because there is generally the greatest blood absorption at these wavelengths and, in reflection mode, it provides a larger plethysmogram AC component than red or near-infrared radiation. In an embodiment, there are three radiation sources, one that can emit green light, one red light and one infra-red light. In an alternative embodiment, two radiation sources that can emit at each wavelength are provided, i.e. six emitters in total. The emitters may be aligned or arranged to be spaced around a central sensor e.g. in a ring or square.

The at least one radiation source may be an LED, a low-powered laser or laser diode, or another photon output device could be used. In an embodiment, the device comprises a plurality of LEDs. There may be at least one red light emitting LED, at least one infra-red light emitting LED and/or at least one green light emitting LED. In an embodiment there are two red light emitting LEDs, two infra-red light emitting LEDs and/or two green light emitting LEDs. Other numbers and combinations may be used as required. The LEDs may all emit at substantially the same frequency (i.e. be substantially the same colour). The detector may be or comprise a photodiode, a camera, a photodetector, a reverse biased pn junction, a phototransistor or any other photosensitive material or device. Illumination (e.g. white light) may be provided for the photosensitive materials or devices e.g. by shining light on top of, or passing light under, the skin and detecting the change in light level with a photo-sensitive material or device. The illumination source may be diffuse or distributed, e.g. with sources located between the LEDs.

In an embodiment, the actuator is a plunger moveable with respect to the device in response to gas being provided to the device (e.g. air being pumped into the device). The device may comprise a housing and the plunger may sit or be located within the housing. Preferably the housing is an open-ended cavity and the plunger sits within the cavity. Preferably, the housing and the plunger are indirectly coupled together. A flexible coupling may be provided between the housing and the plunger to couple the housing and plunger together and permit relative movement therebetween.

In an embodiment, the actuator is a pneumatic actuator. The pneumatic actuator may comprise an inflatable means such as a bladder which can apply said pressure when inflated with a pressurized gas such as air. The pressurized gas may be provided from a source of pressurized gas, or a pump or other pressurizing means may be provided for pressurizing the gas. Air is very convenient, but other gases or fluids may also be used. Alternatively, or as well, the device can be configured to comprise a chamber with a flexible surface or portion that is placeable on and/or attachable to a person's skin. When pressurized gas is fed into the chamber, the pressure urges the flexible surface towards the person's skin. Alternatively, the actuator may be a mechanical actuator e.g. a piston or cam etc. In each embodiment, applying the pressure has the effect of blanching the area of skin in the vicinity of where the pressure is applied.

The actuator may be operable for providing a pressure in excess of atmospheric pressure, such as greater than substantially 2.0 psi and optionally or preferably substantially 2.5 psi. This ensures there is always some contact pressure. There has been found to be no particular advantage to using higher pressures, and it does of course take longer to pressurize the device to a higher pressure which is undesirable. A range of approximately 1 .4-4 psi could, however, be used. The device may further comprise an exhaust port for exhaustion of pressurized gas from said bladder and, optionally or preferably, wherein the pressure within the bladder does not decrease to zero. The device or system may be further configured to determine the amount of oxygen in the person's blood by pulse oximetry. At least one of said radiation sources may be configured to emit near infrared or visible light, or green light, for the pulse oximetry and a heart rate measurement. The device or system may also comprise a temperature sensor, e.g. a thermistor, for measuring the temperature of the person. The device or system may therefore advantageously provide monitoring of multiple physiological parameters.

In an embodiment, the device or system is further configured to monitor movement of the device to enable movement artefacts to be identified. That is to say, if the person moves, this may have an effect on the CRT measurement. This may be achieved by using an additional sensor such as an accelerometer. Additionally or alternatively, the device or system can be configured to identify and deal appropriately with erroneous measurements. This may be achieved by analysing the optical intensity of light detected to identify periods of motion artefacts since motion gives rise to anomalous refill shapes. In embodiments the device may be configured to attach to one surface of a person's skin i.e. does not need to clip around a digit or similar. Such embodiments advantageously enable the device to be placed anywhere on the person's body. In an embodiment, the device comprises means for attachment to a person's skin such as an adhesive, a shear and/or tensile resistive adhesive or adhesive tape. Alternatively, the device may comprise self-securing or attachment means such as a Velcro band or a clip or hook and eye type arrangement. The device or system may also be configured to provide an indication of the correct orientation for use and/or for attaching to a person's skin. The system may further comprise a second device, also configured to automatically measure the capillary refill time of a said person as above. At least one of the device and the second device may be configured to provide a photoplethysmogram from the at least one radiation source to determine capillary refill time by reflectance from the person's skin. The transmission could also be used for either device. Additional, similar devices may also be provided.

The provision of a compact sensor device, secured to the skin with adhesive, advantageously facilitates use at a wide range of sites around the body, particularly for a reflectance mode sensor. The use of two devices enables the CRT to be measured at different sites, the measurements compared, and the significance or reliability of each measurement to be considered.

Aspects and embodiments of the invention thus provide a non-invasive sensor device incorporating a pressure-applying actuator and a processor or data-logging means for storing data relating to measurements obtained by the device. The processor or data-logger may be programmed with software that analyses the raw measurement data or this functionality may be provided by remote software that runs on another processing or computing device e.g. a PC. The software may compare the measurements of the capillary refill time from the device and the second device

In an aspect or embodiment, a computer program (or the software), when run on a computing device such as a PC or mobile phone, may cause the computing device to perform any method disclosed herein. The computer program may be a software implementation, and the computing device may be considered as any appropriate hardware, including a digital signal processor, a microcontroller, and an implementation in read only memory (ROM), erasable programmable read only memory (EPROM) or electronically erasable programmable read only memory (EEPROM), as non-limiting examples. The software implementation may be an assembly program.

The computer program may be provided on a computer readable medium, which may be a physical computer readable medium, such as a disc or a memory device, or may be embodied as a transient signal, Such a transient signal may be a network download, including an internet download.

In an embodiment, the processor is programmed to initiate a measurement of capillary refill time at time intervals of between substantially 10 and 30 seconds, or between substantially 15 and 25 seconds, or between substantially 20 and 23 seconds. The processor may be programmed to initiate a measurement of capillary refill time at time intervals that are chosen to not coincide with internal bodily cycles (e.g. Mayer waves). The system may further comprise a temperature sensor. The processor may be configured to take temperature measurements from the temperature sensor and provide temperature compensation to the measurement of capillary refill time. This is to compensate for any effect environmental temperature may have on the measurements. The system may further comprise an alarm means. The alarm means and/or processor may then provide an indication of when the capillary refill time falls below a predetermined threshold value. An alarm means may be provided within the system to provide an audible or visual alarm, or the processor may send an alarm signal to the monitor/display system.

The processor or software may be further configured for adaptive filtering of the measurements in order to weight the capillary refill time measurements and provide a confidence indicator associated therewith. The confidence indicator can be based upon the modulation depth, the presence of a pulsatile PPG with no blanching that it goes away or reduces during blanching, the baseline variability, and/or rms noise in the baseline, for example. The processor may also be configured to stop taking measurements if the device becomes detached from the person (e.g. if CRT measurements cease or go outside of expected range(s)), or if a leak in pressurized gas is detected (e.g. by a pressure sensor sensing a drop in pressure in the device below a predetermined threshold), or if the device becomes too hot (e.g. as determined from a measurement of temperature exceeding a predetermined threshold). The processor may be configured to vary the amount of radiation each radiation source provides and provide feedback based on the photoplethysmogram obtained from the radiation sources. This is done to optimise the signal to noise ratio (SNR) of the optical signals without saturating the electronic components. The processor or software may be programmed to calculate the CRT as a function of the time taken for the PPG signal to return to a predetermined fraction of its maximum elevation above baseline, e.g. substantially 30-40% or approximately 35% of the PPG signal height. The AC and DC PPG signal components may be filtered separately for the CRT calculation. In an embodiment, the AC (or pulsatile) signal is analysed to check the signal is valid and the DC signal used to provide the ratio for the CRT measurement. The processor or software may be configured to analyse the signals from the radiation sources using frequency division multiplexing.

In an embodiment, the system is configured to be powered by a battery, a rechargeable battery or mains power.

Aspects and embodiments of the invention thus provide for automated CRT measurement using: a non-invasive sensor, a processing or data logging unit, and data analysis software for extracting the refill time and other data. Aspects and embodiments of the invention advantageously provide for the sensor being placed anywhere on a person's body. This is an improvement over known sensors which are clamped onto a person's finger, as these do not provide flexibility for use elsewhere on the body and are unsuitable for use on babies and infants whose fingers are too small. Since aspects and embodiments of the invention provide for software-driven measurements, the disadvantages associated with manual methods are avoided. A software-driven measurement ensures consistency and reliability, as well as the ability to provide continual monitoring. A more objective measurement can therefore be obtained. Embodiments of the invention will now be described with reference to the Figures of the accompanying drawings in which:

Figures 1 a-1 c show example results of CRT assessment;

Figures 2a and 2b show alternative embodiments of a device according to the present invention; Figures 2c-2d show alternative embodiments of a device according to the present invention;

Figure 2(e) shows bottom, side, top and overlaid top views of an exemplary layout of the LEDs and the sensor on a chip of an embodiment of the present invention;

Figure 3 shows a schematic cross sectional view of an embodiment of a device according to the present invention;

Figure 4a shows a schematic cross sectional view of an embodiment of a device according to the present invention;

Figures 4b-4e show a schematic cross sectional view of another embodiment of a device according to the present invention;

Figure 5 shows another embodiment of a device according to the present invention;

Figure 6 shows a device and connector according to an embodiment of the present invention;

Figure 7 shows a device and connector according to an embodiment of the present invention;

Figures 8 and 9 show a base unit for use in a system according to an embodiment of the invention; Figure 10 shows schematically a system of the according to an embodiment of the present invention in use; Figure 1 1 shows an exemplary CRT measurement obtained using an embodiment of the prevent invention;

Figure 12 shows invention schematic of a frequency division scheme that can be used with the datalogger device;

Figure 13 shows a single amplifier photodiode amplifier for use in an embodiment of the invention;

Figure 14 shows a plot of the trans-impedance of the single amplifier photodiode amplifier of Figure 13;

Figure 15 is a schematic of a digital signal processing (DSP) scheme that can be used with the datalogger device;

Figure 16 is a system diagram of the CRT datalogger electronics;

Figure 17 is an exemplary raw optical intensity data plot, prior to processing;

Figure 18 shows plots of the median intensity profile during refills for refills used (a) and rejected

(b);

Figure 19 shows a quality index (a) and plot of refill time and temperature versus time (b);

Figure 20 shows plots of the median intensity profile during refills from a typical healthy adult for refills used (a) and rejected (b);

Figure 21 shows a quality index (a) and plot of refill time and temperature versus time (b) for a typical healthy adult;

Figure 22 shows plots of the median intensity profile during refills from a typical healthy child for refills used (a) and rejected (b);

Figure 23 shows a quality index (a) and plot of refill time and temperature versus time (b) for a typical healthy child;

Figure 24 shows a scatter density plot of adult refill times versus temperature at three wavelengths;

Figure 25 shows a scatter density plot of child refill times versus temperature at three wavelengths;

Figure 26 shows 'box and whisker' plots of Pearson's r for inverse refill time versus temperature for healthy adults and children at three different wavelengths; and

Figures 27 and 28 show plots for data from volunteers using another embodiment of the invention.

Detailed description of embodiments of the invention Throughout, features in common with the previously described embodiments are shown with and discussed with respect to corresponding reference numerals.

The principle underlying the invention is to provide a device that applies pressure to the skin to force blood out from the underlying capillaries and then to monitor the capillary refill after the pressure is released. For manually assessing capillary refill time (CRT) by blanching the skin and measuring how long it takes for blood to refill the blanched area, guidelines (ALSG Advances Paediatric Life Support 5th Ed.: John Wiley & Sons; 201 1) recommend applying 5 seconds of pressure. However, as shown in Figure 1 a, the Applicant has found that healthcare workers varied significantly with 27% of assessments being less than or equal to approximately 3 seconds.

The Applicant has quantified, for the first time, the precise pressure applied by the healthcare workers. As shown in Figure 1 b, this had a median of 2N, but values ranged from 0.26N to almost 8N (Figure 1 b shows IQR and 95% CI).

Figure 1 c shows the quantification of CRT assessments greater than 2 seconds. There was a significant shortening of CRT assessment with increasing pressure from 0.5N through to 5N. This variability equates to a 10% reduction in the number of CRTs that would be greater than 2 seconds and hence deemed abnormal.

The need for a reliable device that can consistently apply a predetermined amount of pressure for a predetermined amount of time in order to reliably measure the CRT is clearly desirable. The Applicant has found that direct use of a photoplethysmogram can provide a useful and accurate measurement of the capillary refill time.

A photoplethysmogram is obtained from a photoplethysmograph, which is an apparatus used to measure variations in blood volume in the body using light. Soft bodily tissue transmits and reflects visible and near-infrared radiation and directing such radiation onto a person's skin and detecting the radiation emerging from/through the skin enables the changes of radiation intensity to be observed. Blood absorbs light, but in differing amounts depending on the wavelength of radiation used. However, variation over time in measurements obtained at a particular wavelength can be indicative of changes occurring within the body. The plethysmogram comprises both AC and DC components. Components such as non-pulsatile blood, bone and tissue is constant and provides the DC component. This represents the volume of non-pulsative blood below the sensor and light reflected from and scattered off the skin, bone and other tissues. The temporal changes in blood volume, caused by cardiovascular regulation, blood pressure regulation, thermoregulation and respiration, below the sensor provide the AC component. As such, the plethysogram can be analysed to provide information on parameters such as pulse rate, breathing rate, blood pressure, perfusion, and blood constituents (as in pulse oximetry).

Figures 2(a) (or a slightly different, alternative embodiment 2(b)) and 3 show a photoplethysmograph device 10 according to an embodiment of the invention. The device 10 comprises a plurality of radiation sources 12 and a sensor 14. In the embodiment shown, the sensor is a photodiode 14 and the radiation sources comprise three LEDs 12. In other embodiments, more or fewer radiation sources 12 may be provided, in any suitable configuration, and/or one or more other photosensitive sensor devices 14 may be used. Preferably, the sensor 14 is in direct contact with the person's skin to help avoid movement artefacts (i.e. if a person moves their body during a measurement. As such the sensor 14 is positioned on or adjacent a surface (or base) of the device 10. The sensor 14 and LEDs 12 are arranged such that, in use, radiation from each LED 12 is reflected from a person's skin and reflected towards the sensor 14. The CRT device 10 in this embodiment is thus configured to operate in a reflectance mode.

The sensor 14 and LEDs 12 are provided on a member or PCB 13 (e.g. polyamide) which is preferably flexible. The housing 15 of the device 10 can be formed of a plastics material, e.g. a vacuum formed polyurethane cover. The housing 15 may be embedded with an antibiotic, antibacterial and/or antimicrobial composition. This provides a sealed, clean and hygienic device. Other materials may also be used. The interior of the cover 15 may be provided or coated with black polyolefin foam 17. This provides shielding to prevent external light entering the device and interfering with the measurements.

A gas such as air can be pumped into the interior of the device 10. Air is pumped directly into a chamber 62 within the device 10. When sufficient air has been pumped in, this exerts a force on the flexible PCB 13 to which the sensor 14 is attached or is adjacent. The force acts to push the device 10 towards the patient's skin in order to blanch it. The body 15 of the device surrounding the air chamber may be formed of or comprise a foam, e.g. a closed cell foam, to form the chamber 62 whilst being a lightweight material. The outer surface 25 may be flexible, as will be described below, allowing the sensor 14 to be urged into contact with a person's skin, or a rigid layer, e.g. of hard plastic such as PET.

Figures 2(c) and 2(d) show an exemplary LED 12 / sensor 14 arrangement on a PCB support 17. The support 17 is substantially "S" shaped and supports PCB portions 13a on a first (top) surface 13b and a second (lower surface) 17b. The LEDs 12 and sensor 14 are provided in a unit 17c. The unit 17c is, in the embodiment shown, attached to an outer surface/underside of the support 17. The "S" configuration is convenient since it allows the flexible electronics components to move when the plunger 58' moves in and out. However, the support 17 could be arranged differently, e.g. a "C" shape or otherwise, but the configuration shown is convenient for location within the housing 15, as will be discussed later. Wires/cables 30b are connected to the PC13/PCB support 17. The support 17 has one or more apertures 17d that facilitate location within a housing 15', as will be discussed later.

Figure 2(e) shows bottom, side, top and overlaid top views of an exemplary layout of the LEDs 12 and the sensor 14 on a chip 13d. The pins 13e of the chip 13d are shown schematically in Figure 2(e). Figure 4 shows a schematic cross sectional view of an alternative embodiment of the device 10 in situ on a patient's skin S. Features in common with the previously describes embodiments are shown with corresponding reference numerals. The device 10 comprises an outer or top housing 15 fabricated e.g. from a plastics material such as ABS. Epoxy resin 21 may be used to seal and/or protect various components. A temperature sensor 19 such as a thermistor can be mounted on an optical sensor PCB 13 to provide an approximate skin surface temperature measurement. The device 10 comprises an inflatable bladder 58. A gas, such as air, can be pumped into the bladder 58 via connector 16. In its uninflated state the bladder 58 exerts no pressure on the interior of the device 10. In its inflated state, when air is pumped into the bladder 58, the bladder 58 expands and exerts a force FT towards the patient's skin. As the bladder 58 contacts the opposite side of the interior of the device 10, a force F₂ is exerted and the reaction increases the force against the patient's skin. The exertion of a force on the patient's skin blanches the skin allowing a CRT measurement to be performed. The base 25 of housing 15 and/or PCB 13 may be formed of a biocompatible polyurethane elastomer such as to be flexible and moveable, as will be described below, allowing the sensor 14 to be urged into contact with a person's skin, or a biocompatible rigid layer, e.g. of hard plastic such as PET. Such an embodiment can advantageously be of very small thickness e.g. about 15mm or within the range of substantially 10-20mm.

In an alternative embodiment, a mechanical actuator could be utilised. For example, a rod may be driven to exert a force against the person's body instead of using the air bladder. Using air to provide the force may be less likely than a mechanical system to cause problems in the event of malfunction, and may provide for a gentler application of force which is desirable for use with young children.

In an alternative embodiment, the CRT device 10 is configured to operate in a transmission mode, through the person's skin and bodily tissue. For example, the device 10 can be configured to surround a fingertip, earlobe etc. In this embodiment, the device 10 is configured such that the radiation emitters 12 and sensor 14 are placeable either side of the person's fingertip, earlobe etc. The reflectance device 10 advantageously allows for placement anywhere on the body; the transmission device 10 is only suitable for thin parts of the body, such as a digit or earlobe. Since babies' extremities are very small, the use of a transmission device can be difficult with the device 10 prone to becoming detached. The use of a transmission device is also limited to use on a person's extremities and not on their core. However, embodiments of the invention provide for both reflection and transmission modes.

Figure 4(b) shows another embodiment. The device 10 comprises an outer or top housing 15' fabricated or moulded e.g. from a plastics material such as ABS. The device 10 comprises a plunger 58'. The housing 15' is a substantially hollow cavity, open at one end (the "bottom" end). The housing has an inward projection 15a locatable within aperture 17d of the support 17. The housing 15' may have one or more radially outwardly extending projections or flanges 15b configured to engage with a lip 58"' of the plunger 58' to prevent total separation of the two components i.e. to restrict the range of movement of the plunger 58' with respect to the housing 15'.

The plunger 58' sits within the hollow 62' of the housing 15'. The plunger 58" is also substantially a hollow cavity, open at one end (the "top" end). The plunger 58' is not directly connected to the housing 15'. A coupling such as a rolling diaphragm 25' is provided between the housing 15' to couple the housing 15' to the plunger 58'. It may be formed of a biocompatible polyurethane elastomer such as to be flexible and moveable, as will be described below, allowing the sensor 14 to be urged into contact with a person's skin. The housing 15' and plunger 58' are provided with attachment means, and the diaphragm 25' is provided with complementary attachment means to enable the components to be coupled together. In the embodiment shown, the exterior of the plunger 58' and the housing 15' each have a groove or channel into which a correspondingly shaped projection on the diaphragm 25' can be located. The projection(s) may be fixed in the groove(s) with adhesive/sealant or may be a tight interference fit.

A transparent or semi-transparent film window 58" is provided on the exterior (lower surface) of the plunger 58 and covers the LED/sensor unit 17. This enables emission and sensing by the unit 17c, but protects the components from direct contact with the patient's skin. The window 58" is preferably a thin sheet of material IT may be formed of or comprise ISO10993 compliant (biocompatible) PolyUrethane (PU) film. A number of materials would be suitable, so long as they have a suitable transparency, flexibility and biocompatibility (so that it can be in contact with skin for long periods without problem).

A ring of thin film or double sided adhesive 59 is provided around the film window 58" for placement against/adherence to a patient's skin. The adhesive ring 59 is attached to the housing via an attachment ring 61 . The exterior of the housing 15' is provided with a groove/channel 15b in which a projection/lip 61 a of the attachment ring is located.

Where components are described as having grooves, channels etc. and corresponding projections which fit therein, it is to be appreciated that the male/female connections could be provided the other way around such that a groove/channel could instead be a projection, and a projection could instead be a grove channel.

A temperature sensor, as discussed above, could be incorporated into the unit 17c or elsewhere in the device 10, in any location where it would be in close proximity to a patient's skin so that the skin temperature can be measured without too much influence of thermal mass of materials between the sensor and the skin. Such an arrangement can advantageously be of very small thickness e.g. about 15mm or within the range of substantially 10-20mm. In this embodiment, as shown in Figure 4(b), the diameter of the plunger 58' is 14.8mm, the diameter of the attachment ring 61 is 30.5mm and the diameter of the adhesive ring 59 is 42.5mm.

These sizes are exemplary only. The size of the sensor can be chosen such that it can be applied to different areas of the body - smaller sensors are better able to cope with curves etc. However, the sensor still needs to be large enough to ensure it can be firmly attached to the skin (i.e. enough sticky contact area]. Similarly, it is undesirable for the sensor to have too much height as this protrusion from the skin would make it likely to be knocked more frequently, which could introduce motion artefact into the data.

Components which come into contact with skin would preferably be or comprise biocompatible material.

The embodiment shown is substantially circular in cross section, but could be shaped differently e.g. spare, elliptical etc. In use, a gas, such as air, can be pumped into the housing 15' via the connector 16. Air is pumped into a chamber 62' within the device 10. When sufficient air is pumped into the device 10, the plunger 58' is forced downwardly and exerts a force F on the plunger, which is urged towards the patient's skin. The exertion of a force by the plunger on the patient's skin blanches the skin allowing a CRT measurement to be performed.

As above, in an alternative embodiment, the CRT device 10 may be configured to operate in a transmission mode, through the person's skin and bodily tissue.

In an alternative embodiment, shown in Figure 5, the device 10 may comprise a sensor or camera 18 having a lens 24 mounted above the surface of the skin 'S' instead of (or as well as) the sensor 14. Illumination is provided by way of one or more emitters 22 e.g. white light bulbs or LEDs. This provides distributed illumination, but other arrangements e.g. to provide diffuse illumination could be used. The camera 18 may be provided in the same housing 10, or in additional housing 1 1 that is removably attachable to housing 10 e.g. via a clip fit. A transparent membrane or window 23 is provided to enable the camera to detect radiation reflected from the skin. Where a separate camera unit 1 1 is used, this is provided at the device 10/camera 1 1 interface to enable radiation transmission therebetween. Using a camera will add to the size of the device, and so using a detector such as a photodiode or other photosensor instead may be preferable to minimize the device size, especially for use on small children. Any configuration of device 10 may be used with any other features or components shown in the drawings and e.g. reference to "device 10" may refer to any embodiment.

The device 10 comprises a connector 16. As shown in Figures 6 and 7, a lumen tube 30 is attached to connector 16 providing or housing an air supply tube 30a and enclosing an electrical cable 30b. The provision of a single tube rather than a separate tube and cabling is, advantageously, less cumbersome in use, whilst still providing a flexible connector. Preferably, the lumen tube 16 is formed of a flexible but reasonably thick plastics material e.g. PVC or Tygon^® tubing. This protects the wires or electrical cabling 30b inside, and prevents the pressurized air escaping. The electrical cabling terminates in an electrical connector 30c. The connector 30c is attachable to a CRT monitoring system which is, in turn, attached to a monitoring/display system (not shown in Figure 6 or 7). The cabling30b/connector 30c may also allow for downloading of data from the CRT system 26 and charging. The lumen tube 30, 30a terminates in a port connector 30d.

The device 10 is preferably attached to a person's skin with adhesive (e.g. the adhesive ring 59 of Figures 4(b)-(d)). Use of a shear and/or tensile resistive adhesive is useful since it ensures the device remains securely in place for measurement taking whilst still allowing removal when the use of the device is no longer needed. Alternatively, adhesive tape can be provided on the underside of the device to enable attachment to the person's skin. This may, however, be less desirable, since the tape itself can exert a force and pull on or compress the skin meaning that inaccurate measurements may be obtained. Where tape is used, this is preferably formed of or comprises a bio-compatible material, e.g. Tegaderm tape. An additional attachment point, spaced from the first attachment point, may optionally be provided to provide adherence to the skin e.g. in a manner as described above. This is to help ensure the device 10 remains attached to the patient and in the correct location. In another embodiment, the device 10 may be configured to attach or clip to a person's clothing. The device 10 may be constructed and/or marked or decorated so as to indicate the correct orientation for use - i.e. so the surface that is for adherence to the person's skin is easily identifiable. This can be achieved by configuring or marking the device 10. The device may also be configured/marked to make it aesthetically pleasing to children e.g. by decorating with an animal character etc. Different colours or markings may also be used to show the type of device (10, 48, 50 as will be discussed later).

Figures 8 and 9a-d show the electronic and mechanical components of the CRT system 26. The CRT system 26 comprises a housing 32. A socket 32a is provided within the housing 32 for receiving electrical connector 30c. Another socket 32b is provided within the housing 32 for receiving lumen connector 30d. Inside the housing 32, a tube or hose 34 provides fluid connection between the connector 16a and an air pump 36. An air dump solenoid valve 38 and an exhaust port 39 are also in fluid connection with the air pump 36. A suitable pump 36 is a diaphragm pump that is capable of pumping to pressures of about 40 kPa or more with flow rates in the range of about 1 L/minute. The solenoid valve 38 is provided to rapidly vent air from the system to release the applied pressure, since the pump used is not reversible. Alternatively, a reversible pump could be used. A further tube or hose 40 provides fluid connection to a pressure sensor 41 such as a pressure transducer. The pressure sensor is mounted on a control board 42 that also has and a processor and, optionally, a Bluetooth or other wireless link to a nearby display unit or central data collection for clinical viewing. The housing and electronics in Figures 8 and 9 are only prototypes and hence are relatively large. The electronics and power consumption can be greatly miniaturised and presented in a small unit suitable for attaching to the body of the subject thereby greatly improving the convenience for both bed bound and ambulatory subjects. The enclosure can incorporate a display to present the most recent or historical CRT data along with device status such as battery life, percentage of refills rejected, etc.

A battery, such as a lithium polymer battery 44 is also provided within housing 32, to provide power to the electronics, and an on/off control button 46 is also provided to control power to the electronics.

Figure 10 shows how the CRT measurement can be employed as part of a larger, multifunctional system. Here, the device 10 is shown attached to the chest of a baby. A respiratory and temperature sensor 48 is also attached to the baby's chest. A pulse oximetry sensor 50 is attached to the baby's wrist. Each sensor 10, 48, 50 is connected to the monitoring/display system 28 by connectors/cables 30, 52, 54 respectively. Alternatively the data can be transferred wirelessly to the bedside or centrally located display. A display screen 56 on the monitor 28 shows various measured parameters. In this example, the CRT device 10 provides a measurement of the capillary refill time (CRT); the respiratory and temperature sensor 48 provides measurements of the baby's respiratory rate (RR) and temperature (Temp.); and the pulse oximetry sensor 50 provides a measurement of the baby's oxygen saturation levels 0₂ Sats) and the heart rate (HR). The data are combined in order to calculate an illness severity score that provides an early warning when the health of a person, and especially a child, is deteriorating enabling action to be taken more quickly. A simple numerical score or confidence indicator is shown on the display 56 to provide a simple and clear indication of the health of the child.

In another embodiment, two or more CRT devices 10 may be placed on a patient's body. For example, a second device 10' as shown in Figure 10 may be used, connected in any appropriate way to the base unit 26. The second device 10' may be in accordance with the aspects and embodiments described previously and following. The devices 10 are preferably provided at different locations on the patient's body and are therefore spaced from each other. For example, it is advantageous to provide one sensor on the 'core' of a person e.g. their chest, and another on the 'periphery' e.g. on a limb. Since, when a person's health starts to deteriorate, the peripheral systems start to decline first, an ongoing measurement of the difference between a peripheral and a core sensor can provide valuable information and possibly an early warning that a patient is entering a decline in health state. This is because it is likely that the CRT at the peripheral sensor will decline before the core sensor. Use of two or more CRT devices also provides for confirmation of results/redundancy. If a single sensor 10 is used and does not provide a reading it may, wrongly, be assumed that the patient has a cardiovascular problem, for example, causing potentially unnecessary action to be taken. There may, instead, be a fault with the device, or the device may have become loose such that an accurate measurement cannot be obtained. However, since it is unlikely that both or all devices would develop problems, or become detached, at the same time, the use of multiple devices provides redundancy and enables a back-up measurement or cross-check to be undertaken. Each device 10 of the multiple devices may be operated in reflectance or transmission mode, and one or more devices of each kind may be used in the system.

Aspects and embodiments of the invention thus provide a "two-part" apparatus - a disposable device 10 (and optionally tubing 30) and a reusable system 26 (and possibly tubing 30). This has the advantage that the more expensive system electronics (in system 26) can be reused, but the less expensive sensor part itself (device 10) can be disposed of to ensure safety and hygiene as well as accurate measurements. Analysis software, hosted on the processor 42 or externally/remote therefrom, provides another element.

In use, the device 10 is attached to a patient's skin ensuring connections to the CRT system 26 and display 28 are in place. The CRT system 26 is switched on. The processor in the CRT system 26 is programmed to activate the pump 36, and to inflate the bladder 58 periodically at a time interval that does not coincide with the person's natural body cycles/rhythms and/or to ensure that baseline drift partly due to breathing is removed in some manner. Actuation of the bladder 58 exerts pressure on the person's skin to blanch it and then releases. A fast release is desirable to ensure that the capillary refill is being measured and not a reaction of the device 10 itself. Fast release is achieved by the large exhaust port 39. Importantly, the solenoid valve 38 is configured to provide fast release of air from the CRT system 26, but not to allow all air to exit the system. In an embodiment, pressure is applied for approximately 7 seconds (but may be within the range of approximately 4-8 seconds, for example, with release in under substantially 100ms and, preferably, release under substantially 50 ms. An amount of air is needed within the bladder 58 at all times to maintain contact of the sensor 14 with the skin. As such, when the air is released, the pressure within the bladder afterwards remains at venous/capillary pressure rather than being reduced to zero (relative to atmospheric pressure). Alternatively, all air pressure may be released, with a mechanical means of contact pressure application being incorporated into the sensor. In an alternative embodiment, an adhesive material may be used beneath the PPG optodes to maintain contact with the skin surface. The application of pressure also forces the sensor 14 into contact with the person's skin, especially in embodiments where the base 25 of housing 15/PCB 13 is flexible and can move towards the skin when pressure is applied. The CRT system 26 monitors the capillary refill over time as blood returns to the area of skin that has been blanched. A typical refill time might be of the order of approximately 2 seconds or so. There are background physiological events occurring in the body, such as Mayer waves which occur at approximately 10 second intervals. A suitable measurement interval is therefore a period that does not coincide with either of these. It is convenient to take measurements at intervals longer than 10 seconds. Taking measurements so frequently is, generally not necessary - every few minutes would suffice - but this essentially provides for continual monitoring of the patient. Taking frequent measurements does, however, provide a large sample of data to be collected.

The embodiments utilising a bladder 58 or plunger 58', although not the only way of achieving blanching, have been found to be particularly effective, and are the result of painstaking research and experimentation in order to achieve accurate and reliable results.

Adaptive filtering can also be applied - to identify and discard erroneous measurements and assign good quality measurements a high weighting and lesser quality measurements a low weighting. Rolling quantile/median filtering may be employed to obtain an average result. The Applicant has also found that, when a patient moves around, there is a tendency for the capillary refill time to be longer, leading to biased results. As such, those results can be omitted, e.g. by using only the lower refill times (e.g. the lowest fifth of measured CRTs). Here, a quality metric can be employed that compares the refill "shape" (i.e. the brightness versus time) to a reference function (i.e. a function that represents what a refill should look like). The parameters of the reference function are then adjusted to obtain the best match to the measured refill shape. The goodness of fit and the parameters of the reference function are then used to determine a quality index.

The processor may be programmed to give a warning or to not apply the pressure or take the measurement if the device 10 becomes detached from the patient, or if an air leak is detected, or if the device 10 gets too hot (e.g. above 41 °C).

Figure 1 1 exemplifies how a CRT measurement can be obtained in an embodiment of the present invention. In Figure 1 1 , an exemplary PPG (measured voltage versus time) that could be obtained from placement of the device 10 on a patient's forearm is shown. Section A of the PPG represents the baseline. A blanching pressure of 2N was then applied in section B. After the determined length of time (5s in this study) the pressure was released and the signal returns to the baseline over section C. The CRT measure is a function of the ratio of signal height (D) to time to return to baseline (C, within 2 standard deviations of A). This technique has been found to have excellent reproducibility with a coefficient of variation of 8%. Other algorithms for quantifying the CRT include the time taken for the signal to return to a threshold percentage of the signal height such as approximately 35% that presents consistent results. Alternatively the slope of the refill signal can be used taken typically at approximately 10% below the signal height using this method avoids the problems of large baseline variability.

In embodiments of the invention, the AC (or pulsatile) signal is analysed to check the signal is valid and that the sensor is in contact correctly with the skin. If so, the DC signal is then used to obtain the CRT measurement. The Applicant has found that measurement of the PPG until it decreases to approximately 35% of the signal height gives an accurate measurement of the CRT. Other ranges could also be used. The signals from each of the radiation emitters 12 are modulated. Known techniques used in prior art pulse oximetry utilise time division multiplexing. Embodiments of the present invention instead utilise frequency division multiplexing. The radiation emitters 12 are modulated at a frequency of 1 1 kHz. The frequency is then changed slightly to produce another signal. Frequency division multiplexing facilitates separation of the signals from each of the emitters, which may have different wavelengths. E.g. as mentioned above, six emitters may be used: two with wavelengths in the green part of the spectrum, two in the red and two in the infra-red. Frequency division multiplexing advantageously results in improved rejection of fluctuating ambient lights (e.g. from compact fluorescent lighting) as compared to time division multiplexing.

Three factors were considered in an evaluation of modulation techniques: signal to noise ratio (thermal, shot, and 1/f noise), susceptibility to optical interference (e.g. light sources, compact fluorescent lights etc.), and the impact of artefacts (this is especially relevant given that capillary refill studies involve inducing relatively sudden changes in tissue properties).

A frequency division scheme was adopted based on a consideration of amplifier 1/f noise (by adopting a frequency division scheme it is easier to operate above the 1/f corner frequency). It is also possible to minimise interference from ambient light sources such as compact fluorescent lights (which often contain electronic ballast modulating the light in the <5kHz range). Additionally, for CRT use, the demodulated output data rate needs to be sufficiently fast that aliasing is minimized. Considering the typical time scale of capillary refills, with intensity transients over as little as 100ms, this rate needs to be of order 100Hz. However, given the transient nature of the refill, it seems likely that some aliasing will still be experienced at a high output data rate. Time division multiplexing leads to mapping of artefacts more strongly to some channels than others, whereas frequency division gives rise to broadening of the modulation spectrum peaks, and cross-talk between channels. Cross-talk is a more preferable effect, so frequency division is optimal for mitigation of artefacts.

Many micro-controllers include PWM (pulse width modulation) hardware, but these are only capable of generating orthogonal periods, not orthogonal frequencies. However, using PWM controllers with a "gate" input allows a PWM output from one unit to control the time period for which a second unit is clocked from a central source. Unfortunately this leads to a small amount of jitter, giving cross-talk between the carriers. Since the extent of the jitter is affected by the precise topology of the gating system, an optimisation algorithm was employed to find the optimal configuration for a 3 channel system. The adopted scheme is shown in Figure 12, with the precise choice of centre frequency and carrier spacing made based on the available clock tree configurations of the micro-controller, with the 62.04Hz spacing and 1 1 .67kHz central carrier allowing simple integer multiplication and DFT to be used for carrier separation.

For optimal SNR, the carrier frequencies need to be above the 1/f corner frequency of the amplifier, and preferably above 5kHz, as already discussed. A common solution is to use a JFET voltage follower combined with a low voltage noise op-amp in a trans-impedance configuration. This configuration allows use of a low input referred voltage noise but high input current noise JFET op-amp (e.g. Texas Instruments LMH6624). However, a JFET voltage follower combined with such an op-amp can lead to a relatively high current consumption and operating voltage of 5V or more, requirements that are not optimal for a portable battery powered device. There are few low operating voltage op-amps with a voltage noise in the < 5nV/V77z region and low input current noise.

However, it is only necessary to reduce amplifier noise to the optically limited shot noise floor, and the worst case DC photocurrent was of order 1 μΑ with the sensor 10 placed against the skin surface when a 20mA mean current was passed through the LEDs. This DC photocurrent was set as the operating point for the front end noise analysis. For most photodiodes 14 suitable for PPG applications, the dark current is a negligible shot noise source (e.g. Vartec, VTB8440B < 1 nA). Since if the light intensity is too high, the front end may saturate, a means to detect this and reduce LED 12 brightness is also required. A design based around a single op-amp was developed by the applicant. In order to exclude as much wideband noise from the ADC as possible, a trans-impedance design incorporating a high Q filter based on a modified gyrator circuit was employed. As the gyrator was difficult to model analytically when a parallel capacitor was incorporated into the design, the SPICE simulation package was used to iteratively improve the design until resonance was at around 1 1 .7kHz with both a high Q and a high magnitude trans-impedance. Figure 13 is a schematic of the design.

An analysis of the effects of component tolerance and parasitic op-amp bias current was conducted in SPICE, and it was found that ±1 % tolerance was acceptable for all the resistors, and ±10% for the 9.1 nF capacitor, meaning a ±5% X5R ceramic capacitor could be used. However, the circuit was found to be very sensitive to variation in the size of the 9.1 pF feedback capacitor. For example the resonant frequency experiences a 40% shift in sensitivity with a 10% change in capacitance. This meant that a high quality ceramic capacitor was required, i.e. NP0 with a tolerance of ±2% or better. It can be seen that a thermal current noise will originate from the 470kQ resistor, and also that the virtual ground serves only to set the operating level of the op-amp, so decoupling of the virtual ground is trivial as there is negligible current sourced or sunk.

Figure 14 shows the effective trans-impedance of the Figure 13 amplifier. The resonant peak is approximately 5ΜΩ at a frequency of 1 1 .8kHz. The amplifier design incorporates DC coupling, meaning that saturation of the front end due to excessive photocurrent can be detected by monitoring the DC component of the ADC signal; i.e. ADC saturation.

By way of an example, a MCP6021 (Microchip Inc.) op-amp was used due to its availability in a small 5 pin SOT23 package, low operating voltage, low input referred voltage noise, and low 30pA typical bias current.

A virtual ground voltage of 1 .26V was found to be optimal under typical operating conditions (i.e. ambient light level), and a supply rail at 3.3V. This resulted in a peak to peak photocurrent of approximately 500nA, and mean of approximately 250nA. The photocurrent shot noise density can be found using equation 1 ,

Oshot = V²⁽?eW (1)

giving a_sh0, = 283f A/V77z. The amplifier noise can be estimated from the trans- impedance thermal current noise (in this case the 470kQ resistor), and the effect of voltage noise from the op-amp specification (8.5nV/V77z at 1 1 .67kHz) acting across the effective parallel capacitance of the photodiode and cable (200pF from the photodiode and 1 m of miniature shielded cable).

The thermal current noise can be found as a_R = 190f A/V77z, and by calculating the effective impedance of the 200pF capacitive load at 1 1 .67kHz, the effect of op-amp voltage noise can be calculated as σ_ην = 126f A/V77z. <r_To_t = ¾² + σ„² _ν + a _hot = 364f A/yf (2)

The opamp noise current density of 3fA/v77z is negligible compared to the other noise sources so has been ignored. Thus the total input referred noise current density is considerably higher than the shot noise density, meaning the single op-amp amplifier is not shot noise limited, but is nevertheless close to the noise floor. The SNR and Effective Number Of Bits (ENOB) figures can now be calculated. Assuming an RMS AC photocurrent of 177nA (250nA/V2):

SNR = ^177x10-9 = 4.9 x 10⁵/J (3)

ENOB = ^ln(4-⁹^°^{S 27)} = 18.9 - 0.721n(/- /) (4)

This is a high enough SNR to allow the small PPG cardiac synchronous intensity modulation to be accurately monitored (e.g. 17.2bits, with Δί bandwidth of 10Hz).

Figure 15 shows the demodulation architecture designed to demodulate the three optical channels. ADC values are passed to RAM via DMA, before being read from an interrupt service routine. A complex (i.e. in-phase and quadrature) local oscillator at 1 1 .67kHz is used to downconvert the data to a complex baseband, and a DFT (with 1 /62.04s or 16.1 ms bin length) then separates the three optical carriers. Threaded routines running through an RTOS (Real Time Operating System) then process the data and store it. Pneumatic control and status code logging is carried out by other RTOS threads.

Figure 16 shows a symbolic diagram of the datalogger 36 electronics. The datalogger 36 may be based around an STM32F103 micro-controller from ST-microelectronics (Geneva, Switzerland). A Bluetooth module was attached via the microcontroller's UART, allowing wireless data streaming and device firmware updates (using a bootloader).

A single 18 pin interface connector on the front face of the enclosure allowed PPG sensors to be connected to the device, or alternatively for the datalogger to be connected to a PC, allowing data download (using the mass storage device class), and charging of the logger's 3.7V lithium polymer cell (using 500mA charging current). A microSD memory card formatted with a FAT32 filesystem was used to store logged data, and the real time clock peripheral built into the STM32 microcontroller used to timestamp files.

Dataloggers were assembled for use in a volunteer study of CRT change induced by cooling of the forearm. An off-the-shelf 120 by 60 by 30mm high polycarbonate enclosure was used, with slots and holes milled for the connectors and the on/off/control button, and the PCB, pump, solenoid valve and a 2Ah lithium polymer cell secured inside.

Experiments and results Capillary refill time estimation (PC based post-processing)

In an embodiment, the measurements obtained can be used to train the system 26. The intensity or amount of radiation from the emitters 12, and the frequency of the radiation, can be varied to determine the optimum return signal. This can be especially useful for skin of different colours which will absorb/reflect the radiation differently.

A simple intensity threshold based technique was applied to the optical intensity data recorded by the device, with a refill time in seconds being estimated for each release of pressure. Each of the three wavelength channels stored by the datalogger was independently processed, leading to three refill time traces in the following figures.

Figure 17 shows approximately 100 seconds of typical raw data from the device. It can be seen that there is a much larger modulation depth in the 520nm channel than at 640 or 950nm, but that the 520nm baseline is also less stable and contains a cardiac synchronous component. This was also present in the 640nm and 950nm channels, but is not apparent at this plotting scale. Some residual air pressure is visible after release. The ADC value is proportional to intensity.

A script written in the GNU-Octave language was used for processing the data, with the air pressure data used to isolate each refill interval as the ten seconds following each point where air pressure dropped below a 3.1 kPa threshold having previously risen above 3.5kPa and remained above that level for at least one second. To reduce the impact of volunteer motion upon the refill time metric, a fitting process was then used to produce a baseline and "data quality" measure for each refill. This was based on a two part fitting process, with a second order polynomial fit (representing the capillary refill) and a straight line fit (representing the baseline) made to two regions of intensity data. The transition time between these regions (corresponding to the end of the refill period) was varied from one to six seconds after the pressure release, and the point of minimum fit error found. Refills were excluded if they had an excessive root mean squared fit error at this point, a positive gradient for the first line fit, or an excessive gradient for the second fit (i.e. too much baseline drift). Rejection thresholds were chosen based on visual inspection of the intensity curves from the unrejected refills, with the threshold being increased to approach the point where clearly erroneous refills were used. Finally, refill times were calculated for the accepted refills using a threshold method; the time post release at which intensity first fell to some fraction (the "threshold level") of the initial height above baseline. These refill times were interpolated and resampled in the time domain to give a consistent 0.1 Hz refill time sample rate. Data from experimental subjects ("bladder design")

Figures 18 and 19 show processed capillary refill data recorded over a 6 hour period with the sensor placed on a healthy adult volunteer's forearm. A capillary refill was conducted by the datalogger every 23 seconds, giving a total of 922 refills over the entire time period (2766 refill datasets for all wavelengths). In Figure 18(a), the median normalised optical intensity is shown (in arbitrary units) over the six seconds following pressure release, together with the InterQuartile Range (IQR, indicated using thinner lines for the upper and lower quartiles). A total of 256 capillary refills datasets (9%) were rejected by the rejection algorithm, these are shown in Figure 18b. The dotted trace is the 950nm channel, the dashed is 640nm, and the solid 520nm.

Figure 19(b) shows refill times (with a threshold level of 35%) and sensor temperature (measured from the thermistor built into the sensor) versus time of day. The capillary refill time measurements having been low pass filtered with a 2mHz second order forward-reverse Bessel filter (0.5mHz was also applied at 520nm). These frequencies were chosen based upon the fact that in existing clinical practice, CRT is rarely taken more often than every 15minutes, a sampling rate with a Nyquist frequency of 0.55mHz. Figure 19(a) shows the percentage of used refills for each wavelength (over a low pass filtered ten minute rolling window). The refill intensity modulation depth (after 2mHz low pass filtering) is plotted using a grey background. This was defined as the fractional increase in 520nm channel intensity above baseline at the point of maximum intensity during the pressure application period. It can be seen that blanching causes an optical intensity increase of approximately 60%. It is hoped that a quality index, perhaps consisting of some function of modulation depth and used refill percentage, could be useful in a clinical care scenario, for example as a means of automated identification of poor sensor attachment.

The sensor 10 was briefly removed from the volunteer's arm at 13:50. This can be seen as a downward spike in temperature, as the sensor started to cool to room temperature before being rewarmed by skin contact. The refill time is slightly elevated upon re- attachment to the arm, although it trends back towards the original value over the next hour. It is speculated that this is a temperature related effect. Ambient temperature has been found to influence capillary refill time measured using the conventional manual method.

For this reason, ambient temperature change was employed as a surrogate for an illness induced change in refill time, and a study of the effect of environmental temperature upon automated capillary refill time conducted in healthy adult (n=15) and child (n=15, age 5 to 15 years) volunteers. A 5°C chamber was used to cool the forearm after a 20 minute acclimatization period at room temperature. The CRT sensor 10 was placed on forearm, and the effect of temperature change upon CRT measured.

The refill times (to 35% threshold) for a typical healthy adult and healthy child volunteer are plotted in Figures 20 to 23, using the same format as in Figures 18 and 19. No significant differences were noted between the adult and child refills, although there were more rejected data in the child datasets. It is suspected that this was due to motion, as the child volunteers were more restless during the experiment. It can be seen that sensor temperature begins to decrease sharply as the forearm is placed into the chamber (at approximately 16:20 and 1 1 :40), and there is a corresponding increase in capillary refill time across all three sensor channels in both volunteers. This result is in agreement with published studies, although the percentage change in refill time (both volunteers saw 80% CRT increase over a 8°C temperature reduction) is considerably larger than the change seen in the study by Anderson et al (5% increase per °C).

Figures 24 and 25 plot refill times versus temperature from the 15 adult and 15 child volunteers. Refills were binned according to CRT (0.1 second bins) and sensor temperature at the time when the refill was recorded (0.25°C bins). A downward trend in refill time with increasing temperature can be seen in all the plots, with the refill times being more widely scattered in the child datasets. Lines of best fit through the datapoints are overlaid (white dotted lines), and it can be seen that the 520nm channel has the highest gradient, followed by the 950nm and 640nm channel respectively. Due to the limited amount of data, it is not possible to draw definitive conclusions from these scatter plots, but it would appear that there is a true sensitivity difference between channels, at least in the adult volunteers, where most refill points are within ±0.5 seconds of the fit line in all three channels. Assuming a CRT baseline of 2s, the adult fit at 520nm gives a 7% increase per cooling.

The Pearson product-moment correlation coefficient r was used to quantify the relationship between inverse capillary refill time and temperature. The inverse refill time (1 /refill time) was used so as to produce a positive r and allow easier comparison (a higher plot implies better performance). This test used refill time data that was unfiltered in the time domain, i.e. not the filtered data displayed in the Figures 21 and 23, but rather the set of discrete capillary refill time measurements that were not rejected by the rejection process outlined earlier, paired with the corresponding spot temperature measurements from the sensor at the time point where pressure was released. Confidence intervals on each r were calculated using Fisher's z' transformation.

From Figure 26, r tended to be higher in the adult datasets. It is unclear if there is any physiological component to this effect, but it was noted that there was a decrease in the data quality (percentage of rejected refills) in the child volunteers, apparently due to motion artefacts. The used refills also had an intensity profile with a larger interquartile range.

The confidence intervals were used to identify datasets with a significant (p < 0.05) correlation between temperature and inverse refill time. At 520nm, 67% (10) of the child volunteers and 73% (1 1) of the adult volunteers saw a significant correlation. This fell to 40% (children) and 53% (adults) at 640nm, and 60% (children) and 67% (adults) at 950nm. It is believed that the greater modulation depth of the optical refill signal at 520nm (due to the haemoglobin absorption peak at this wavelength) may be responsible for the improved performance of automated CRT at this wavelength.

Data from experimental subjects ("plunger design")

Figures 27 and 28 show data similar to that shown in Figures 18-23, so the commentary provided above applies here as well. The data were obtained from healthy volunteers. When the data were recorded, the volunteers were moving, and the sensor appears to reduce the influence of motion artefacts.

Figure 27 shows data from a "baseline recording". This consisted of an acclimatisation period of about 30 minutes, with the volunteer seated indoors (room temperature about 20°C), followed by a 10 minute period spent walking up and down a flight of stairs as a "motion artefact" test (internal staircase at room temperature). Despite the volunteer walking up and down stairs, there was a drop in temperature during the "motion artefact" test, and a matching increase in CRT. The data show few motion artefacts.

Figure 28 shows a "cold challenge recording". This consisted of an acclimatisation period of approximately 20 minutes, followed by a period of tending outside (exposure to cold ambient temperature, around 10°C), followed by a further baseline period. This sequence induces a change in skin surface temperature, allowing correlation between skin surface temperature chance and CRT to be examined. Again, few severe motion artefacts are observed in this data, with little CRT change with temperature for this volunteer, probably as their refill time was already quite slow at room temperature. The data do, however, show a correlation between CRT and temperature. The data also demonstrate that the adhesive ring 59 and attachment ring 61 provide for secure fixing to the patient's skin and low susceptibility to motion artefacts.

In summary, therefore, aspects and embodiments of the present invention can advantageously provide an automated process that allows the removal of variability and the need for continuous assessment. A fully automated device 10 capable of carrying out measurements of capillary refill time has been demonstrated. Preliminary results from healthy volunteers indicate that accurate and repeatable measurements are possible with a high repetition rate (up to three refills per minute). A series of measurements from 15 healthy adult and 15 healthy child volunteers subjected to forearm cooling in a 5°C chamber saw a statistically significant (p < 0.05) change in refill time in the majority of the volunteers when the 520nm or 950nm wavelength channels were used for refill time measurement, with the 520nm channel producing the most significant data. A close to linear relationship was found between sensor temperature (close to skin surface temperature) and refill time, in agreement with published studies of temperature effects upon manual CRT. A six hour baseline observation showed little drift compared to the cooling induced refill time changes, demonstrating potential for automated CRT as a practical clinical tool. The "plunger" data also a correlation between CRT and temperature. Through application of an automated device capable of making repeatable measurements free from any observer related bias, it is hoped that questions concerning the clinical utility of the capillary refill test can be answered definitively in future clinical trials.

It has therefore been shown to be feasible to measure changes in the microcirculation of children using an automated PPG and pressure application device to detect changes in CRT. It is expected that the device can be used to monitor children and detect changes in perfusion that could signal evolving cardiovascular compromise.

From reading the present disclosure, other variations and modifications will be apparent to the skilled person. Such variations and modifications may involve equivalent and other features which are already known in the art of wireless communication, and which may be used instead of, or in addition to, features already described herein.

Although the appended claims are directed to particular combinations of features, it should be understood that the scope of the disclosure of the present invention also includes any novel feature or any novel combination of features disclosed herein either explicitly or implicitly or any generalisation thereof, whether or not it relates to the same invention as presently claimed in any claim and whether or not it mitigates any or all of the same technical problems as does the present invention.

Features which are described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. The applicant hereby gives notice that new claims may be formulated to such features and/or combinations of such features during the prosecution of the present application or of any further application derived therefrom. For the sake of completeness it is also stated that the term "comprising" does not exclude other elements or steps, the term "a" or "an" does not exclude a plurality, a single processor or other unit may fulfil the functions of several means recited in the claims and any reference signs in the claims shall not be construed as limiting the scope of the claims. References to "top" and "bottom", "upper" and "lower" etc. used throughout are not to be construed as being limiting, but refer to the orientation as shown in the Figures.

Claims

1 . A device attachable to a person and configured to automatically measure the capillary refill time of a said person, the device comprising at least one radiation source and at least one detector for detecting radiation reflected from or transmitted through the person's body, and an actuator for applying pressure directly or indirectly to the person's skin.

2. The device of claim 1 , wherein the capillary refill time is determined from the photoplethysmogram obtained from the reflected or transmitted radiation.

3. The device of claim 1 or 2, further comprising a connector for connecting to a computing and/or display device and/or to a source of fluid such as air, and wherein said device and connector are integrally formed or are attachable to and detachable from one another.

4. The device of claim 3, wherein the device is a single-use device and is disposable.

5. The device of any preceding claim, wherein the at least one radiation source is configured to emit radiation within the near infrared and visible light spectrum and each is, optionally or preferably, an LED or laser diode.

6. The device of claim 5, wherein the at least one radiation source is configured to emit red, infrared or green light.

7. The device of any preceding claim wherein the detector is or comprises a photodiode or a camera.

8. The device of any preceding claim, wherein the actuator is a pneumatic or mechanical actuator.

9. The device of claim 8, wherein the actuator is a plunger moveable with respect to the device in response to gas being provided to the device.

10. The device of claim 9, wherein the device comprises a housing and the plunger sits within the housing, and wherein the housing and the plunger are indirectly coupled together.

1 1. The device of claim 10, further comprising a flexible coupling provided between the housing and the plunger that permits relative movement therebetween.

12. The device of claim 8, wherein the actuator is a pneumatic actuator comprising a bladder which can apply said pressure when inflated with a pressurized gas such as pressurized air.

13. The device of any preceding claim, wherein the actuator is operable for providing a pressure in excess of atmospheric pressure, such as greater than substantially 2.0 psi and optionally or preferably substantially 2.5 psi.

14. The device of any preceding claim further configured to determine the amount of oxygen in the person's blood by pulse oximetry.

15. The device of claim 14, wherein at least one of said radiation sources is configured to emit near infrared or visible light, optionally or preferably green light, for the pulse oximetry measurement.

16. The device of any preceding claim, further comprising a temperature sensor.

17. The device of any preceding claim, further configured to monitor movement of the device to enable movement artefacts to be identified.

18. The device of any preceding claim, configured to provide an indication of the correct orientation for use and/or for attaching to a person's skin.

19. The device of any preceding claim, wherein the device is configured for attachment anywhere on a person's body and may further comprise means for attachment to a said person's skin such as an adhesive, a shear and/or tensile resistive adhesive or adhesive tape.

20. A system comprising the device of any preceding claim, further comprising a unit remote from said device, the unit comprising one or more of a processor for determining a measurement of capillary refill time and a source of fluid such as air.

21. The system of claim 20, wherein the unit further comprises an exhaust port for exhaustion of pressurized gas from said housing and, optionally or preferably, wherein the pressure within the bladder does not decrease to zero.

22. The system of claim 20 or 21 , further comprising a second device according to any of claims 1 to 19, said processor being operable for obtaining measurements from the device and the second device.

23. The system of claim 22, wherein at least one of the device and the second device is configured to provide a photoplethysmogram from the at least one radiation source to determine capillary refill time by reflectance from the person's skin.

24. The system of any of claims 20 to 23, wherein the processor is configured to initiate a measurement of capillary refill time at time intervals of between substantially 10 and 30 seconds, or between substantially 15 and 25 seconds, or between substantially 20 and 23 seconds.

25. The system of claim 24, wherein the processor is configured to initiate a measurement of capillary refill time at time intervals that are chosen to not coincide with internal bodily cycles.

26. The system of claim 25, wherein the processor is configured to initiate a measurement of capillary refill time at time intervals greater than approximately 10 seconds.

27. The system of any of claims 20 to 26, wherein the device comprises a temperature sensor for measuring the temperature of a person's skin and/or the unit further comprises a temperature sensor and the processor is configured to calculate temperature compensation of the measurement of capillary refill time.

28. The system of any of claims 20 to 27, the unit further comprising an alarm means to provide an indication of when the capillary refill time falls below a predetermined threshold value.

29. The system of any of claims 20 to 28, wherein the processor is configured to stop taking measurements if the device becomes detached from the person, or if a leak in pressurized gas is detected, or if the device becomes too hot.

30. The system of any of claims 20 to 29, configured to be powered by a battery, a rechargeable battery or mains power.

31. The system of any of claims 20 to 30, further comprising data analysis software configured to run on the processor or remotely on a remote processing or computing device, the software being configured to provide an indication of the refill time, and, optionally, of the patient skin surface temperature and sensor signal quality from the measurements taken with the device or second device of any of claims 20 to 30.

32. The system of claim 31 , wherein the processor or software is further configured for adaptive filtering of the measurements in order to weight the capillary refill time measurements and provide a confidence indicator associated therewith.

33. The system of any of claims 20 to 32, wherein the processor is configured to vary the amount of radiation each radiation source provides and provide feedback based on the photoplethysmogram obtained from the radiation sources.

34. The system of any of claims 20 to 33, wherein the software is configured to calculate the CRT as a function of the measured time taken for the PPG signal to return to a predetermined fraction of its maximum elevation above a baseline; or wherein the software is configured to calculate the CRT as a function of the slope of the refill signal.

35. The system of claim 34, wherein the AC component of the PPG signal is analysed to check the signal is valid and the DC component of the PPG signal is used to calculate the CRT.

36. The system of any of claims 20 to 35, wherein the processor or software analyses the signals from the radiation sources using frequency division multiplexing.

37. A device substantially as hereinbefore described with reference to Figures 2 to 7 of the accompanying drawings.

38. A system substantially as hereinbefore described with reference to Figures 2 to 10 of the accompanying drawings.