Editorial

specialist societies in this work is

that it is possible both to organise
the studies and then to disseminate
best practice, as ACTA have
recently shown with their study on
mortality [12]. They are well placed
to carry the burden, and it gives me
much pleasure and much hope for
the future to see ACTA so active in
this role.

Competing interest
Dr Feneck was Chairman of ACTA
from 1993-96; he has no other competing interests to declare.
R. O. Feneck
Consultant Anaesthetist
St Thomas Hospital
London UK
Email: rob_feneck@msn.com
Keywords: blood transfusion; perioperative morbidity; pre-operative
anaemia

Anaesthesia 2016, 71, 611626

References
1. Klein AA, Collier TJ, Brar MS, et al. The
incidence and importance of anaemia
in patients undergoing cardiac surgery
in the UK the first Association of
Cardiothoracic Anaesthetists national
audit. Anaesthesia 2016; 71: 62735.
2. Nashef SA, Roques F, Sharples LD, et al.
Euroscore II. European Journal of Cardiothoracic Surgery 2012; 41: 73444.
3. Karkouti K, Beattie WS, Wijeysundera
DA, et al. Hemodilution during cardiopulmonary bypass is an independent risk factor for acute renal failure
in adult cardiac surgery. Journal of Thoracic and Cardiovascular Surgery 2005;
129: 391400.
4. Maddux FW, Dickinson TA, Rilla D,
et al. Institutional variability ofintraoperative red blood cell utilization in
coronary artery bypass surgery. American Journal of Medical Quality 2009;
24: 40311.
5. Bennett-Guerrero E, Zhao Y, OBrien SM,
et al. Variation in use of blood transfusion in coronary artery bypass graft surgery. Journal of the American Medical
Association 2010; 304: 156875.
6. Cote C, Macleod JB, Yip AM, et al. Variation in transfusion rates within a single institution: exploring the effect of
differing practice patterns on the

7.

8.

9.

10.

11.

12.

likelihood of blood product transfusion

in patients undergoing cardiac surgery.
Journal of Thoracic and Cardiovascular
Surgery 2015; 149: 297302.
Murphy GJ, Pike K, Rogers CA, et al.
Liberal or restrictive transfusion after
cardiac surgery. New England Journal
of Medicine 2015; 372: 9971008.
Spertus J. TITReing the Approach to
Transfusions after Cardiac Surgery. New
England Journal of Medicine 2015;
372: 106970.
Goodnough LT, Shander A. Patient
blood management. Anesthesiology
2012; 116: 136776.
Thomas DW, Hinchliffe RF, Briggs C,
et al. Guideline for the laboratory diagnosis of functional iron deficiency
anaemia. British Journal of Haematology 2013; 161: 63948.
Fowler AJ, Ahmad T, Phull MK, et al.
Meta-analysis of the association
between preoperative anaemia and
mortality after surgery. British Journal
of Surgery 2015; 102: 131424.
Papachristofi O, Sharples LD, Mackay J,
et al. The contribution of the anaesthetist to risk-adjusted mortality after cardiac surgery. Anaesthesia 2016; 71:
13846.
doi:10.1111/anae.13461

Editorial
The INR is only one side of the coagulation cascade: time to
watch the clot
The prothrombin time (PT)-derived
international normalised ratio (INR)
is frequently used to assess the risk
of bleeding for patients receiving
warfarin, or who have had liver surgery, liver dysfunction or transplan-

This editorial accompanies an article by

Mallett et al., Anaesthesia 2016; 71: 657
68.

tation. Anaesthetists will rely on it

when assessing the potential for neuraxial hematoma formation when
placing or removing an epidural
catheter. It is also a key component
of the Model for End-stage Liver
Disease (MELD) score, which is an
objective means of predicting 90-day
patient survival in patients on the
liver transplant waiting list, and is

2016 The Association of Anaesthetists of Great Britain and Ireland

used to prioritise donor organs to

the most needy patients [1]. The
accuracy of PT measurement has
been questioned, as there is marked
variability in the sensitivity of the
thromboplastin reagents used in its
determination [2]. The INR was
designed to standardise anticoagulation therapy, as large differences in
laboratory determinations of PT
613

Anaesthesia 2016, 71, 611626

were found in the same blood sample [3]. These differences caused difculties in prescribing the most
effective amount of warfarin that
would neither over- or under-anticoagulate patients. Therefore, in an
effort to normalise the effects of this
variability
of
thromboplastin
reagents, and present a value as if the
standard World Health Organization
thromboplastin reagent had been
used, the INR was developed. The
INR is a calculation of (patient prothrombin time/control prothrombin
time)ISI, where ISI is the international sensitivity index and control
PT values are obtained from patients
on warfarin therapy [3, 4]. However,
in the prociency testing, there was a
coefcient of variation of 13%
among laboratories. In an independent test, researchers demonstrated a
40% difference in INR on the same
blood sample in patients with liver
disease. Mean MELD score differences of 3-5 MELD points have been
reported when the INR of a single
plasma sample is measured in different laboratories or with different
reagents. This could signicantly
affect the position on the waiting list
(a)

Editorial

of a patient who needs a liver transplant. Therefore, the INR is an unreliable measure as a basis for the
MELD score [510]. However, when
used to assess warfarin activity, the
INR is very consistent [11].

Liver disease and the INR

It has now been well demonstrated
that in liver disease, particularly
liver cirrhosis, there is a reduction
in the production of both pro- and
anticoagulants by the liver [12].
Therefore, the PT-derived INR only
measures the procoagulant side of
the coagulation cascade and not the
anticoagulant side. This balance of
pro- and anticoagulant is what
determines if the patient is hypercoaguable or hypocoaguable. As liver
disease progresses, its synthetic production is impaired and in addition
to
the
procoagulant
factors,
reected by the INR, anticoagulant
factors such as antithrombin, protein C and protein S are also
decreased. To assess the real
in vivo state of the coagulation
system in liver disease, knowledge
of the coagulation cascade is
needed, as is an understanding of

the reasons why routine plasma

tests do not reect the anticoagulant side of the equation but rather
only the pro-coagulant side. The
protein C activator is the thrombinthrombomodulin complex, which is
produced by the endothelial cells in
the liver and is not found in the
plasma. Therefore, the anticoagulant
side of the cascade cannot be accurately assessed in plasma, and
unless thrombomodulin is added to
plasma, the true state of coagulation
cannot be measured. For these reasons, the PT-derived INR does not
reect the true state of the coagulation system in the patient with cirrhosis (Fig. 1).

Liver surgery
Mallett et al. [13], in this edition of
Anaesthesia, have observed that, in
patients with normal liver function
who undergo liver resection, a
hypocoaguable state is commonly
reported, as reected by PT-derived
INR. As a consequence, these
patients may be administered fresh
frozen plasma and thromboprophylaxis is withheld. Yet, bleeding complications are rarely reported [14].

(b)

Figure 1 (a) Protein C activation by thrombin on the membrane of endothelial cells. (b) Activated protein C binds
with protein S and quenches thrombin generation (Reproduced with permission from [11]).
614

2016 The Association of Anaesthetists of Great Britain and Ireland

Editorial

On reviewing the National Surgical

Quality Improvement Program data
for a reported 5500 partial hepatectomies, the incidence of venous
thromboembolism was 2.9%, but
for extended resections, it reached
5.8% [15]. In other case series, the
incidence of venous thromboembolism has been reported to be as
high as 1 in 20 patients in the rst
90 days postoperatively [16]. Liver
resection patients that experience
venous thromboembolism have prolonged hospital stay and increased
mortality, up to 7.4% compared
with those patients that do not have
thrombosis [17, 18]. There is also
an association between the magnitude of the hepatectomy and the
incidence of venous thrombosis.
[15].
It has also been shown that the
incidence of venous thromboembolism after hepatectomy exceeds
that of most other major abdominal
surgeries, including colectomy. [19]
Historically, the PT-derived INR
has been used to guide the timing
of post-hepatectomy interventions
with anticoagulant prophylaxis. It
has now been shown to be an
incorrect assumption that these
parameters reect the coagulation
status of the patient [20].
Mallett and her investigators
designed a prospective study that
would examine conventional coagulation tests, factor levels of pro- and
anticoagulant proteins, thrombin
generation and thromboelastometry
in patients with normal liver function undergoing surgical resection.
The hypothesis was that a similar
imbalance between procoagulants
and anticoagulants may exist, as
seen in cirrhosis, but is not recog-

Anaesthesia 2016, 71, 611626

nised by the conventional PTderived INR. The results clearly

demonstrate that by postoperative
day two there is a prothrombotic
environment that lasts up to day
ve post-surgery. This means that
thromboprophylaxis
should
be
instituted immediately to prevent
the high incidence of venous
thromboembolism that has been
seen in this patient population. The
data presented demonstrate that,
although the conventional tests, PT
and INR, showed a hypocoaguable
state, the thrombin generation
results and thromboelastometry
were normal.
This will have an impact on the
management of living liver transplant donors, where safety is always
paramount. The use of antithrombotic measures should not be
delayed because of a prolonged INR
if the patient can be seen to be
actually prothrombotic by direct
measurements of protein C and
protein S or by observing the viscoelastic presentation of the
patients coagulation integrity.
The question of the management of other branches of medicine
where venous thromboembolism is
common should now also be raised.
The critically ill patient in the
intensive care unit, the sepsis
patient, the postoperative general
surgery patient, the cancer patient
all of these patient groups may
have derangements in their coagulation system because of liver
dysfunction that may prolong the
PT-derived INR, but the patient
may in fact be hypercoaguable and
at increased risk for venous thromboembolism. Should we now be
including global viscoelastic tests of

2016 The Association of Anaesthetists of Great Britain and Ireland

coagulation such as thromoelastometry (TEG; Haemonetics Corporation,

Braintree,
Massachusetts,
USA) and thromboelastometry
(Rotem; TEM International GmbH,
Munich, Germany) in the care of
these patients? These point-of-care
analysers reect both pro-and anticoagulant activity [21]. They
demonstrate the quality of the clot
formation, as it is in vivo, with one
exception, that is, the tests are performed at 37C, regardless of the
patients actual temperature.
If you do not have thrombelastography readily available, the poor
mans test can be performed. This is
what we used to do in the 1960s
when we were concerned about a
surgical patients coagulation status.
We would draw 10 ml of the
patients blood and place it in a
sealed glass test-tube. We would
then tape the tube to the operating
theater wall. The time taken for the
blood in the tube to clot was noted
(clotting time), then the tube was
gently tipped upside down to see if
the clot was strong enough to stay
held in place or would slip down the
tube (clot strength). If the clot stayed
held in place, we would then observe
to see if it broke down and became
liquid again (lysis time). Therefore,
by watching the blood clotting process directly, much can be learned
about the integrity of the coagulation system. Viscoelastic tests allow
the clinician to observe the clot formation as it exists in vivo. These
tests allow a more comprehensive
assessment of the coagulation cascade in real time. In a study by De
Pietri et al. [22], it was demonstrated that, in patients with cirrhosis undergoing invasive procedures,
615

Anaesthesia 2016, 71, 611626

there was a signicant reduction in

the transfusion of blood products if
their use was guided by the thromboelastograph, rather than the standard practice of measuring INR and
platelet count, and there was no
increased risk of bleeding.
The further impact on anaesthetists from this observation of the
unreliability of the PT and INR in
assessing the state of the coagulation
system in patients with normal liver
function undergoing liver resection
will be in the management of epidural analgesia. Several authors have
noted that the PT increases after
liver resection, and that this increase
is related to the size of the resection.
The PT normalises in three to six
days postoperatively, and up until
now, the standard of care has been
to wait until the PT is normal before
pulling out the epidural catheter.
The data that Mallet et al. present
would indicate that, by assessing a
patients coagulation by viscoelastography, the epidural catheter
could be withdrawn safely much
sooner.
This study by Mallett et al.
conrms the work of others related
to liver disease and coagulation but
additionally demonstrates the inadequacy of relying on the PT-derived
INR for assessing the state of the
coagulation system in patients
undergoing hepatic resection with
normal liver function. The value of
the INR may only be in the monitoring of warfarin administration.

Acknowledgements
No external funding and no competing interests declared.

616

Editorial

M. A. E. Ramsay
Chairman
Department of Anesthesiology and
Pain Management
Email: michael.ramsay@bswhealth.
org
J. F. Trotter
Staff Hepatologist
Baylor University Medical Center
Baylor Scott and White Health
Dallas
Texas, USA

10.

Keywords: coagulation factors in

hepatic disease and surgery; monitoring coagulation: prothrombin time
derived INR; thrombelastography

12.

9.

11.

13.

References
1. Wiesner R, Edwards E, Freeman R,
et al. Model for end-stage liver disease
(MELD) and allocation of donor livers.
Gastroenterology 2003; 124: 916.
2. Fowler A, Perry DJ. Laboratory monitoring of haemostasis. Anaesthesia 2015;
70: 68e24.
3. Hirsh J, Poller L. The international normalized ratio. A Guide to understanding and correcting its problems.
Archives of Internal Medicine 1994;
154: 28288.
4. Kirkwood TB. Calibration of reference
thromboplastins and standardization
of the prothrombin time ratio. Thrombosis and Haemostasis 1983; 49:
23844.
5. Trotter JF, Brimhall B, Arjal R, Phillips
C. Specific laboratory methodologies
achieve higher model for end stage
liver disease (MELD) scores for
patients listed for liver transplantation.
Liver Transplantation 2004; 10: 995
1000.
6. Robert A, Chazouilleres O. Prothrombin
time in liver failure: time, ratio, activity
percentage, or international normalized
ratio. Hepatology 1996; 24: 13924.
7. Porte RJ, Lisman T, Tripodi A, Caldwell
SH, Trotter JF. The international normalized ratio (INR) in the MELD
Score: problems and solutions. American Journal of Transplantation 2010;
10: 134953.
8. Trotter JF, Olson J, Lefkowitz J, et al.
Changes in international normalized
ratio (INR) and model for end-stage
liver disease (MELD) based on selection of clinical laboratory. American

14.

15.

16.

17.

18.

19.

20.

Journal of Transplantation 2007; 7:

16248.
Lisman T, van Leeuwen Y, Adelmeijer J,
et al. Interlaboratory variability in
assessment of the model for end-stage
liver disease score. Liver International
2008; 28: 134451.
Arjal R, Trotter JF. International normalized ratio of prothrombin time in the
model for end-stage liver disease
score: an unreliable measure. Clinics in
Liver Disease 2009; 13: 6771.
Kovacs MH, Wong A, MacKinnon K,
et al. Assessment of the validity of the
INR system for patients with liver
impairment. Thrombosis and Hemostasis 1994; 71: 72730.
Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. New
England Journal of Medicine 2011;
365: 14756.
Mallett SV, Sugavanam A, Krzanicki DA,
et al. Alterations in coagulation following
major liver resection. Anaesthesia 2016;
71: 65768.
Lim C, Dokmak S, Farges O, et al.
Reoperation for post-hepatectomy
hemorrhage: increased risk of mortality. Langenbecks Archives of Surgery
2014; 399: 73540.
Tzeng CW, Katz MH, Fleming JB, et al.
Risk of venous thromboembolism outweighs posthepatectomy bleeding
complications: analysis of 5651
National Surgical Quality Improvement
Program patients. Journal of the
Hepato-Pancreato-Biliary Association
2014; 14: 50613.
Ejaz A, Spolverato G, Kim Y, et al.
Defining incidence and risk factors of
venous thromboembolism after hepatectomy. Journal of Gastrointestinal
Surgery 2014; 18: 111624.
Turley RS, Reddy SK, Shortell CK, et al.
Venous thromboembolism after hepatic resection: analysis of 5,706
patients. Journal of Gastrointestinal
Surgery 2012; 16: 170514.
Aloia TA, Geerts WH, Clary BM, et al.
Venous thromboembolism prophylaxis
in liver surgery. Journal of Gastrointestinal Surgery 2016; 20: 2219.
White RH, Zhou H, Romano PS.
Incidence of symptomatic venous
thromboembolism after different elective or urgent surgical procedures.
Thrombosis and Haemostasis 2003;
90: 44655.
Lisman T, Bakhtiari K, Pereboom IT,
et al. Normal to increased thrombin
generation in patients undergoing liver
transplantation
despite
prolonged

2016 The Association of Anaesthetists of Great Britain and Ireland

Editorial
conventional coagulation tests. Journal
of Hepatology 2010; 52: 35561.
21. Mallett SV, Armstrong M. Point-of-care
monitoring of haemostasis. Anaesthesia 2015; 70: 73e26.

Anaesthesia 2016, 71, 611626

22. De Pietri L, Bianchini M, Montalti R,
et al. Thromboelastography-guided
blood product use before invasive procedures in cirrhosis with severe coagu-

lopathy: a randomized controlled trial.

Hepatology 2016; 63: 56673.
doi:10.1111/anae.13480

Editorial
Through a glass darkly ultrasound imaging in obstetric
anaesthesia
The rst descriptions of the use of
ultrasound in clinical anaesthesia
appeared almost forty years ago.
Interest in its role in obstetric anaesthesia developed following a series of
publications in the early 2000s [13].
There continue to be attempts to
develop the areas in which it is used,
with this months issue containing
two papers [4, 5]. Keplinger et al.
performed ultrasound scans at three
lumbar intervertebral levels in pregnant women at four periods during
the course of pregnancy, to more
precisely evaluate the changes in
neuraxial anatomy and thus facilitate
ultrasound-guided epidural anaesthesia [4]. Kristensen et al. compared
the
transverse
and
longitudinal approach to ultrasoundguided identication of the cricothyroid membrane, to determine which
was faster and more successful, utilising a one-hour training program
consisting of e-learning, a lecture

This editorial accompanies an article by

Keplinger et al., Anaesthesia 2016; 71:
66974, and an article by Kristensen et al.,
Anaesthesia 2016; 71: 67583.

and hands-on training. Both

approaches were associated with
high success rates, though it was faster with the transverse approach [5].
Despite the many publications
and signicant research interest, the
evidence that ultrasound is widely
used in obstetric anaesthesia is lacking. A recent UK survey found that
a dedicated ultrasound machine for
the anaesthetists use was present in
less than half of units that
responded, with the main indications being transversus abdominis
plane blocks (56%), vascular access
(52%), and sono-anatomy of the
spine (22%) [6]. A survey of anaesthetists in Canada found that only
21% use ultrasound to guide neuraxial block, but that all routinely
use ultrasound to guide internal
jugular catheterisation [7]. It has
been estimated that it takes in the
region of 15 years for published
research to be implemented in clinical practice [8], so the disparity
between the evidence and its implementation may be related to this
effect. However, the lack of clarity
on what exactly the role of ultrasound is in obstetric anaesthesia is

2016 The Association of Anaesthetists of Great Britain and Ireland

also likely to be a factor. If we

believe ultrasound can improve the
delivery of high-quality obstetric
anaesthesia, we should seek to
dene its role more clearly.

Neuraxial blockade
The areas of obstetric anaesthesia
where ultrasound could be useful
are varied, the rst and most obvious being its use in sono-anatomy
and location of the epidural space.
It is widely recognised that palpation of anatomical landmarks can
be unreliable at determining the
correct vertebral level [9]. Identication of the correct vertebral level
is of particular importance when
performing spinal or combinedspinal epidural anaesthesia to avoid
damage to the conus medullaris
[10]. Ultrasound improves the accuracy when identifying the correct
level of lumbar interspace [11]. A
systematic review and meta-analysis
of ultrasound imaging for lumbar
puncture and epidural catheterisation demonstrated that further
potential advantages of the use of
ultrasound to assist epidural placement include: a reduction in the
617