Real-time monitoring of tissue health by rapid-sampling microdialysis gives better outcomes during surgery and intensive care
Submitting InstitutionImperial College London
Unit of AssessmentGeneral Engineering
Summary Impact TypeTechnological
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences, Neurosciences
Summary of the impact
The Boutelle team has developed a biosensor that uses rapid-sampling
microdialysis (rsMD) to
detect ischaemia (restricted blood supply to tissue) during surgery and
intensive care. The rsMD
biosensor is implanted into tissue at risk and provides a real-time
readout of chemical markers of
metabolism. By 2009, technical improvements researched in the Department
had made the system suitable for routine clinical use. The system has
reduced morbidity and
mortality by alerting the surgical team to otherwise undetected ischaemia.
It has been used by an
international consortium of clinical centres to help decide treatment in
approximately 100 patients
with brain injury. More recently it was adopted by a Portsmouth hospital
to monitor cancer patients
undergoing reconstruction of the face and jaw; the biosensor detected a
failure of perfusion in
transplanted tissue in two of the first ten patients, prompting the
surgical team to remove otherwise
undetected blood clots that could have led to death from septicaemia.
Professor Martyn Boutelle has pioneered the development of enzyme-based
rsMD biosensors for
continuously monitoring multiple metabolites — principally glucose and
lactate — that indicate tissue
health during surgery and intensive care. In this method, a probe is
inserted into the tissue of
interest; substances that diffuse across its dialysis membrane are washed
electrochemical sensor that relies on immobilised oxidase/peroxidase
enzymes to convert specific
analytes into oxidised species, which are then detected by reduction.
An initial prototype was developed by the Boutelle group when they were
based at King's College
London. However, it could only detect large metabolite changes, seen
rarely in patients. Following
Dr Boutelle's appointment to the Department of Bioengineering in December
tests were conducted, sensitivity was improved by an order of
magnitude, and pre-clinical
and clinical validations were carried out. This research made the sensor
suitable for routine use in
hospitals for a number of clinical conditions.
The first target application was detecting brain ischaemia during
depolarisation, a common adverse consequence of brain injury. Trials in 8
surgery for cerebral aneurysm gave proof-of-principle that glucose and
lactate can be continuously
monitored in the human brain by rsMD, and that their concentrations change
detectably when the
blood supply is deliberately interrupted; the system had 30s temporal
resolution and a response
time of only 9 minutes . (This makes it far more applicable than the
microdialysis device, which provides hourly samples that require manual
handling and a lengthy
chromatographic analysis; timely information is essential in the clinic.)
Sensitivity sufficient for
routine use on spreading depolarisation patients was obtained by
developing novel noise reduction
algorithms ; subsequent optimisation of the microfluidics chamber where
analytes contact the
electrodes has further improved sensitivity (and also response time).
Pre-clinical trials in cats
determined the reciprocal relation, time course and absolute value of
glucose and lactate
concentrations during induced depolarisations . A clinical trial  in
10 brain-injured patients
demonstrated reciprocal changes in glucose and lactate during periods of
depolarisation; multiple depolarisations were associated with a stepwise
depletion of glucose of
sufficient severity to compromise tissue viability.
Although originally developed for monitoring injured brain, further
underpinning research has been
required to make the technology suitable for other conditions. To make it
useful for gastrointestinal
surgery, for example, a series of studies was conducted in collaboration
with Professor George
Hanna and Professor Lord Ara Darzi. Pre-clinical trials using pigs showed
that changes in glucose
and lactate concentrations could be detected within 5 minutes of
interrupting the blood supply .
Such changes were also observed in 7 patients undergoing bowel resection.
A stable, highly-selective
ATP biosensor has also been developed to assess metabolic
problems in gut tissue.
The research has been published exclusively in international
peer-reviewed journals [ref 3 features
on the journal cover]. It has been supported by peer-reviewed funding
including a £1.3M Wellcome
Trust / Department of Health Healthcare Innovation Challenge Fund grant.
Industrial interest is
demonstrated by a BBSRC CASE studentship with Sharp Europe and a BBSRC
studentship with GSK, whilst two internally-allocated translational grants
demonstrate institutional support . Recent esteem indicators include
Boutelle's Chairmanship of
the symposium of the International Society for Monitoring Molecules in
References to the research
* References that best indicate quality of underpinning research.
1. Bhatia R, Hashemi P, Razzaq A, Parkin MC, Hopwood SE, Boutelle MG,
Application of rapid-sampling, online microdialysis to the monitoring of
during aneurysm surgery. Neurosurgery. 2006;58:ONS-313-321. DOI:
2. *Feuerstein D, Parker KH, Boutelle MG. Practical methods for noise
removal: applications to
spikes, nonstationary quasi-periodic noise, and baseline drift. Anal Chem.
3. *Hashemi P, Bhatia R, Nakamura H, Dreier JP, Graf R, Strong AJ,
Boutelle MG. Persisting
depletion of brain glucose following cortical spreading depression,
hyperaemia: evidence for risk of an adverse effect of Leão's spreading
depression. J Cereb
Blood Flow Metab. 2009;29:166-175. DOI: 10.1038/jcbfm.2008.108. Cited 32
4. *Feuerstein D, Manning A, Hashemi P, Bhatia R, Fabricius M, Tolias C,
Pahl C, Ervine M,
Strong AJ, Boutelle MG. Dynamic metabolic response to multiple spreading
in patients with acute brain injury: an online microdialysis study. J
Cereb Blood Flow Metab.
2010;30:1343-1355. DOI: 10.1038/jcbfm.2010.17.
5. Corcoles EP, Deeba S, Hanna GB, Paraskeva P, Boutelle MG, Darzi A. Use
of online rapid
sampling microdialysis electrochemical biosensor for bowel anastomosis
monitoring in swine
model. Anal Methods 2011;3:2010-2016. DOI: 10.1039/c1ay05306j.
(i) Boutelle and E. Drakakis. "Real-time detection of the onset of
secondary brain injury in the
intensive care unit," Wellcome Trust/Department of Health,
(ii) Boutelle. Sharp Laboratories Of Europe Ltd. "CASE Studentship for
£13,500. 1/10/2009 - 30/9/2012
(iii) GlaxoSmithKline Services Limited. "Industrial CASE studentship for
£83,470. 1/10/2007 - 30/9/2011.
Details of the impact
The majority of patients benefitting from the rsMD technology have
suffered a brain injury that
reduces the blood supply to their brain. Brain tissue can cope with the
consequent reduction in the
supply of oxygen and nutrients if its metabolic rate is sufficiently low.
Unfortunately, however, as
shown by the Boutelle group, a common consequence of such injury is the
synchronised waves of electrical depolarisation in the brain; generating
the synchronised waves
requires lots of energy and the injured brain consequently suffers from
the ischaemia. It is
therefore unsurprising that the occurrence of waves is associated with a
worse outcome [A]. Since
the unsupported metabolism is itself a direct cause of damage, diagnostic
precision can be
increased by monitoring it locally, continuously and in real time.
Currently this can only be achieved
with the Boutelle group's methods.
Professor Boutelle is a founding member of COSBID [B], an organisation
established for the
investigation and treatment of patients with brain injury depolarisations
resulting from head trauma
or vascular stroke. Its 16 Centres are distributed worldwide. Six of them
(Charité Hospital, Berlin;
King's College Hospital, London; University Hospital, Cologne; St Mary's
Charing Cross Hospital, London; and University of Pittsburgh Medical
Center) monitor eligible
patients not only for depolarisation waves but also for ischaemia, using
rsMD equipment made by
Professor Boutelle. He also trained 15 neurosurgeons and other clinical
staff, and has run briefing
courses for approximately 30 intensive care nurses every 6 months, during
the REF period.
The introduction of routine monitoring of brain ischaemia by rsMD
represents a change in clinical
practice. For example, Cologne uses rsMD to screen every patient with
haemorrhage and some with traumatic brain injury (approx. 10
patients/year) [C]; approximately
100 patients have been screened across all Centres within the assessment
period. The method
provides greater precision in the diagnosis of the patient's condition and
hence helps to guide the
selection of treatment options such as administering glucose, raising
blood pressure or performing
radical hemispheric craniectomy [D]. It was highlighted as being of
"outstanding interest" in a
recent expert clinical review [E].
The method has been extended to clinical practice in other surgical
areas. For example, it is
employed in reconstructive surgery of the tongue or jaw where a flap of
the patient's own tissue is
used as a transplant, usually following cancer treatment. Success in this
procedure depends on
adequate perfusion of the flap with blood; it therefore requires clot-free
blood vessels, and
microsurgical techniques to interface the vessels in the flap with those
of the surrounding tissue.
Inadequate perfusion occurs in 9% of cases (and many more in patient
groups with adverse
conditions such as diabetes); the failure rate at salvage is then up to
66% [F]. It causes flap
ischaemia and necrosis, ultimately leading to life-threatening septicaemia
if left uncorrected.
Mortality for septicaemia in intensive care is approx. 80-90%. Perfusion
is traditionally assessed
only by the feel and appearance of the flap; signs of failure appear late,
by which time surgical
rescue is difficult or impossible.
To overcome this problem, rsMD biosensors from the Boutelle team have
been used to monitor 3
patients per month, starting in November 2011, at the Queen Alexandra
monitoring takes place during both surgery and intensive care [G]. This
represents a change of
clinical practice at the hospital, and improves outcome. After only ten
patients had been examined,
the system had detected a failure of tissue perfusion in two patients
after initial flap placement. The
surgical team responded by disconnecting the flap, where they found blood
clots. These were
cleared and the flap metabolic state dramatically improved. Without rsMD
technology, the clots
would have remained undetected, causing the tissue flap to become ischemic
and then necrotic,
probably leading to septicaemia with its associated high incidence of
mortality. The paper [H]
describing these cases was "highlighted" in the American Chemical
Society's Chemical &
Engineering News [I] 2013;91:30. The surgeon is currently trying rsMD in
other, related classes of
operation including, with colleagues, reconstructive breast surgery.
Overall, the impact of this technology during the REF period has been to
reduce patient morbidity
and mortality, reduce medical costs, and relieve burden on medical
infrastructure at the hospitals in
which the device has been used: Charité Hospital, Berlin; King's College
University Hospital, Cologne; St Mary's Hospital, London; Charing Cross
University of Pittsburgh Medical Center; and Queen Alexandra Hospital,
on commercialisation of the latest version of the rsMD technology are
underway with M Dialysis, a
Swedish company that dominates the clinical microdialysis market [J]. The
technology will be
patented using the translational funds obtained for that purpose.
Sources to corroborate the impact
A. Hartings JA, Bullock MR, Okonkwo DO, Murray LS, Murray GD, Fabricius
M, Maas AI, Woitzik
J, Sakowitz O, Mathern B, Roozenbeek B, Lingsma H, Dreier JP, Puccio AM,
Shutter LA, Pahl
C, Strong AJ; Co-Operative Study on Brain Injury Depolarisations.
and outcome after traumatic brain injury: a prospective observational
study. Lancet Neurol.
2011;10:1058-1064. DOI: 10.1016/S1474-4422(11)70243-5 By showing that
causing waves worsen outcome, this paper explains why the rsMD device
diagnostic precision in traumatic brain injury.
B. www.cosbid.org The
clinical-research collaborative network through which rsMD is applied to
traumatic brain injury in hospitals. Site Archived on 24/10/2013 at
C. Deputy Managing Director, Multimodal Imaging, Max Planck Institute for
Research, Cologne. Describes the number of patients and clinical
benefit of using rsMD at
University Hospital, Cologne.
D. Emeritus Professor of Neurosurgery, Department of Clinical
Neuroscience, Institute of
Psychiatry, King's College London. Describes the origin of COSBID in
Boutelle's work, and the
number of patients and clinical benefit of using rsMD at King's College
E. Goodman JC, Robertson CS. Microdialysis: is it ready for prime time?
Curr Opin Crit Care.
2009;15:110-117. DOI: 10.1097/MCC.0b013e328325d142. This expert review
clinical value of Boutelle's rsMD technique, particularly the research
in Reference 3 of Section
F. Garg S, Deschler D. Saving a free flap with close clinical
postoperative monitoring. JAAPA
2013; 26: 47-49. This publication highlights the severity of the
clinical problem that is
addressed by use of Boutelle's rsMD maxillofacial surgery.
G. Consultant Oral and Maxillofacial Surgeon and Professor of Surgery,
Hospital, Portsmouth. Describes the number of patients and clinical
benefit of using rsMD at
Queen Alexandra Hospital, Portsmouth.
H. Rogers ML, Brennan PA, Leong CL, Gowers SA, Aldridge T, Mellor TK,
Boutelle MG. `Online
rapid sampling microdialysis (rsMD) using enzyme-based electroanalysis for
of ischaemia during free flap reconstructive surgery. Anal Bioanal Chem.
DOI: 10.1007/s00216-013-6770-z. Describes the clinical benefit of
using rsMD at Queen
Alexandra Hospital, Portsmouth.
I. American Chemical Society's Chemical & Engineering News April 15th
2013, page 30:
Describes the clinical benefit of using rsMD at Queen Alexandra
Portsmouth. Archived here
J. Sales & Marketing Director, M Dialysis AB will attest to the
commercial discussions between
Prof Boutelle and M Dialysis concerning rsMD.