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1975 2010

Volume 36 • E 20
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• Validation of blood pressure monitors
• Continuous StO2 monitoring in goal-oriented ICU resuscitation
• Novel radiolabelled probes for imaging tumour angiogenesis
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 Editor’s Letter 3 Apr/May 2010

Progress report on the Millenium

Development Goals: must do better
It’s only ten years are on track to reach the MDG objec- approximately one third, the challenge
ago when they were tives for a reduction in maternal mortal- of malaria remains particularly tough:
first pronounced ity although there has been progress in there are still nearly a million malaria
but already they other countries. In the field of infectious deaths per year and access to appropriate Comments
seem to have faded diseases, the picture is also varied. While medication is still inadequate. With five
away into his- there has been a welcome decline in new years still to run till the 2015 deadline, a
on this article?
please feel free to post them at
tory. As part of the HIV infections and TB mortality in non- huge amount of progress still remains to
www.ihe-online.com/comment/MDG
apparently irresistible human reflex not HIV infected patients has dropped by be achieved.
to let an anniversary pass without tak-
ing the opportunity to summarize the
past or to predict the future, the Millen-
nium Development Goals (MDG) were
solemnly adopted in 2000 by no fewer
than 189 different countries, specify-
ing eight global objectives that should
be attained by 2015. Laudable as these
objectives were, there were few details as
to how exactly the objectives were to be
reached, or, even more crucially, where
the necessary investment and resources
would come from. Of the eight MDG
objectives, three were health-related,
namely to reduce child mortality, to
improve maternal health and to combat
HIV/AIDS, malaria and other diseases,
all of which are, of course, easier to say
than do. Since 2000 there have been so
many non health-related crises such
as 9/11, wars, global recession, credit
crunches, etc., not to mention numerous

concept: www.glamlab.it
natural disasters such as tsunamis and
earthquakes, that it is easy to overlook
the particular MDG health goals and the
progress being made to attain them.
Luckily the assiduous statisticians at the

Anywhere,
World Health Organization (WHO)
don’t get distracted and regularly pro-
duce their progress report on how
close we are to achieving the MDG

when (you) need.

goals (www.who.int/topics/millenium_
development_goals). The latest WHO
progress report has just been published
and, although there is some good news,
there is little room for complacency.
The percentage of underweight chil-
dren is estimated to have declined from Cardiovascular diseases are the world’s largest killers, claiming
25% to 16% in 2010, and annual deaths 17.1 million deaths a year*. Over 40% are caused by heart attack
of children under five years of age has in the presence of a witness. Today the defibrillator is one of the
most effective solutions to help save life.
fallen to 8.8 million, but it is estimated
* World Health Organization, Fact sheet No. 317, Sept, 2009
that 104 million children throughout the
world are still under-nourished. Almost Rescue SAM Rescue Life
Public access defibrillator Professional monitor defibrillator
inevitably, however, the global results
mask inequalities between countries
and regions. For example, few develop-
ing countries (some of which have been
www.progettimedical.com
held back by conflict, poor governance,
or humanitarian and economic crises)
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 Apr/May 2010 6 Blood pressure monitoring

ESH-IP for the validation of blood

pressure monitors:
a success story and its future
The validation of blood pressure monitors is an important prerequisite for the accu- (compared to the use of other protocols), the
rate measurement of blood pressure. In the last decade the European Society of main study results, the performance in follow-
Hypertension International Protocol (ESH-IP) has expanded the device validation ing the protocol’s requirements and criteria, the
problems in data reporting, the issues within
procedure worldwide by three to four-fold compared to the period before its origi-
the protocol that might need modification or
nal publication in 2002 and is now the preferred validation protocol. In keeping clarification, and the impact of applying more
with improvements in device technology, the International Protocol was revised, in stringent validation criteria. This analysis, which
2010 and imposes stricter requirements for device accuracy. relies on data from 104 validation studies con-
ducted using the protocol between 2002 (ESH-
IP publication) and 2009, forms the basis for the
by Dr G.S. Stergiou, Dr N Karpettas, Dr N Atkins and Dr E. O’Brien recommendations in the revised ESH-IP [5].

According to the systematic review, within 8

Blood pressure measurement and
protocols for device validation
Blood pressure measurement is widely used
across the healthcare system, by clinicians of
almost all specialties, nurses, medical assistants
and even patients themselves. People with high
blood pressure generally have their blood pres-
sure measured in the office or clinic and because
of the phenomenon of “white coat hyperten-
sion”, such measurements are often falsely ele-
vated, so 24-hour ambulatory blood pressure
monitoring and/or self-monitoring by patients
at home is often recommended [1]. In all cases,
the accuracy of the blood pressure monitor is
therefore an important prerequisite for the reli-
able assessment of the level of blood pressure so
as to enable the accurate diagnosis of high blood
pressure and to enable reliable decision making
and long-term drug treatment [1].
of blood pressure monitors for home, ambula-
tory and office measurements, it was anticipated
that such a simplified protocol would facilitate
greater use of the validation procedure by more
centers throughout the world, thereby facilitat-
ing independent validation of greater numbers
of devices.
Application of the ESH-IP for device
validation (2002-2009)
A systematic review of the use of the ESH-IP
for validating blood pressure measuring devices
was recently performed [5]. The review cov-
ered the number of reported validation studies
years after the publication of the ESH-IP there
were 48 studies reported using the BHS proto-
col, 38 using the AAMI and 104 using the ESH-
IP [5]. In particular, between January 2007 and
June 2009, 29 studies have been reported using
the BHS and/or the AAMI protocols compared
to 67 using the ESH-IP [5]. Thus, it appears
that the ESH-IP has succeeded in expanding
the validation procedure worldwide by three
to four-fold compared to the period before its
publication [5] and now is the preferred vali-
dation protocol. A total of 26 different research
groups performed ESH-IP studies and evaluated
devices from 32 different manufacturers [5].

In 1987 the US Association for the Advance-

ment of Medical Instrumentation (AAMI) pub-
lished the first protocol for formal validation of
all blood pressure monitors against the mercury
standard [2]. This was followed in 1990 by the
British Hypertension Society (BHS) protocol
[3] and revised versions of these protocols were
published in 1993. In 2002, the European Soci-
ety of Hypertension Working Group on Blood
Pressure Monitoring published the International
Protocol (ESH-IP) for the validation of blood
pressure monitors [4]. The ESH-IP was devel-
oped on the evidence of a large number of vali-
dation studies performed using the AAMI and
BHS protocols. The purpose of developing the
ESH-IP protocol was to simplify the validation
procedure and reduce the sample size required
Whether a blood pressure monitor is designed for use by a healthcare professional or by the patient himself,
without losing the evaluation accuracy of the it is vital that the monitor be validated. The European Society of Hypertension
previous more complicated, cumbersome and International Protocol (ESH-IP) is now the most widely used protocol for BP monitor validation.
costly protocols. In the rapidly expanding market The 2010 revision to the protocol tightens the validation criteria

ESH-IP validations have been conducted in 18
countries, the vast majority of them in Europe
(70%), with some in the USA, in China and
elsewhere [5]. Of these studies, 80% validated
oscillometric devices, 80% upper arm devices
(the rest being wrist devices); 65% of devices
were designed for self-home monitoring, 20%
were professional devices for office/clinic use
and 15% were for ambulatory blood pressure
measurement [5].
Interestingly, the proportion of the reported
validation studies that fulfilled the ESH-IP cri-
teria is impressively high (85%) [5]. This suc-
cess might reflect improved accuracy of devices
due to advancement in technology. However,
other reasons are possible, such as a publica-
tion bias whereby negative studies are not pub-
lished, and that the ESH-IP criteria are too easy
to fulfil and need to be made more stringent.
There were also problems in conducting and
reporting some of the ESH-IP validation studies
that make the interpretation of the results rather
questionable. A total of 21 different types of vio-
lations of the ESH-IP were detected, appearing
33 times and involving 23 studies [5]. Twenty
per cent of the violations were regarded as major
(affecting the protocol integrity, requirements
and stringency of criteria), whereas the rest
were minor with negligible impact [5]. Some of
the studies did not provide a complete report of
recruited and excluded subjects and others did
not report the cuff sizes used, particularly for
observer measurements. These findings suggest
that a more standardized report of the validation
study results is necessary.
With the aim of determining which of the ESH-
IP validation criteria were easily passed by the
currently available accurate devices and which
were only marginally passed, several ‘arbitrar-
ily chosen’ changes in all the validation criteria
of the protocol were tested [5]. The impact of
applying these arbitrary criteria on the evalu-
ation of devices that had passed the ESH-IP in
published validation studies was also investi-
gated and helped to decide on which criteria to
tighten in the revision of the ESH-IP.
ESH-IP revision 2010
On the basis of these analyses a revised ver-
sion of the protocol was published in Febru-
ary 2010 [6]. There are several changes in the
revised protocol, regarding participants’ age,
blood pressure limits for inclusion, distribution
of observer blood pressure measurements and
validation results reporting [6]. However, the
most challenging change is the tightening of
the validation criteria for the pass level. It has
been estimated that about one third of valida-
tions that passed the ESH-IP 2002 will not sat-
isfy the criteria of the revised ESH-2010 (Ster-
giou G, et al. unpublished data 2010). Thus, the
7 Apr/May 2010
application of the revised ESH-IP is expected validation of blood pressure measuring devices in
to more than double the validation fail rate. adults. Blood Press Monit 2010;15:23-38.
Indeed it appears that time has come to increase The authors
the level of minimal accuracy requirements for George S. Stergiou1* MD, FRCP,
device approval. First, 85% of the devices tested Associate Professor of Medicine & Hypertension
so far using the ESH-IP have been successful Nikos Karpettas1 MD, Clinical Research Fellow
[5], implying an improvement in current tech- Neil Atkins2 PhD, Statistician
nology of blood pressure monitors (although Eoin O’Brien3 Professor of Molecular Pharmacology
as mentioned above a publication bias cannot
be excluded). Second, a recent analysis of suc- 1
 ypertension Center, Third University Depart-
H
cessful ESH-IP validation studies showed a ment of Medicine, Sotiria Hospital, Athens,
trend towards an improvement in accuracy of Greece.
the electronic devices in the period between 2
dabl Ltd, 34 Main Street, Blackrock, Co. Dublin,
2002-2010, as assessed by their performance in Ireland.
passing several validation criteria (Stergiou G, 3
Conway Institute of Biomolecular & Biomedical
et al. unpublished data 2010). Research, University College Dublin, Ireland.
Conclusions * Corresponding author:
Eight years after its publication, the ESH-IP George S. Stergiou, MD
has proven to be successful in achieving its Hypertension Center
goals. The large number of published stud- Third University Department of Medicine
ies, devices tested, and investigators involved Sotiria Hospital
indicate that the protocol has succeeded in 152 Mesogion Avenue
expanding the validation procedure world- Athens 11527, Greece
wide by three to four-fold compared with the Tel: +30 210 7763117
period before its initial publication. However, E-mail: gstergi@med.uoa.gr
there is a need to tighten the accuracy criteria
so as to encourage the manufacture of better
devices and there is also a need to improve the
Comments on this article?
Feel free to post them at
validation methodology by standardizing the
www.ihe-online.com/comment/ESH-IP
reporting of validation studies. These issues
have been successfully addressed in the 2010
revision of the ESH-IP.
References
1. O’Brien E, Asmar R, Beilin L, Imai Y, Mallion JM,
Mancia G, et al. European Society of Hypertension This disposable
recommendations for conventional, ambulatory Eschmann-style
and home blood pressure measurement. J Hyper-
“bougie” is used
tens 2003;21:821-48.
2. Association for the Advancement of Medical
to guide the
Instrumentation. The national standard of elec- endotracheal
tronic or automated sphygmomanometers. Arling- tube during
ton, VA: AAMI;1987. difficult
3. O’Brien E, Petrie J, Littler W, De Swiet M, Pad- intubations. The
field P, O’Malley K, et al. The British Hypertension tube slides over
Society protocol for the evaluation of automated the introducer
and semi-automated blood pressure measuring which helps to
devices with special reference to ambulatory sys- guide the way,
tems. J Hypertens 1990;8:607-19.
especially
4. O’Brien E, Pickering T, Asmar R, Myers M, Parati
G, Staessen J, et al. European Society of Hyperten-
helpful for
sion International Protocol for validation of blood “blind”
pressure measuring devices in adults. Blood Press intubations.
Monit 2002;7:3-17. straight curved Malleable
5. Stergiou G, Karpettas N, Atkins N, O’Brien E. Euro-
pean Society of Hypertension International Proto-
col for the validation of blood pressure monitors:
a critical review of its application and rationale for
revision. Blood Press Monit 2010;15:39-48. U.S.A. 813-889-9614 • Fax 813-886-2701
6. O’Brien E, Atkins N, Stergiou G, Karpettas N, Parati
G, Asmar R, et al. European Society of Hyperten-
sion International Protocol revision 2010 for the
www.ihe-online.com & search 45555
 Apr/May 2010
Continuous StO2 monitoring in goal-
directed shock and ICU resuscitation
Throughout the years, ICU technology has allowed physicians to obtain reliable
physiological parameters to guide goal-oriented ICU resuscitation. A number of
studies have validated the use of tissue hemoglobin oxygen saturation (StO2) as a
reliable index of tissue perfusion. StO2 monitoring offers a continuous assessment
of the adequacy of ongoing shock resuscitation and aids in early identification of
high-risk patients in septic and hemorrhagic shock.
by Dr Rachel J. Santora and Dr Frederick A. Moore
Near-infrared Spectroscopy (NIRS) has
emerged as a new monitoring tool that is a reli-
able, noninvasive means of continuously meas-
uring tissue perfusion. In this review we sum-
marize our experience with the value of StO2
monitoring in a number of settings including
a) ICU shock resuscitation, b) predicting out-
comes in the emergency department, c) ICU
sepsis resuscitation.
ICU traumatic shock resuscitation
In the 1980s, William Shoemaker wrote a
series of papers addressing the use of physi-
ological monitoring to predict outcome and
assist in clinical decision making [1-3]. He
identified two key variables, oxygen deliv-
ery (DO2) and oxygen consumption (VO2),
as predictors of survival and popularised
“supranormal oxygen delivery” as a resusci-
tation strategy. He proposed that unrecog-
nised flow-dependent oxygen consumption
contributed to the devel opment of multiple
organ failure (MOF) and believed that this
deficit could be corrected by maximising
DO2 [2, 3]. Although, it is now recognised
that resuscitation to achieve supranormal
indices is not beneficial in all patients, the
use of physiological parameters to guide
resuscitation and predict outcomes is central
to all ICU resuscitation.
The introduction of new technology into
intensive care units, including continuous
venous oximetry and continuous cardiac
output monitoring with PA catheters [4] per-
mitted wide spread use of oxygen transport
variables to guide resuscitation. In an effort
to further refine the logic for traumatic shock
resuscitation, surgical intensivists employed
computerised clinical decision support to
prospectively collect data on responders and
nonresponders and optimise resuscitation
strategies. Computerised protocols also pro-
vided the opportunity to test the utility of
various monitors in shock resuscitation, such
8 Patient Monitoring
as the tissue hemoglobin oxygen saturation
(StO2) monitor. Prospective studies utilising
protocol-driven shock resuscitation demon-
strated that changes in skeletal muscle StO2
showed a strong correlation with changes in
DO2, blood base deficit (BD, and lactate. This
observation that the StO2 as an index of per-
fusion that tracks DO2 during active resuscita-
tion led laboratory investigators to explore the
role of StO2 monitors in large animal models
of hemorrhagic shock [5].
In these studies, hemodynamic and NIR
spectroscopic measurements were used to
identify early predictors of irreversible shock.
Measurements of hind-limb StO2 in each
group diverged within 30 minutes of shock,
such that by the end of the 90 minute period,
the StO2 value for unresuscitatable remained
low despite resuscitation. Animals destined
to survive shock and resuscitation did not
exhibit an irreversible decline in StO2. These
The use of modern oxygenation monitors to determine StO2 levels can identify life-threatening conditions before
there are any visible clinical signs.
findings demonstrate that skeletal StO2 is a
reliable, noninvasive means for early differen-
tiation between resuscitatable and nonresus-
citatable animals. Similarly, studies utilising
noninvasive StO2 to guide fluid resuscita-
tion after traumatic shock showed StO2 as
a reliable assessment tool to determine the
adequacy of shock resuscitation in response
to colloids [6].
Taken together these clinical and research
data suggest that StO2 (derived from a non-
invasive monitor) could provide informa-
tion about the effectiveness of resuscitation
equivalent to that of a invasive PA catheter or
serial blood draws to measure base deficit or
lactate levels.
Predicting outcomes in MOF
Post injury Multiple Organ Failure is well
recognized as a significant cause of mortal-
ity following traumatic injury. In an effort to
identify critically ill patients at risk, a number
of studies focused on identifying early pre-
dictors of postinjury MOF [7,8]. Through a
series of studies, investigators determined
base deficit as the earliest independent pre-
dictor of postinjury MOF [9], an observation
that was validated by a number of clinical
studies [10].
With this in mind, Cohn et al decided to per-
form a study using StO2 monitoring in the
 9 Apr/May 2010

emergency room to determine if it could pre-
dict MOF [11]. The group performed a pro-
spective observational study involving seven
US trauma centers evaluating the efficacy of
thenar StO2 as an early predictor of MOF in
major torso trauma patients compared to the
accepted standard (base deficit). StO2 monitors
were placed upon arrival and MOF and death
were the primary outcomes. They determined
that 1) StO2 was equal to base deficit analysis
for predicting MOF development and 2) StO2
out-performed both base deficit and systolic
blood pressure as an early predictor of death
[11]. Subset analysis comparing StO2 levels to
lactate levels also validated StO2 as an early pre-
dictor of death when compared to conventional
parameters[12].
Figure 1
(A)
From these observations, we conclude that
StO2 obtained within the first hour after ED
admission is an equally reliable predictor of
adverse outcomes as the more conventionally
used parameters of lactate and base deficit in a
continuous, noninvasive fashion.
ICU sepsis resuscitation and the role
of the StO2 monitor
In recent years, it has been recognized that
severe sepsis and septic shock are the leading
cause of ICU mortality [13-16]. Recent efforts
have been directed at updating the surviving
sepsis campaign guidelines and improving
early delivery [16]. To assist with consistent
implementation of these interventions, sur-
gical intensivists at the Methodist Hospital in
Houston, TX, USA have developed a compu-
terized clinical decision support application.
To facilitate early identification of sepsis and
facilitate implantation of this support appli-
cation, a three step screening process was
developed to collect physiologic parameters
that characterize the systemic inflammatory
response syndrome (SIRS) and to compile a
SIRS score. If the SIRS score exceeds 4, efforts
are focused on ascertaining presence of an
infection. For patients that are identified as
having sepsis, the computerized clinical deci-
sion support application is utilized to imple-
ment our sepsis protocol and provide a tool
for ongoing assessment.
Our current sepsis protocol is composed of two
distinct phases. Phase one is for management
of simple sepsis; it dictates that the patient get
appropriate cultures, antibiotics, a fluid chal-
lenge and repeat laboratory determinations.
Phase two of our protocol is for septic shock,
which is much more complex and is a data
driven protocol that insures the appropriate
use of fluid resuscitation, inotropes, vasopres-
sors and testing for adrenal insufficiency. In
this setting, we have been using StO2 data and
have found it to provide valuable information
regarding the adequacy of resuscitation.

The following case presentation emphasizes the

ability of StO2 monitoring to detect life-threat-
ening clinical deterioration before derangement
of other physiologic parameters.
Case Report: A 38 year old man who initially
presented with pancreatitic necrosis and retro-
peritoneal abscesses managed with IV antibiot-
ics and percutaneous drainage, was transferred
(B)
24h Sepsis Protocol to our institution after developing severe sep-
24 Hour Sepsis Protocol- First 12 Hours sis from methicillin resistant staphylococcus
aureus (MRSA) bacteremia. Upon arrival in
Physiologic Parameters Interventions
our ICU, we implemented our sepsis proto-
Hour MAP CVP HR StO2 [Hb] LR Hextend PRBCs col and he responded to our sepsis resuscita-
1 103 10 150 58 10.1 1000 tion. Despite improved percutaneous drainage
for source control, he continued to have SIRS,
2 93 11 158 57 1000
characterized by spiking temperatures and
3 77 15 99 51 tachycardia. He remained ventilator depend-
4 77 10 151 61 9.0 1000 1 unit ent and required ongoing dialysis. Based on
5 73 8 140 69 500
repeat CT scans, the left IR drain was upsized
to a chest tube in the ICU for improved source
6 71 9 141 66 7.9 500 1 unit
control. As his SIRS resolved, he was weaned
7 67 11 134 67 250 from the ventilator and his renal failure also
8 67 8 140 68 9.4 250 resolved. The patient was transferred to the
9 69 9 134 71 250
floor with tachycardia and purulent drainage
material from the left chest tube. Repeat CT
10 70 12 117 71
showed resolution of the upper retroperito-
11 69 11 109 72 neal abscesses, however lower retroperitoneal
12 71 12 106 69 9.6 abscesses extending into his scrotum were now
present. After operative drainage and debride-
Figure 1 A & B: Case Report ment of these retroperitoneal fluid collections
StO2 tracings over the first 36 hours of postoperative ICU admission, where the first 24 hours represents
through a bilateral groin retroperitoneal explo-
ongoing resuscitation with our sepsis protocol (A). Physiologic Parameters and Interventions corresponding
with the StO2 tracings above (B); Hour, hour on sepsis resuscitation protocol; MAP, mean arterial pressure; ration, he was readmitted to the intensive care
CVP, central venous pressure; HR, heart rate; StO2, skeletal muscle tissue hemoglobin saturation; [Hb], unit for worsening sepsis and was placed on
hemoglobin concentration; LR, lactated ringers; PRBCs, packed red blood cells. phase II of our sepsis protocol.
 Apr/May 2010 10 Patient Monitoring

Figure 1 illustrates the StO2 tracings over the
first 36 hours, where the first 24 hours repre-
sents ongoing resuscitation with our sepsis
protocol. The patient initially dropped his
StO2 as he became septic, and it rose up to the
70 range over the first 4 hours with ongoing
resuscitation. There was some variability over
the next several hours and then the StO2 value
increased and plateaued and remained con-
stant until the completion of this sepsis pro-
tocol. Following sepsis resuscitation, the StO2
monitor was left in place. That evening the
patient remained persistently tachycardic, his
urine output decreased and his hemoglobin
Figure 1
(A)
concentration decreased from 9.6 to 7.9. Dur-
ing this time he received three 500ml boluses
of isotonic crystalloid. Initially the decrease in
hemoglobin was attributed to hemodilution;
due to his persistent tachycardia, he was given
2 units of packed red blood cells. At 6 am the
next morning the ICU resident examined the
patient, noted the patient to be persistently
tachycardic but with a good MAP and ade-
quate urine output. His dressings were noted
to be nonsanguinous, however, at 8 am, dur-
ing ICU team rounds the dressing was soaked
with blood. The patient returned to operat-
ing room for immediate exploration and was
found to have a small arterial bleeder that was
ligated. Postoperative mesenteric angiogra-
phy confirmed that there was no pseudoan-
eurysm or sources of ongoing bleeding. After
reviewing the StO2 tracing, at approximately 8
pm prior to this event, there was a presumptu-
ous drop in StO2 from 70 down to 35. With
ongoing fluid resuscitation and blood transfu-
sions the StO2 value and went back up to 70
[Figure 2].
However, in the early morning hours, the StO2
number began to drift downwards prior to
recognition of the patient’s ongoing bleeding.
Comparison of the StO2 tracings with other
physiologic parameters shows that the StO2
monitor provides more precise information
regarding the adequacy of resuscitation at spe-
cific points in time. This case is an example of
how the StO2 can provide additional informa-
tion that could help a clinician identify a life
threatening complication long before it is clini-
cally recognized.

Conclusion
In our ongoing experience with ICU resusci-
tation, NIRS or StO2 monitoring offers a con-
tinuous, non-invasive index of tissue perfusion.
Early clinical trials utilizing StO2 monitors dur-
ing active shock resuscitation validated changes
in skeletal muscle StO2 as an index of perfusion
that was equivalent to serial measurements of
base deficit and lactate levels. In the setting of
ICU sepsis we have observed that StO2 responds
to interventions, and may be useful in titrating
vasopressors to avoid excessive vasocontrictors
and for monitoring for significant clinical dete-
24h Sepsis Protocol riorations. We concluded with a case presenta-
(B)
24 Hour Sepsis Protocol- First 12 Hours
tion in which StO2 identified life threatening
postoperative bleeding nearly 12 hours before
Physiologic Parameters Interventions it became clinically evident to the clinicians.
Hour MAP CVP HR StO2 [Hb] LR Hextend PRBCs

1 103 10 150 58 10.1 1000

Competing interests
Dr. Frederick Moore is a member of the Hutch-
2 93 11 158 57 1000 inson Technology Inc. Trauma and Critical
3 77 15 99 51 Care Advisory Board.
4 77 10 151 61 9.0 1000 1 unit
5 73 8 140 69 500
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4. N elson L. Continous Venous Oximetry in Surgical
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Shock. J Trauma 2005, 58: 1119-1125.
6. C rookes BA, Cohn SM, Burton EA, Nelson J,
Proctor KG. Noninvasive muscle oxygenation to
guide fluid resuscitation after shock. Surgery 2004,
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11. C  ohn SM, Nathens AB, Moore FA, Rhee P, Puy-
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Comments on this article?
Feel free to post them at
Guidelines Committee; American Association of
www.ihe-online.com/comment/ST02
Critical-Care Nurses; American College of Chest

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www.ihe-online.com & search 45562
 Apr/May 2010 12
Whole body MRI is highly
accurate in the early detection
of breast cancer metastases
Whole body magnetic resonance imaging
(MRI) should be the imaging modality of
choice for the detection of breast cancer metas-
tases, as it is highly accurate and can detect bone
metastases while a patient is still asymptomatic,
according to a study presented at the American
Roentgen Ray Society (ARRS) 2010 Annual
Meeting in San Diego, CA, USA. Breast cancer
cells commonly spread to the bones, lungs, liver
or brain; metastatic breast cancer tumours may
be found before or at the same time as the pri-
mary tumour, or months and even years later.
The study, performed at Deenanath Man-
geshkar Hospital and Research Center in Pune,
India, included 99 patients with known breast
cancer who were evaluated for metastases
using whole body MRI. Of the 99 patients, MRI
accurately revealed that 47 patients were posi-
tive for metastases while 52 were negative. Of
those patients who were positive for metastases,
whole body MRI frequently detected bone
metastases earlier when the patient was still
asymptomatic. Whole body MRI is an effective
tool for the detection of metastases and unlike
other procedures commonly used in this role,
it emits no radiation.
http://womensimagingonline.arrs.org/
High-pressure jobs increase younger
women’s heart disease risk
A large study of female nurses, published
recently in Occupational and Environmen-
tal Medicine, suggests that high pressure jobs
increase the risk of ischemic heart disease in
women. Previous research has indicated a link
NEWS IN BRIEF
between a demanding job and heart disease
risk, but the findings have been largely confined
to men.
This research assessed the impact of work pres-
sure and degree of personal influence in the
workplace on the heart health of 12,116 nurses,
who were taking part in the Danish Nurse
Cohort Study. The nurses were all aged between
45 and 64 in 1993, when they were quizzed
about their daily work pressures and personal
influence, after which their health was tracked
for 15 years, using hospital records.
By 2008, 580 nurses had been admitted to hospi-
tal with ischemic heart disease, which included
369 cases of angina and 138 heart attacks.
Nurses who indicated that their work pres-
sures were a little too high were 25% more
likely to have ischemic heart disease as those
who said their work pressures were manage-
able and appropriate; those who felt work
pressures were much too high were almost
50% more likely to have ischemic heart dis-
ease. After taking account of risk factors for
heart disease, such as smoking and lifestyle,
the risk fell to 35%, but still remained sig-
nificant. Poor job control in the workplace
did not influence heart disease risk, while
the amount of physical activity at work,
which is known to affect health, had a small
although significant impact. When the find-
ings were analysed by age, only the nurses
under the age of 51 were at significant risk of
heart disease.
In a separate analysis, the researchers looked
at the impact of work pressures on the same
group, but for just five years up to 1998. Nurses
who felt themselves to be moderately pressu-
rised at work were 60% more likely to have
ischemic heart disease while those who said
they faced excessive pressures at work were
almost twice as likely to have it. These findings
held true even after taking account of other
risk factors.
http://www.bma.org.uk/
On-site pathology improves the
inadequacy rate of ultrasound-guided
thyroid biopsies
Having a pathologist on-site during ultra-
sound-guided thyroid biopsies can decrease
the number of repeat biopsies that are often
performed due to an inadequate sample from
the first procedure, according to a study pre-
sented at the ARRS 2010 Annual Meeting in
San Diego, CA, USA.
Requests for ultrasound-guided biopsies for
the diagnosis of thyroid nodules have increased
rapidly in recent years, putting a strain on radi-
ology departments everywhere, according to
Wui K. Chong, MD, lead author of the study.
Unfortunately, there are a number of inadequate
biopsies (where the pathologist deems there is
an insufficient amount of information to make
a diagnosis) that ultimately must be repeated.
Repeat biopsy is unpleasant and inconvenient
for the patient and is obviously wasteful. Hav-
ing a pathologist on-site to review the speci-
men can cut down on the number of patients
returning for repeat biopsy, thus making more
efficient use of resources.
The study compared 200 biopsies that were
performed with a pathologist on-site and 200
that were not. It was found that all other factors
being equal, 13.5 percent of biopsies performed
without a pathologist on-site were inadequate,
compared to only 5 percent that were per-
formed with a pathologist on-site. The authors
thus recommend that radiologists performing
large numbers of thyroid biopsies use on-site
pathology as it may reduce the need for repeat
biopsy by up to 60 percent.
http://womensimagingonline.arrs.org/
Study finds everolimus-eluting
stent safer, more effective than
paclitaxel-eluting stent
Results from the SPIRIT IV clinical trial, which
were first presented at the Transcatheter Car-
diovascular Therapeutics (TCT) 2009 scientific
symposium, were published recently in the
New England Journal of Medicine.
Data from the trial, a large-scale multi-centre
study of nearly 4,000 patients in the US, showed
that everolimus-eluting stents demonstrated
enhanced safety and efficacy in the treatment
of de novo native coronary artery lesions when
compared to paclitaxel-eluting stents. The trial,
which was powered for superiority for clinical
endpoints without angiographic follow up, also
examined the differences in performance of the
two stents in patients with diabetes.
The primary endpoint of the trial was target-
lesion failure (TLF) at one year, a composite
measure of cardiac death, target-vessel heart
attack or ischemia-driven target-lesion revas-
cularization (TLR). Major secondary endpoints

of the trial were ischemia-driven TLR at one
year, and the composite rate of cardiac death or
target-vessel heart attack at one year.
For everolimus-eluting stents, TLF at one
year was 4.2 percent, and for paclitaxel-
eluting stents, TLF was 6.8 percent, a sig-
nificant 38 percent reduction. At one-year,
ischemia-driven TLR was 2.5 percent for
everolimus-eluting stents and 4.6 percent for
paclitaxel-eluting stents, a significant 45 per-
cent reduction. The composite rates of car-
diac death or target-vessel myocardial infarc-
tion through one year were not statistically
different with the two stents (2.2 percent
for everolimus-eluting stents and 3.2 per-
cent for paclitaxel-eluting stents). The one-
year rates of myocardial infarction and stent
thrombosis, however, were also lower with
everolimus-eluting stents than with pacli-
taxel-eluting stents (1.9 percent vs. 3.1 per-
cent for myocardial infarction and 0.17 per-
cent vs. 0.85 percent stent thrombosis). The
results were consistent regardless of lesion
length, vessel size and the number of lesions
treated. However, in the diabetic-patient sub-
group, the study found a comparable rate of
TLF with both stents, whereas in patients
without diabetes, everolimus-eluting stents
reduced TLF by 53 percent compared to
paclitaxel-eluting stents.
http://tinyurl.com/37sfo7s
Outcomes of early vs. late
tracheotomy for mechanically
ventilated ICU patients
Adult ICU patients who received tracheotomy
6 to 8 days vs. 13 to 15 days after mechanical
ventilation did not have a significant reduction
in the risk of ventilator-associated pneumonia,
according to a study published in a recent issue
of JAMA.
Tracheotomy replaces endotracheal intubation
in patients who are expected to require pro-
longed mechanical ventilation. Advantages of
tracheotomy include prevention of ventilator-
associated pneumonia (VAP), earlier wean-
ing from respiratory support and reduction in
sedative use. There is considerable variability
in the time considered optimal for performing
tracheotomy.
Pier Paolo Terragni, M.D., of the Uni¬versita di
Torino, Turin, Italy, and colleagues inestigated
NEWS IN BRIEF 13 Apr/May 2010
whether tracheotomy performed earlier (6-8
days) vs. later (13-15 days) after laryngeal (lar-
ynx) intubation would reduce the incidence of
VAP and increase the number of ventilator-
free and intensive care unit (ICU)-free days.
The randomized controlled trial, performed
in 12 Ital¬ian ICUs from June 2004 to June
2008, enrolled 600 adult patients without lung
infection who had been ventilated for 24 hours.
Patients who had worsening of respiratory con-
ditions, unchanged or worse sequential organ
failure assessment score, and no pneumonia
48 hours after inclusion were randomized to
early tracheotomy (n = 209; 145 received tra- significantly more common in smokers than
cheotomy) or late tracheotomy (n = 210; 119 in non-smokers. These results suggest the need
received tracheotomy). to be aware of nicotine withdrawal syndrome
The researchers found that 30 patients (14 per- in critically ill patients, and support the need
cent) had VAP in the early tracheotomy group for improved strategies to prevent agitation or
and 44 patients (21 percent) had VAP in the treat it earlier”.
late tracheotomy group. The numbers of venti- None of the smokers in the study were
lator-free and ICU-free days and the incidences allowed nicotine replacement therapy (NRT)
of successful weaning and ICU discharge were during the study period. According to du
significantly greater in patients randomized to Cheyron, NRT remains a controversial topic
the early tracheotomy group compared with in intensive care and has been associated with
patients randomized to the late tracheotomy mortality. Due to the serious consequences
group; there were no differences between the of withdrawal-induced agitation, including
groups in survival at 28 days. sedation and physical restraint, the authors
The data show that in intubated and mechani- suggest that the use of nicotine replacement
cally ventilated adult ICU patients with a therapy should be tested by a well-designed,
high mortality rate, early tracheotomy did not randomized controlled clinical trial in the
result in a significant reduction in incidence ICU setting.
of VAP compared with late tracheotomy. http://tinyurl.com/37ko8d5
Although the number of ICU-free and ven-
tilator-free days were higher in the early tra-
cheotomy group than in the late tracheotomy
group, long-term outcome did not differ. Con-
sidering that anticipation for tracheotomy of
1 week increased the number of patients who
received a tracheotomy, and more than one-
third of the patients experienced an adverse
event related to tracheotomy, these data sug-
gest that a tracheotomy should not be per-
formed earlier than after 13 to 15 days of
endotracheal intubation.
www.jamamedia.org
Harm caused by nicotine withdrawal
during intensive care
Nicotine withdrawal can cause dangerous
agitation in intensive care patients. Research-
ers writing in BioMed Central’s open access
journal Critical Care found that, compared
to non-smokers, agitated smokers were more
likely to accidentally remove tubes and cath-
eters, require supplemental sedative, analgesic
or anti-psychotic medications, or need physical
restraints.
Damien du Cheyron, from Caen Univer-
sity Hospital, France, worked with a team of
researchers to study the effects of nicotine
withdrawal in 44 smokers and 100 non-smok-
ers in the hospital’s intensive care unit, finding
that agitation was twice as common in smok-
ers than controls. He said that agitation was
www.ihe-online.com & search 45344
Anesthesiology special
Selection of peer-reviewed literature
on anesthesiology
The number of peer-reviewed papers
covering the vast field of anesthesiol-
ogy is huge, to such an extent that it is
frequently difficult for healthcare profes-
sionals to keep up with the literature.
As a special service to our readers,
IHE presents a selection of key litera-
ture abstracts from the clinical and sci-
entific literature chosen by our edito-
rial board as being particularly worthy
of attention.
An anesthesiologist’s perspective on
inhaled anesthesia decision-making.
The practice of anesthesiology requires com-
plex monitoring, detailed knowledge of phar-
macology, and the ability to make quick deci-
sions about patient management. In the United
States, most general anesthesia involves inhaled
agents. The minimum alveolar concentration
(MAC) of inhaled anesthetic agents, which
anesthesiologists use in dosing these drugs,
can be affected by age, a variety of medications
and other patient-specific factors. MAC can be
thought of as a measure of drug potency. Both
MAC and solubility in blood and tissues differ
among inhaled anesthetic agents. Agents with
low solubility have a rapid onset and offset of
effect and may allow for faster recovery. The
choice among inhaled anesthetic agents may
depend on their solubility, as well as the pro-
pensity to cause airway irritation and coughing,
drug cost and characteristics such as patient
age, obesity and duration of surgery. Anesthesia
care providers’ experience and habits may also
influence drug choice. Emergence delirium
(i.e., agitation) can occur with all three inhaled
anesthetic agents in common use (isoflurane,
desflurane, and sevoflurane). Other potential
issues such as hepatotoxicity and nephrotoxic-
ity are of minimal concern with these agents.
Using low flow rates of fresh gas is one strategy
for minimising inhaled anesthesia costs, but it
is not always feasible.
Prielipp RC. Am J Health Syst Pharm. 2010 Apr
15;67(8 Suppl 4):S13-20.
Risk in anesthesia.
Modern anesthesia is still associated with a risk
of serious complications. This article focusses
on frequency, causes, and prevention of the
most important anesthetic complications. The
article is based on literature identified through
a non-systematic search in Pub-Med, and the
author’s research and experience in this field.
The risk of death associated with anesthesia is
International
hospital
Equipment & Solutions
April / May
closely related to patient age and physical sta-
tus. In otherwise healthy patients (ASA 1), the
risk of such deaths is approximately 1:250 000.
2010
Medication errors occur in approximately 1:1
000 anesthetic procedures. The risk of aware-
ness during general anesthesia is approximately
1:650. Neural injury from epidural and spinal
anesthesia is rare, especially in obstetrics. Ana-
phylaxis caused by muscle relaxant drugs is
Anesthesiology
more common in Norway than in many other
industrialised countries. Pulmonary aspira-
tion occurs in approximately 1:7 000 anes-
Special
thetic procedures, but with low morbidity in
healthy patients. The incidence of anesthetic
accidents is higher in infants than older chil-
dren, and requires special competence. Serious
anesthetic complications are most often related
to the cardiovascular and respiratory system.
The complications are often multicausal, and Paracetamol:
human errors and organisational factors con-
tribute in 50-70 % of the cases. Optimisation
the OTC pain reliever
of the patient’s preoperative health is important becomes a player in
to improve safety. The focus of the anesthesi- operating theatres
ology department should be education and
guidelines. Systems and routines for improved Page 16
safety must also take into account that
human and organisational factors may cause
anesthetic accidents. Anesthesia for
Fasting S. Tidsskr Nor Laegeforen. 2010 Mar
11;130(5):498-502.
cosmetic surgery
Page 18
General anesthesia occurs fre-
quently in elderly patients during
propofol-based sedation and spinal
anesthesia.
This study tested the hypothesis that sedation
in elderly patients is often electrophysiologically
equivalent to general anesthesia (GA). Forty eld-
book reviews
erly patients (>or=65 yrs of age) undergoing hip
fracture repair with spinal anesthesia and propo-
fol-based sedation were observed. In the routine Pediatric
practice group (RP; n = 15), propofol sedation Anesthesiology Review
was administered as usual. In the targeted seda-
tion group (TS; n = 25), sedation was titrated to Page 21
an observer’s assessment of alertness/sedation.
Both patient groups underwent processed elec-
troencephalographic monitoring using bispectral Anesthesia Student
index (BIS) intraoperatively. BIS levels were com-
pared between groups to determine amount of
Survival Guide
surgical time spent in GA (BIS <or= 60). Overall,
13 of 15 (87%) RP group patients and 11 of 25
Page 21
(44%) TS group patients (P < 0.010) experienced
some period of GA. Altering routine practice such
that sedation is titrated to a targeted clinically-
determined sedation level reduces - but does not
eliminate - this incidence.
Sieber FE et al. J Clin Anesth. 2010 May;22(3):
179-83.
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www.ihe-online.com & search 45458

 Apr/May 2010 16 Anesthesiology
Paracetamol : the OTC pain reliever
becomes a protagonist in operating theatres
The new intravenous formulation of paracetamol has transformed the most popu-
lar over-the-counter (OTC) pain reliever into a valuable analgesic option for pain
management in the peri-operative setting. However, more than 100 years after its
original introduction into clinical practice, there are still many questions about the
drug’s mechanism of action, its analgesic efficacy and safety.
by Prof. Flaminia Coluzzi, Dr Giada Nardecchia and Dr Consalvo Mattia
The introduction onto the market of a ready-to- well as which analgesic pathway is principally
use intravenous paracetamol formulation has affected by its administration.
created a new future for a drug that is in fact A commonly posed question is whether para-
more than 100 years old. The new formulation cetamol inhibits cyclooxygenase (COX)
has stimulated interest on the part of anesthe- like nonsteroidal anti-inflammatory drugs
siologists to use paracetamol in the peri-opera- (NSAIDs) or whether its analgesic activity
tive setting. The most popular over-the-counter is due to modulation of other endogenous
pain relieving and antipyretic drug has become pathways. In 1972, Flower and Vane showed
a major protagonist in operating rooms. How- that the anti-pyretic effect of paracetamol
ever, physicians still have many questions and was related to the inhibition of prostaglandin
concerns about its use, its mechanism of action synthetase in the brain. Recent investigations
and its safety profile. showed that paracetamol has no direct affinity
for the active site of COX, but rather acts as a
Is paracetamol a NSAID? — a look reducing agent — by reducing the active oxi-
at its mechanism of action dised form of the enzyme to an inactive form,
Paracetamol, also known as acetaminophen, it blocks the activity of COX. Because COX is
was first synthesised in 1878 but had only lim- sensitive to the local oxidation environment,
ited use until the 1950s, when it was identified which is influenced by a high organic peroxide
as the active metabolite of two well-known concentration such as is found in peripheral
antipyretic drugs, acetanilide and phenacetin, sites of inflammation and in platelets, para-
which were themselves withdrawn from the cetamol is a weak inhibitor of prostaglandin
market for their nephrotoxicity. synthesis. In the central nervous system and
in the endothelial cells, however, where the
Despite its widespread use, the detailed mech- concentration of hydroperoxides is low, para-
anism of action of paracetamol is still poorly cetamol selectively inhibits the enzyme [Figure
understood; questions remain open as to 1]. This explains why paracetamol is not associ-
whether it acts peripherally and/or centrally, as ated with the gastric side-effects and inhibition
of platelet activity traditionally observed with
NSAIDs. However, paracetamol does not have
the anti-inflammatory efficacy of NSAIDs, but
only analgesic and antipyretic activity.
The hypothesis that paracetamol could selec-
tively inhibit a particular isoform of the COX
enzyme, namely COX-3, which is highly
expressed in the brain and in the heart, has
been recently ruled out. COX-3 is just a variant
of COX-1, with a significantly lower potency
(about 1/5th) in generating prostaglandins.
Other possible mechanisms of the analgesic
action have been postulated:
a) Paracetamol interacts with the endogenous
opioid pathways, but it does not bind to opi-
Figure 1. The effect of hydroperoxide concentration oid receptors.
on the action of paracetomol. b) P aracetamol is associated with changes in
the serotoninergic system, the endogenous
descending pain inhibitory pathway, known
as the “analgesic system”.
c) Paracetamol inhibits substance P-mediated
hyperalgesia, by interaction with the nitric
oxide pathway.
d) Paracetamol can indirectly activate cannabi-
noid receptors (CB1) by increasing brain lev-
els of endogenous cannabinoids. One of the
metabolites of paracetamol, namely AM404,
acts as an inhibitor of cellular re-uptake of
anandamide, which is the first recognised
endocannabinoid.
Hepatotoxicity: myth or reality?
Paracetamol is a safe drug when used at the
recommended therapeutic doses. However,
overdose can lead to serious and even fatal liver
injury. This potential hepatotoxicity could still
represent a perceived barrier to its use by some
physicians. Paracetamol is responsible for up to
40% of cases of acute liver failure in the United
States and the United Kingdom.
Damage to the liver following paracetamol
ingestion is not due to the drug itself, but to a
toxic metabolite, namely N-acetyl-p-benzoqui-
nine imine (NAPQI). Once absorbed, approxi-
mately 90% of the paracetamol is metabolised
by conjugation and sulphation, 5% is eliminated
unchanged, and the remaining 5% is oxidised to
form NAPQI. This is quickly combined in the
liver with the endogenous antioxidant, glutath-
ione, to form non-toxic conjugates, which are
eliminated in the urine. After an overdose, when
glutathione stores in the liver become depleted,
free NAPQI begins to accumulate and causes
life-threatening liver injury.
Excluding suicide attempts, unintentional over-
doses constitute at least half of all paracetamol-
related hepatotoxicity cases. The median dose
ingested in subjects who developed acute liver
failure was 24 g, i.e. six times the maximum 4g
daily dosage. Risk factors include excessive dos-
ing (repeated dosing in excess of package label-
ling specified doses, or use of multiple para-
cetamol-containing products), increased P450
activation, simultaneous use or abuse of alcohol
and narcotics, very young age, and comorbidi-
ties including liver disease and depression.
The recommended dose for intravenous paraceta-
mol injection in adults is 1 g every 6 hours. Recent
studies evaluated the efficacy and safety of higher
doses. Serum hepatic aminotransferase activity
remained in the normal ranges, even when up to

8 g/day of paracetamol was used for three days
in healthy young adults. Similarly, in alcoholic
patients treated with 4 g/day for three consecu-
tive days, no increases in serum transaminases
or other measures of liver injury were observed.
The perception that paracetamol should be
avoided in patients with chronic liver disease arose
from the awareness of the association between
massive paracetamol overdose and acute liver
failure. However, the literature supports the use of
paracetamol in patients with liver disease.
Optimal formulation and dose
Different routes of administration have been
extensively studied for the peri-operative use of
paracetamol. With oral administration, a large
variability is observed in individual plasma para-
cetamol levels. Intravenous administration is the
route of choice when oral administration is not
possible or when rapid analgesia is required, such
as in the post-operative setting.
What is the right dose for adequate analgesia?
The minimum plasma paracetamol level required
for analgesia and anti-pyresis is thought to be
10-20 mg/L. However, recent studies have shown
that it is the concentration in of the drug in the
effect compartment, rather than in plasma, that
relates more consistently to the analgesic effect.
It is therefore important to administer the right
dose at the right time in order to reach an ade-
quate concentration in the central nervous sys-
tem — the ready-to-use intravenous formulation
shows the best pharmacokinetic profile for post-
operative pain management. This formulation
penetrates readily into the cerebrospinal fluid and
provides rapid and predictable analgesia in the
post-operative setting.
Paracetamol in adults
In adults, the standard dose of paracetamol is 1g
every 6 hours administered as an intravenous
infusion every 15 minutes. Several studies have
demonstrated that the efficacy of 2g of intra-
venous paracetamol is significantly superior
to 1g. In healthy subjects, the administration
of a 2g starting dose and 5g during the first 24
hours does not change the pharmacokinetics
17
of paracetamol, and the
peak plasma concentra-
tion did not rise above the
toxic threshold. When a
single intravenous dose
of 3g of paracetamol
was administered, no
serious adverse events
were observed, but the
opioid-sparing effect was
similar to that reported
after conventional doses
of paracetamol. In con-
clusion, even though no
hepatotoxicity has been
reported, the administra-
tion of paracetamol at doses higher than 4g daily
is not recommended, since it does not improve
the drug’s analgesic efficacy.
Paracetamol in children
Rectal administration is preferred in children,
even though absorption is slower and more
variable compared with intravenous admin-
istration. Plasma concentrations after admin-
istering 1g paracetamol are 1.2µg/mL for the
rectal route versus 2.7 µg/mL for the oral route.
In children, the analgesic efficacy of rectal
paracetamol increases in a linear manner as the
dose is increased from 0 to 60 mg/kg. However,
rectal doses greater than 30 mg/kg are not rec-
ommended. In pediatric surgical patients, the
recommended dose of intravenous paracetamol
is 15 mg/kg. Precautions must be taken when
using paracetamol in neonates and infants, as
they have an increased risk of forming the reac-
tive intermediate metabolite that causes hepa-
tocellular damage, particularly after multiple
doses. Neonates and infants have an immature
glucuronide conjugation system, and the sul-
phation metabolic pathway is the main route
of metabolism for paracetamol.
Opioid sparing
The opioid-sparing effect of paracetamol,
when used in combination with opioid recep-
tor agonist for multimodal analgesia, is still
controversial. After major surgery, the use of
paracetamol significantly reduced morphine
use by approximately 20%, compared to 40%
with NSAIDs, and 25% with COX-2 inhibi-
tors. However, it did not change the incidence
of morphine-related adverse events during the
post-operative period. A meta-analysis proved
that adding an NSAID may increase the anal-
gesic efficacy of paracetamol, but their combi-
nation does not provide a better analgesic effect
than NSAID alone.
Paracetamol in combination with
other drugs
Paracetamol is also available in fixed combina-
tions with other molecules, such as codeine, tra-
madol and oxycodone, for oral administration
Apr/May 2010
only. These formulations have proved effective
for post-operative pain management, especially
in day-surgery, where analgesia must be pro-
vided at home. Combining drugs from different
classes with different modes of action may offer
the opportunity to optimise efficacy and tolera-
bility, by using lower doses of each drug to reach
a similar degree of pain relief. After orthopedic
surgery, a paracetamol/tramadol combination
(325 mg/37.5 mg) showed an analgesic efficacy
significantly superior to placebo and compara-
ble to that obtained with codeine/paracetamol,
with better tolerability and a lower incidence
of constipation.
Conclusion
In conclusion, paracetamol is a safe and effec-
tive centrally-acting analgesic for acute and
chronic pain management. The multiple inter-
actions with different endogenous systems
(cyclooxygenase, opioid, serotoninergic, nitric
oxide, and endocannabinoid pathways) make
it difficult to identify the exact mechanism of
action of the molecule. Its role in the peri-oper-
ative setting has been widely demonstrated.
Advantages compared to traditional NSAIDs
are the lack of gastrointestinal side effects and
low interaction with platelet aggregation.
References
1. M
 attia C, Coluzzi F. What anesthesiologists should know
about paracetamol (acetaminophen). Minerva Aneste-
siol 2009; 75: 644-53
2. Oscier CD, Milner QJ. Peri-operative use of paracetamol.
Anaesthesia 2009; 64: 65-72
3. Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R,
Leone S. Paracetamol: new vistas of an old drug. CNS
Drug Reviews 2006; 12: 250-75
4. Elia N, Lysakowski C, Tramer MR. Does multimodal
analgesia with acetaminophen, nonsteroidal antiinflam-
matory drugs, or selective cyclooxygenase-2 inhibitors
and patient-controlled analgesia morphine offer advan-
tages over morphine alone? Anesthesiology 2005; 103:
1296-304
5. Remy C, Marret E, Bonnet F. Effects of acetaminophen
on morphine side-effects and consumption after major
surgery: meta-analysis of randomized controller trials.
Br J Anesth 2005; 94: 505-13
6. Mattia C, Coluzzi F, Sarzi Puttini P, Viganò R. Paraceta-
mol/Tramadol association: the easy solution for mild-
moderate pain. Minerva Med 2008; 99: 369-90
The authors
Flaminia COLUZZI, M.D, Giada NARDEC-
CHIA, M.D. and Consalvo MATTIA, M.D.
I.C.O.T. – Polo Pontino
Department of Anesthesiology, Intensive Care
Medicine and Pain Therapy
Sapienza University of Rome, Rome, Italy
Corresponding author:
Prof. Flaminia COLUZZI
Research Associate Professor
Via India, 7 – 00196 Rome, Italy
E-mail: flaminia.coluzzi@uniroma1.it
 Apr/May 2010 18 ANESTHESIOLOGY

Anesthesia for cosmetic surgery

The number of patients undergoing cosmetic surgery is steadily increasing as the Pre-operative care
surgical procedures themselves become more advanced and less invasive. How- Prior to the induction of anesthesia, an intra-
ever, just as patients undergoing cosmetic surgery are generally well informed venous line is inserted for administration
of medications. The American Society of
regarding the nature of the procedure and the reputation of their surgeon, they
Anesthesiology (ASA) has outlined a stand-
frequently overlook the importance of the anesthetic technique needed to effec- ard for which monitoring devices should be
tively perform the procedure. An overall successful procedure involves not only a used during outpatient general anesthesia.
plastic surgeon skilled in cosmetic surgery but also an anesthesiologist proficient These include a continuous electrocardio-
in cosmetic anesthesia. This article reviews the principal aspects to be considered gram (EKG), a cycling blood pressure cuff,
in the anesthesiology of cosmetic surgery. a pulse oximeter for oxygen saturation meas-
urements, an end tidal carbon dioxide moni-
tor, and a temperature probe. A constant sta-
by Dr Peter J. Taub and Dr Laurence Hausman ble blood pressure in the low-normal range
for the duration of the cosmetic procedure is
desirable to minimize blood loss and bleed-
The American Board of Plastic Surgeons most appropriate since it covers all foods ing into the tissues that could contribute to
(ABPS) recently reported that more than 11 and liquids. prolonged postoperative ecchymosis and
million cosmetic procedures were performed edema. Compression boots should be placed
last year in the United States [1]. Many expect It is common for patients to feel anxiety and prior to the induction of general anesthe-
this number to rise as plastic surgery proce- apprehension before surgery.A preoperative ben- sia to prevent the incidence of deep venous
dures become more advanced and less inva- zodiazepine, such as alprazolam or lorazepam, is thrombosis [4]. A bladder catheter is rec-
sive. Largely because of meticulous preop- suitable because in addition to inducing somno- ommended for cases longer than four hours
erative screening and technological advances lence, this class of drug is also associated with to safely manage fluid resuscitation and
in outpatient anesthesia for elective cosmetic anxiolysis. In fact, many plastic surgeons treat to keep the bladder decompressed during
surgery, morbidity and mortality resulting preoperative anxiety prophylactically. abdominal procedures.
from outpatient anesthesia are rare [2].

Pre-hospital care
Patients should be medically optimized
before receiving any type of anesthetic. In
preparing for surgery, the American Society
of Anesthesiologists has developed a Physi-
cal Status Score (ASA PS) that places patients
into one of six categories. Class I (completely
healthy) or Class II (mild controlled illness or
disease with no interference to the patient’s
daily life) patients are generally deemed suit-
able for cosmetic surgery, while a Class III
patient would most likely need additional
assessment before being cleared for such
procedures. In addition to a thorough history
and physical exam, laboratory screenings
are often required. Commonly ordered tests
include hemoglobin and hematocrit, electro-
lytes, blood glucose, urinalysis, an electro-
cardiogram (EKG) and a pregnancy test for
women within child-bearing age.

Prior to surgery, the American Society of

Anesthesiologists Task Force on Preopera-
tive Fasting recommended a minimum fast-
ing period for clear liquids of two hours and
a minimum of six hours for milk or a light Although there are currently more cosmetic surgical and nonsurgical procedures performed in the
meal. They further recommended a fast- United States than in Europe, the inevitable tendency is that the Europe follows the practices carried out
ing period of eight hours for patients who in the United States. The statistics above show the dramatic increase in procedures carried out
over the decade prior to 2008 (latest data available).
have ingested any meal containing fried or
It can be seen that breast augmentation and lipoplasty remain the most common cosmetic surgical procedures.
fatty foods [3]. Since it is easiest and safest For each surgical procedure it is estimated that there are four non-surgical procedures or minimally invasive
to adopt a single “nothing by mouth” rule procedures. These include Botulinum Toxin A ( so-called Botox), soft tissue peelers, chemical peel,
prior to elective surgery, eight hours is the microdermabrasion and laser hair removal.
 19 Apr/May 2010

The temperature of the operating
room is a vital consideration when
planning a surgical procedure.
Due to the vasodilatory nature
and the direct inhibition of the
hypothalamus caused by many
anesthetic agents, all patients are
susceptible to hypothermia during
surgery. Consequences of this can
be platelet dysfunction and bleed-
ing, enzymatic inactivity, cardiac
dysfunction, or postoperative
shivering [5]. Hence, the ambi-
ent temperature of the operating
room should be kept at a tempera-
ture that minimizes body heat loss
and a warming blanket be used for
available antiemetics to minimize
PONV. Granisitron and Ondanset-
ron are serotonin antagonists that
reduce the autonomic neuro-activ-
ity in the vomiting center of the
brain. Dexamethasone, a steroid,
and Scopalamine, a tropane alka-
loid, may both be used to resolve
dizziness and nausea. Additionally,
metochlopromide and Amend,
a newer antiemetic, are increas-
ingly being used. Combination
therapy using several antiemetics
is advisable for patients that have
a high risk of PONV, including
young women and non-smokers
who have a history of PONV
or car-sickness.
General anesthesia
General anesthesia is defined as
the controlled state of uncon-
sciousness accompanied by a loss
of protective airway reflexes [6].
With this type of anesthesia, the
patient may require respiratory
or cardiovascular support. The
insertion of an endotracheal tube
or laryngeal mask airway (LMA)
that sits just above the vocal cords
after induction will allow control
of ventilation. For procedures that
do not involve frequent head turn-
ing, the LMA provides a safe alter-
native to the ETT since it does not
risk vocal cord injury and has less
of an incidence of postoperative
laryngeal irritation and “bucking
on the tube” [7]. However, since
the LMA does not occlude the tra-
chea, a traditional ETT should be
used for patients at high risk for
aspiration.
General anesthesia can be divided
into three phases: induction

Professionals
longer procedures.

It is believed that a patient’s state

Demand
on induction (i.e. when the patient
loses consciousness) mirrors that
of emergence (i.e. when the patient
regains consciousness). Accord-
ingly, a smooth induction with the Best
in Medical
minimal hypertension and tachy-
cardia is desirable for cosmetic
anesthesia. Prior to induction,
the anesthesiologist should con-
sider giving several medications.
Midazolam, a short-acting benzo-
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diazepine, can produce sedative-
hypnotic effects or can even induce
anesthesia at very high doses. It is
also characterized by its ability to
cause amnesia, hypnosis, and the
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Postoperative nausea and vomit-

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 Apr/May 2010 20
(loss of consciousness); maintenance (i.e.
when unconsciousness is maintained dur-
ing the procedure), and emergence (regaining
of consciousness).
Drugs for anesthesia induction
Various drugs can be used for the induction of
general anesthesia. One commonly used agent
is propofol, a short-acting intravenous drug
used in adult and pediatric patients. It may
also be utilized during the procedure for the
maintenance of anesthesia. Side effects include
hypotension and apnea, as well as pain on injec-
tion, which can be ameliorated by pretreatment
with intravenous lidocaine [8]. Propofol is
often used for cosmetic procedures because it
is associated with reduced PONV and can even
be used as an antiemetic. Thiopental, another
induction agent, is a barbituate that affects fine
motor skills and is notorious for producing a
heavy “hangover” effect and significant PONV
[9]. Midazolam and ketamine can also be used
for induction, although they are associated
with a longer recovery time postoperatively.
Ketamine, a phencyclidine derivitive, is an
anesthetic agent approved for human and vet-
erinary use, whose popularity in the outpatient
arena has increased over the past several years.
Its effects include analgesia and sedation with
minimal to no respiratory depression. However,
hallucinations, hypertension, increased intrac-
ranial pressure and salivation have limited its
appeal. It has been used successfully with pro-
pofol and midazolam for cosmetic procedures
since it may be used without the need for
endotracheal intubation, supplemental oxygen,
or narcotics [10, 11].
Drugs for anesthesia maintenance
The choice of drugs used to maintain anesthe-
sia is also important to minimize PONV and
allow for a rapid recovery process. Nitrous
oxide is commonly used as an inhalational
agent to maintain anesthesia. Its use reduces
the need for higher concentrations of the
volatile inhalational agents for maintenance
of anesthesia. It is, however, associated with
PONV and should be limited to concentra-
tions under fifty percent, especially in patients
with evident coronary disease [12].
Isoflurane is one of a number of volatile inha-
lation agents commonly used for maintenance
of anesthesia. Desflurane is a shorter acting
member of this class of drugs and may be
more suitable for cosmetic surgery. However,
desflurane often causes postoperative respira-
tory irritation and coughing largely due to its
pungent smell. Sevoflurane is better tolerated
than desflurane since it lacks a characteris-
tic odor. As a result of the lower solubility of
these newer volatile agents, cognitive func-
tions return to baseline more rapidly when
compared to inhaled isoflurane.
ANESTHESIOLOGY
Continuous intravenous anesthetics are com-
monly employed in cosmetic surgery. Propofol,
remifentanil, dexmetatomidine and ketamine
are among the most commonly used. Remifen-
tanil may be used just prior to induction to
suppress the autonomic responses to intu-
bation and during maintenance to suppress
other autonomic responses to surgical stimuli.
Because it is also a short acting narcotic, it is
ideal for the end of the procedure since it is a
potent cough suppressant. However, like all nar-
cotics it can cause PONV [13]. Ketamine, like
Propofol, can be used for both induction and
maintenance, though it is often associated with
an increase in blood pressure and salivation, as
well as bad hallucinations. Fortunately, it is not
associated with PONV.
...Patients about to undergo
cosmetic surgery should
be medically optimized
before receiving any type of
anesthetic. A Physical Status
Score (ASA PS) developed by
the the American Society of
Anesthesiologists can help to
determine whether the patient is
suitable for cosmetic surgery...
Emergence
The ideal emergence from anesthesia follow-
ing cosmetic surgery should not increase blood
pressure or heart rate, lead to “bucking” from
irritation of the endotracheal tube, or have
any respiratory complications [14]. While the
concentration of inhalational and intravenous
anesthetics are lowered to allow the patient
to regain consciousness, additional medica-
tions are administered to restore muscle activ-
ity and allow the patient to breathe spontane-
ously to permit extubation. Maneuvers that are
particularly stimulating, such as nasogastric
decompression or suctioning, are done while
the patient is still deeply sedated to prevent
hypertension and gagging. Patients should be
reminded as they emerge from anesthesia that
they may have blurred vision due to the oint-
ment and should be prevented from attempting
to rub their eyes.
Monitored anesthetic care
Most patients associate surgery with general
anesthesia but other forms of anesthesia exist
along the spectrum of choices for intraoperative
sedation/analgesia and are effectively utilized
for such procedures. Monitored anesthesia care
(MAC) may be offered to patients undergo-
ing compatible procedures. In this technique,
a combination of local anesthetic and intrave-
nous analgesic and sedative drugs produces a
“minimally depressed level of consciousness
that retains the patient’s ability to maintain an
airway independently and continuously and to
respond to physical stimuli and verbal com-
mands” [15, 16]. This anesthetic technique is
often referred to as “conscious sedation” and
the patient will be sedated so as to not feel any
pain or have any keen sense of environmental
awareness. However, unlike in general anesthe-
sia where unconsciousness is induced and
spontaneous respiration is depressed, patients
will continue to breathe on their own.
Monitored anesthetic care has been shown to be
effective and safe in large study populations [17,
18 , 19]. Typically, a combination of two or more
medication types is used to achieve the desired
level of sedation and analgesia. Commonly used
agents include rapid acting opioids, such as fen-
tanyl, and sedatives, such as midazolam, and
propofol [20, 21].
Postoperative care
Anesthetic care does not end once the patient
is restored to consciousness. Patients must be
closely monitored postoperatively for signs
and symptoms of hypoxia, hypertension, pain,
PONV and even unconsciousness. A patient
may be discharged once an assessment of
home readiness test is conducted to ensure
that their vital signs are stable, to make sure
they are environmentally aware, and to make
sure they can walk without falling or becom-
ing excessively dizzy [22]. Patients are also
evaluated for pain, PONV, and bleeding at
the surgical site. Most delays in discharge are
due to pain, PONV, hypotension and dizzi-
ness upon ambulating [23]. All patients require
analgesia postoperatively and some may
require stronger medications than acetami-
nophen or NSAID type drugs as part of their
postoperative regimen.
Patients undergoing cosmetic surgery are
generally well informed regarding the nature
of the procedure and the reputation of their
surgeon, but overlook the importance of the
anesthetic technique needed to effectively
perform the procedure. A successful proce-
dure involves both a plastic surgeon skilled
in cosmetic surgery and an anesthesiologist
proficient in cosmetic anesthesia.
References
1. “2000/2005/2006 National Plastic Surgery Statis-
tics.” American Society of Plastic Surgeons (ASPS)
www.plasticsurgery.org/
2. “Overall risk of ambulatory anesthesia morbidity
and mortality” In: Miller’s Anesthesia 6th Edition.
Churchill Livingstone, 2004, p. 2234.
 21 Apr/May 2010

3. Practice guidelines for preoperative fasting and Analgesia by Non-Anesthesiologists. Anesthesi-

the use of pharmacologic agents to reduce the risk ology 2002; 4,1004.
of pulmonary aspiration: Application to healthy 17. Bitar G et al. Plast Reconstr Surg 2003;
patients undergoing elective procedures. Anesthe- 111, 150.
siology. 1999; 90, 896-905. 18. Kryger ZB et al. Plast Reconstr Surg 2004;
4. Okuda Y et al. Surg Endosc. 2002; 5: 781-4. 113, 1807.
5. Rundgren M et al. Anesth Analg. 2008 Nov;107(5): 19. Marcus JR et al. Plast Reconstr Surg
1465-8. 1999;104(5):1338-1345.
6. N ique, TA. “Ambulatory Office General Anesthe- 20. Cinella G et al. Plast Reconstr Surg. 2007; 119(7):
sia.” In: Anesthesia for Facial Plastic Surgery. New 2263-2270.
York: Thieme Medical Publishers, 1993. 21. Yoon HD et al. Plast Reconstr Surg 2002;
7. Cork RC et al. Anesth Analg. 1994; 79: 719-27. 109, 956.
8. Maleck, Mattinger, Piper, Rohm, Papsdorf and 22. “Assessment of home readiness” In: Miller’s
Boldt “Dolasetron reduces pain on injection of Anesthesia 5th Edition. Churchill Livingstone,
propofol.” Anasthesiol, Intensivmed, Notfallmed, 2000, p. 2232.
Schmerzther. [German].2004; 37: 528-31. 23. “Delays in discharge” In: Miller’s Anesthe-
9. “Thiopental produces hangover-like effect” In: sia 5th Edition. Churchill Livingstone, 2000,
Miller’s Anesthesia 5th Edition. Churchill Living- p. 2232.
stone, 2000, p. 2224.
10. Friedberg BL. Dermatol Surg 1999; 25:569. The authors
11. Friedberg BK. Aesthetic Plast Surg 1999; 23:70. Peter J. Taub MD, FACS, FAAP Monitor Your Costs While
12. Moffitt EA et al. Can Anaesth Soc J. 1983; 30: and You Monitor Temperature
5-9. Laurence Hausman, MD
13. E  gan TD et al. Anesthesiology. 1993; 79(5):881- Division of Plastic and Reconstructive Surgery
with Crystaline®
92 and
14. K  oga K et al. Anaesthesia 1998; 53(6): 540-4. Department of Anesthesiology
15. “MAC” In: Miller’s Anesthesia 5th Edition. Mount Sinai Medical Center
Churchill Livingstone, 2000, p. 2230. New York, New York, USA
16. T  ask Force on Sedation and Analgesia by Non- U.S.A. 813-889-9614 • Fax 813-886-2701
Anesthesiologists. Practice guidelines for seda-
tion and analgesia by non-anesthesiologists:
Comments on this article?
Feel free to post them at
An updated report by the American Society of
www.ihe-online.com/comment/anesthesia
Anesthesiologists Task Force of Sedation and www.ihe-online.com & search 45554

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1st Edition, 340 p., Softcover, Publ. by Springer, 2010 1st Edition, 515 p. Softcover, Publ. by Springer, 2010

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cians. The book combines astute clinical instruction, basic science explana-
tion and practical tips from physicians that have been there before.

Springer Springer
New York, USA New York, USA
www.ihe-online.com & search 45565 www.ihe-online.com & search 45566
 Apr/May 2010 22 NUClear medicine

Internal radionuclide dosimetry

The development of patient – specific treatment planning systems is of outmost activity is given in the term Ã. Hence all other
importance in the evolvement of radionuclide dosimetry, because the quantifica- terms of the basic equation are lumped in the S
tion of the activity in different organs from planar data is hampered by inaccurate factor, that is:
attenuation and scatter correction as well as by background and organ overlay.
Quantitative three-dimensional nuclear medical imaging can be utilized towards
this direction, allowing a more individualized approach.

by Dr I. Tsougos, Dr P. Georgoulias and Dr K. Theodorou
The energy absorbed per unit mass of tissue, the
absorbed dose, mediates the biologic responses
of radionuclide therapy. Specifically for radio-
nuclide therapy the energy absorbed, E, in a
particular mass of tissue is defined as:
Ε = number of radionuclide disintegrations in
a particular volume X energy emitted per
disintegration of the radionuclide X frac-
tion of emitted energy that is absorbed by
a particular (target) mass [1].
Nevertheless, to state that the absorbed dose
alone would predict the radiobiologic response
of tissue is an oversimplification that would
certainly lead to hypo- or hyper- estimation of
radiation-induced effects.
Currently, nuclear medicine dosimetry is based
on the measurement of the biokinetics of the
radionuclide by serial gamma camera scans,
followed by calculations comprising three steps.
Firstly, the percentage of administered activ-
ity of the radiopharmaceutical must be deter-
mined for the accumulating organs for several
scan times. Secondly, these biokinetic data must
be integrated to obtain the percentage of the
number of decays in the source organs, i.e the
residence times. Thirdly, the radiation absorbed
doses of critical organs must be determined.
The significance of patient
specific dosimetry
In order to understand the limitations, problems,
challenges and research directions of Patient Spe-
cific Dosimetry (PSD), it is useful to consider its
standard clinical practice and compare it with
external beam therapy. Currently, in almost all
PSD treatments the administered activity is fixed;
the clinician empirically modifies it according
to patient characteristics including age, size and
clinical findings [2]. However, clinical studies
have shown that this approach leads to errors in
the order of 30%-100% or even higher. The main
reason for such errors is that the absorbed dose is
not only a function of the administered dose, but
is highly correlated to a number of other factors
that are patient-specific, including both anatomi-
cal and functional variations. It is obvious that no
radiation oncologist or medical physicist would
suggest the same protocol in all patients with a
given type of cancer [3]; Variations in beam type,
energy, beam exposure time, geometry, etc are
decided individually for different patients.
Moreover the radioisotope type defines the par-
ticles emitted by the used radionuclide. The emit-
ted particles can be alpha, beta particles, gamma
rays or a combination. The type of the emitted
particles and their energy is known. However, the
interaction between the particles and tissue is a
statistical process and accurate calculations are
not straightforward. Radiopharmaceutical kinet-
ics gives information about a) where the radio-
nuclide is concentrated, b) in what percentage (at
least theoretically), c) how fast it accumulates in
target organs (both tumors and normal organs)
and d) for how long it remains in these areas [4].
Patient anatomy provides accurate information
about tumor(s) and organs size, as well as possible
non homogeneous areas. Finally, the disease type
plays a critical role in the selection of radiophar-
maceuticals and can affect their kinetic properties.
Patient Specific Dosimetry aims to personalize
the above-mentioned parameters and overcome
the limitations of the standard procedures [5],
resulting in an accurate dose calculation model
that addresses all those issues.
Equation-based dosimetry software
The system that defined medical internal dosim-
etry for many years is the system developed in
1988 by the Medical Internal Radiation Dose
(MIRD) Committee of the Society of Nuclear
Medicine [6]. The equation for absorbed dose
in the MIRD system is as follows:
In this equation, rk represents a target region and
rh represents a source region. The cumulated
The use of the ‘S factor’ approach greatly facili-
tated dose calculations. The S values were initially
calculated based on idealized models of human
anatomy defined as a collection of appropriately
placed distinct organ volumes with mass and
composition that were selected to reflect a typi-
cal or standard human anatomy. These calcula-
tions were performed with very limited compu-
tational power, with the result that there had to
be several simplifying assumptions.
Phantom-based dosimetry software
The MIRD methodology has been utilized by
several groups who develop software in which
the S factors were implemented. The software
known as MABDOSE [7] allows the user to
place spherically shaped tumors within the
simplified anatomic model originally described
by the MIRD Committee. The most widely
used software was the MIRDOSE software
which has had versions 1, 2, 3 and 3.1 [8]. The
code automated, with great success the cal-
culation of internal dose for a large number
(>200) of radiopharmaceuticals in 10 different
anthropomorphic models, until it was replaced
by a newer code called OLINDA/EXM (Organ
Level INternal Dose Assessment with EXpo-
nential Modelling) [9].
Image-based dosimetry software
Imaging plays a critical role since the image
provides personalized anatomical as well as
functional information [5]. The most evident
information that (tomographic) imaging pro-
vides is the location, the size and the volume
of the organs and the tumor. While anatomi-
cal imaging has obvious importance, the func-
tional imaging techniques SPECT and PET pro-
vide complementary information about tracers
kinetics and the functionality of tumors
Furthermore the use of 3D imaging modalities,
such as PET/CT and SPECT/CT has allowed
the use of both tomographic functional data and
anatomical data in the development of patient-
specific nuclear medicine dosimetrical systems.
This is made possible by the increase in compu-
ter processing power and the implementation of
point-kernel or Monte Carlo calculation method-
ologies for the estimation of absorbed fractions.

In order to achieve 3D image based dosimetry,
there are two requisites. The first is a 3D anatomic
imaging study, in order to define the anatomy
and provide tissue density information (e.g CT or
MRI), in conjunction with a 3D imaging of the
radioactivity distribution (e.g. PET or SPECT).
The second requisite is appropriate software that
implements the absorbed fraction calculation
(point kernel or Monte Carlo) in order to estimate
the spatial distribution of the absorbed dose.
Based on the above approach several groups
have sought to contribute to the development
of such software, including the following: the
3D-Internal Dosimetry (3D-ID) code [10], the
RTDS code [11] the DOSE3D code [12] and
the SIMDOS code [13].
Monte Carlo and dose kernel-based
dosimetry software
Monte Carlo (MC)
MC is a widely used tool for the simulation, study
and modeling of several processes that limit accu-
racy of tomographic and planar images [14]. In
dosimetry the role of MC is to provide additional
tools and methods that will improve image quan-
tification, thus increasing the accuracy of func-
tional planar, SPECT or PET images. The main
steps include i) scanner and source simulation ii)
study of scatter distributions, attenuation effects,
collimator penetration etc and iii) incorporation
of all this information in reconstruction probabil-
ity matrix. Especially in attenuation correction,
MC can be used to correlate CT X-ray attenua-
tion coefficients to gamma ray photons attenua-
tion, resulting in improved quantification.
In addition, MC allows the introduction of
advanced phantoms, including patient imaging
data. This leads to advanced correction tech-
niques optimized for human studies and spe-
cific scanners; When scanner geometry is accu-
rately modeled, it is possible to assess the effects
of patient size and injected dose on the system’s
count rate e.g. NECR estimation in PET [15].
Anthropomorphic phantoms and MC simula-
tions are increasingly being used for modeling
heart and respiratory motion. The latter can
severely affect image quantification, especially
in the case of CT attenuation correction [16].
Dose kernels
These are defined as the absorbed dose per decay
at a point r distant from the source. A common
strategy is the MC simulation of a point source in
a homogeneous media, after which the absorbed
dose is calculated using convolution methods [17].
This method assumes a uniform patient body,
although recently CT values were used to define
different regions and dose kernels were calculated
by MC for other materials [18]. Dose is determined
by convolving those kernels with the activity of the
nuclear medicine image in 3D space.
23
The main drawback of the method is the dif-
ficulty of incorporating tissue inhomogene-
ity, even though it is known from anatomical
images. The dose kernel can only be generated
assuming an infinite, homogeneous medium.
In the paper by Loudos et al a method is ana-
lytically described in order to have an accurate
dose estimation that takes into account the CT
information [18]. In that sense the structure of
each patient has to be taken into account. This
information can be obtained by analyzing the
CT image, which provides accurate informa-
tion about anatomy and tissue density, provided
that image values in the CT image are scaled as
Hounsfield units. However it has to be taken
into account that the conversion of Houns-
field units to attenuation coefficients that cor-
respond to different materials is a complicated
and challenging problem.
Conclusion
Internal radionuclide dosimetry still stands
at an early stage of development, although
it has evolved greatly with the development
of the MIRD models and advanced calcula-
tional techniques. The physics of absorbed
dose estimation is improving through active
research in the fields of patient-specific
dosimetry supported by the application
of 3D quantitative imaging. The availabil-
ity of faster and more powerful computers,
improved and accurate Monte Carlo meth-
ods and imaging devices that support both
anatomy and radioactivity tomography (PET/
CT) will push internal dosimetry into a new
era of individualized therapy.
Nevertheless, it has to be noted that the correc-
tion of the images for all effects that degrade
the quantitative content is especially difficult
to achieve for SPECT or PET images obtained
using non-pure positron emitting nuclides
[19]. However, a treatment-planning approach
Apr/May 2010
to radionuclide therapy as in external radio-
therapy will eventually require incorporation
of biologic and radiobiologic considerations
in order to predict response in an individual
patient [20]. Work on this is just beginning.
References
1. Sgouros G. J Nucl Med. 2005 Jan;46 Suppl 1:18S-27S.
2. Flux G et al. Med. Phys. 2006 16 47–59.
3. Siegel JA et al. Cell Mol Biol 2002; 48(5):451-9.
4. Stabin MG et al. Biomed Imaging Interv J 2007;
3(2):e28.
5. Cremonesi M et al. J Nucl Med 2006; 47:1467–1475.
6. Loevinger R et al. MIRD Primer for Absorbed Dose
Calculations 1988 (New York: Society of Nuclear
Medicine).
7. Johnson TK et al. Med Phys. 1999; 26:1389 –1395.
8. Stabin M. J. Nucl. Med. 1996 37 538–46.
9. Stabin M G et al. J. Nucl. Med. 2005 46 1023–7.
10. Kolbert K S et al. J. Nucl. Med. 1997 38 301–8.
11. Liu A et al. J. Nucl. Med. 1999 40 1151–3.
12. Clairand I et al. J. Nucl. Med. 1999 40 1517–23.
13. Dewaraja Y K et al. J. Nucl. Med. 2005 46 840–9.
14. Zaidi H et al. J Nucl Med. 2003 Feb; 44(2):291-315.
15. Watson CC et al. J Nucl Med 2005; 46:1825–1834.
16. Osman MM et al. Eur J Nucl Med Mol Imaging
2003; 30:603–606.
17. Furhang EE et al. Med. Phys. 1996; 23 (5).
18. G Loudos et al. Nucl Med Commun. 2009
Jul;30(7):504-12.
19. G  latting G et al. Nuklearmedizin. 2006;
45(6):269-72.
20. Tsougos I et al. Phys. Med. Biol. 2005; 50 3535-54.
The authors
Ioannis Tsougos1,2, Panagiotis Georgoulias2, Kiki
Theodorou1
Department of Medical Physics and
1
Department of Nuclear Medicine
2
Medical School,
University of Thessaly, Larissa, Greece
 Apr/May 2010 24 NUCLEAR MEDICINE

Radiolabeled probes for imaging of

tumor angiogenesis
Positron Emission Tomography (PET) and Single Photon Emission Computed Tom- peptides have been evaluated as potential radi-
ography (SPECT) are the two radiotracer-based imaging modalities for noninvasive otracers for noninvasive imaging of integrin
depiction and quantification of biochemical processes. The development of ang- αvβ3-positive tumors by SPECT or PET. After a
systematic search, the group in Munich devel-
iogenesis-targeted radiotracers is mainly concentrated on peptides, proteins and
oped a stable 18F-labeled galactosylated cyclic
antibodies which bind to the αvβ3 integrin receptor, vascular endothelial growth pentapeptide ([18F]Galacto-RGD), with a high
factor (VEGF) and its receptor, prostate-specific membrane antigen (PMSA), matrix affinity and selectivity for αvβ3 that accumulates
metalloproteinases (MMPs) and Robo-4. Several ligands targeting these markers specifically in αvβ3-positive tumors and clears
have been tested as a radiotracer for imaging angiogenesis in tumors in animal rapidly via the kidneys. [18F]Galacto-RGD and
models. The potential of some of these tracers has already been tested in cancer [18F]-AH111585 (of which the core peptide
sequence was originally discovered from a
patients. In this article we present a brief overview of the imaging probes cur-
phage display library as ACDRGDCFCG), are
rently used for noninvasive visualization using PET and SPECT of αvb3 and VEGF currently under clinical investigation. Recently,
expression is given. a 99mTc-labeled RGD-containing peptide
(NC100692) was evaluated in ischemic models
by Dr I. Dijkgraaf and Dr O. C. Boerman and showed high uptake in areas of neovascu-
larization with αvβ3 integrin overexpression.
In these models it was shown that NC100692
Introduction expressed on normal quiescent endothelial bund to αvβ3-expressing endothelial cells in the
Angiogenesis, the formation of new blood cells, but significantly upregulated on activated regions of angiogenesis.
vessels from existing ones, is an essential endothelial cells during angiogenesis. In addi-
process if solid tumors are to grow beyond tion, αvβ3 is expressed on the cell membrane of Clinical studies
2 to 3 mm3, since diffusion is no longer suf- various tumor cell types such as: ovarian can- [18F]Galacto-RGD was the first radiotracer
ficient to supply the tissue with oxygen and cer, neuroblastoma, breast cancer, melanoma, applied in patients and could successfully
nutrients. Tumor-induced angiogenesis is among others. image αvβ3 expression in human tumors with
a complex multistep process that follows a good tumor-to-background ratios. It has been
characteristic cascade of events mediated This integrin interacts with the arginine-gly- shown that molecular imaging in humans of
and controlled by growth factors, cellular cine-aspartic acid (RGD) amino acid sequence αvβ3 expression using [18F]Galacto-RGD cor-
receptors and adhesion molecules. Based on present in extracellular matrix proteins such as related with αvβ3 expression as determined by
a balance between pro-angiogenic and anti- vitronectin, fibrinogen, and laminin. immunohistochemistry. In another study, the
angiogenic factors, a tumor can stay dormant tracer uptake of [18F]FDG was compared with
for a very long time period until the so-called Several research groups have investigated the that of [18F]Galacto-RGD in patients with
“angiogenic switch” occurs. In most tissues potential of RGD-containing peptides to target non-small cell lung cancer (NSCLC, n=10)
tumors can only grow to a life threatening with gamma- or positron-emitting radionu- and various other tumors (n=8). It was found
size if the tumor is able to trigger angio- clides αvβ3 expressed in tumors [Table 1]. Over that [18F]FDG uptake in tumor lesions did
genesis. In tissues with high vessel densities the past decade, many radiolabeled cyclic RGD not correlate with [18F]Galacto-RGD uptake.
(e.g. liver, brain, among others), tumors may
also progress via angiogenesis-independent
Isotope Half-life (h)
co-option of the pre-existent vasculature.
γ-emitter (SPECT) 99mTc 6.02
Inhibition of angiogenesis is a new cancer treat-
ment strategy that is now widely investigated 111In 67.2
clinically. Researchers have begun to search
for objective measures that indicate pharma- 123I 13.0
cological responses to anti-angiogenic drugs.
Therefore there is a great interest in techniques 125I 59.4 days
to visualize angiogenesis in growing tumors β+-emitter (PET) 18F 1.83
noninvasively. During the past decade several
markers of angiogenesis have been identified 11C 20.4 min
and specific tracers targeting these markers
have been developed. 64Cu 12.9

The αvβ3 integrin receptor 68Ga 1.14

The αvβ3 integrin is a transmembrane pro-
tein consisting of two non-covalently bound 124I 100.3
subunits, α and β. Integrin αvβ3 is minimally Table 1. Half-life of several radionuclides for SPECT or PET. Half-life is given in hours unless stated otherwise.
 25 Apr/May 2010

These results showed that αvβ3 expression and

glucose metabolism are not closely correlated
in tumor lesions and consequently [18F]FDG
cannot provide similar information as [18F]
Galacto-RGD [Figure 1].

The second radiotracer which was applied

in patients was 99mTc-NC100692. A clinical
study was performed to provide an initial
indication of the efficacy and safety of imag-
ing malignant breast tumors. Nineteen out of
22 tumors were detected with this radiotracer.
In an additional study, integrin scintimam-
mography with 99mTc-NC100692 using a
dedicated γ-camera was performed to inves-
tigate the ability to detect malignant breast
cancer lesions. All patients were known to
have lesions highly suspicious of malignancy.
Dedicated integrin scintimammography
(DISM) detected malignant lesions in seven
out of eight patients with focal uptake in all
but two tumor lesions. In a subsequent open-
label, multicenter, phase 2a study in late-stage
cancer patients, 99mTc-NC100692 was able to
detect lung and brain metastases from breast
and lung cancer with scintigraphy.

Multimeric RGD peptides
To improve the efficiency of tumor targeting
and to obtain better in vivo imaging properties,
multimeric RGD peptides were synthesized and
characterized. The first cyclic RGD multimers
that were developed, were E[c(RGDfK)]2-based
dimers. Subsequently, the use of E[c(RGDyK)]2-
based dimers labeled with 64Cu or 18F for PET
imaging was reported.
During the last years, various other RGD dim-
ers, tetramers, and even octamers labeled with
different radionuclides have been developed
and studied in vitro and in vivo. Generally, the
results of these studies have demonstrated that
increasing the multiplicity of the peptide can
significantly enhance the integrin αvβ3-binding
affinity of RGD peptides and improve tumor
targeting capability of the radiotracer. In addi-
tion, incorporation of the right spacer between
the RGD motifs can enhance the affinity for
αvβ3 and improve the tumor uptake even fur-
ther. Among mono-, di-, tetra- and octameric
Figure 2. Scintigraphic images of 3 athymic male mice with s.c. LS174T tumors immediately after injection and
at 1, 3 and 7 days p.i. of 111In-bevacizumab (0.9 MBq/mouse, 3 µg/mouse).
Figure 1. [18F]FDG-PET of a patient with non-small cell lung cancer (NSCLC) showed intense tracer uptake in
the lesion (a). PET imaging of αvβ3 integrin expression with [18F]Galacto-RGD showed heterogeneous tracer
uptake in the lesion, with a different pattern compared to the [18F]FDG-PET (b). PET/CT (c) and PET/MRI (T2w)
image fusion (d) are useful for a good correlation of anatomical and biological information.
cyclo(RGDfK)-based peptides, the octamer had anemia, myocardial ischemia and tumor pro-
the highest αvβ3 affinity and usually the high- gression to initiate neovascularization. Via
est tumor uptake. From this point of view, fur- alternative mRNA splicing, the human VEGF-A
ther increase of RGD peptide multiplicity may gene gives rise to four isoforms having 121, 165,
result in formation of oligomeric or polymeric 189 and 206 amino acids (VEGF121, VEGF165,
cyclic RGD peptides with improved integrin VEGF189 and VEGF206, respectively).
αvβ3-binding affinity and tumor targeting effi-
cacy. So far, no radiolabeled multimeric RGD VEGF binds two related receptor tyrosine
peptide have been tested in patients. The stud- kinases (RTKs), VEGFR-1 and VEGFR-2. Both
ies on multimeric RGD peptides have recently receptors consist of seven Ig-like domains in
been reviewed [1]. the extracellular domain, a single transmem-
brane region and a consensus tyrosine kinase
VEGF receptors sequence that is interrupted by a kinase-insert
Vascular endothelial growth factor (VEGF) is a domain. VEGFR-1 binds VEGF with a higher
key regulator of angiogenesis during embryo- affinity compared to VEGFR-2 (Kd : 25 vs.
genesis, skeletal growth and reproductive func- 75-250 pM).
tions. The expression of VEGF is upregulated
by environmental stress caused by hypoxia, Bevacizumab is a humanized variant of the
anti-VEGF-A monoclonal antibody (mAb)
A.4.6.1. Nagengast et al were the first to
demonstrate non-invasive VEGF imaging
using radiolabeled bevacizumab [2]. In their
study, they demonstrated the potential of
89
Zr-bevacizumab and 111In-bevacizumab as
a specific VEGF tracer in nude mice with
human SKOV-3 ovarian tumor xenografts.
At the same time, our group showed specific
imaging of VEGF-A expression using 111In-
bevacizumab in mice with s.c. human colon
carcinoma xenografts LS174T [Figure 2].
Recently, the potential of 111In-labeled beva-
cizumab to image the expression of VEGF-A
 Apr/May 2010 26 NUCLEAR MEDICINE

in tumors was investigated in cancer patients.
In a study in colorectal cancer patients with
liver metastases, the liver metastases in nine
out of 12 patients were visualized with 111In-
bevacizumab. In this study, the liver metas-
tases were resected after scintigraphic imag-
ing allowing further immunohistochemical
analysis. The VEGF-A expression in these
resected liver metastases was determined by
in situ hybridization and by ELISA. Surpris-
ingly, no correlation was found between the
level of antibody accumulation and expres-
sion of VEGF-A.
Cai et al. labeled VEGF121 with 64Cu via DOTA for
PET imaging of VEGFR expression [3]. Small-
animal PET imaging revealed rapid, specific
and prominent uptake of 64Cu-DOTA-VEGF121
in highly vascularized small U87MG human
glioblastoma tumors (high VEGFR expression),
and significantly lower uptake in large U87MG
tumors (low VEGFR expression).
Conclusions
Numerous markers of tumor vasculature have
been identified, but only a few radiotracers of
angiogenesis have been tested clinically. The
most extensively studied marker of angiogenesis
is the integrin αvβ3. For this marker the SPECT- Acknowledgment
tracer, 99mTc-NC100692, and the PET-tracer The authors would like to thank Dr. Ambros J.
18
F-galacto-RGD have been successfully tested Beer at the Technische Universität München
in cancer patients. for providing the PET and the PET/CT-, PET/
MRI images.
Other targets exclusively expressed on acti-
vated endothelial cells may eventually be better The authors
targets for imaging angiogenesis. Dr Ingrid Dijkgraaf and
Dr Otto C. Boerman
In conclusion, a few radiotracers for imaging Department of Nuclear Medicine
angiogenesis in tumors have been tested in Radboud University
humans. The role of these tracers in assessing Nijmegen Medical Center,
the response to anti-angiogenic therapies has Nijmegen,
yet to be assessed. The Netherlands
References Correspondence to:
1. Liu S. Radiolabeled multimeric cyclic RGD pep- Ingrid Dijkgraaf
tides as integrin alpha-v-beta-3 targeted radi- Department of Nuclear Medicine
otracers for tumor imaging. Mol Pharm 2006; 3, Radboud University Nijmegen Medical Center
472-487. PO Box 9101
2. Nagengast WB et al. 89Zr-bevacizumab PET of 6500 HB Nijmegen,
early antiangiogenic tumor response to treat- The Netherlands
ment with HSP90 inhibitor NVP-AUY922. J E-mail: I.Dijkgraaf@nucmed.umcn.nl
Nucl Med. 2010 May; 51(5):761-7. Epub 2010
Apr 15.
3. Cai W et al. PET of vascular endothelial growth
Comments on this article?
Feel free to post them at
factor receptor expression. J Nucl Med. 2006 Dec;
www.ihe-online.com/comment/radiolabels
47(12): 2048-56.

KIMES 2010 fulfils high expectations as global economic

recovery begins
The 26th edition of the
Korean International Medi-
cal and Hospital Equipment
(KIMES) opened in Seoul,
South Korea in mid-March
so becoming for four days
the place to be for leading
international and Korean
The bustling exhibition was complemented by medical and hospital devices
many high level symposia and presentations. and service providers.
Since KIMES first opened in 1980, the show has grown in parallel with the
rapid development and advances of the Korean medical and healthcare
industry. Over the years, KIMES has always tried to ensure that the show
is the “must be” place so that everyone in the industry can gather informa-
tion on advanced medical and healthcare-related items and can share the
latest trends and developments in the sector. As always, there was strong
support from Korean government ministries at this year’s KIMES. The
supporting organisations included the Ministry of Knowledge Economy,
the Ministry of Health, Welfare and Family Affairs, the Seoul Metropoli-
tan Government, and the Korean Food & Drug Administration. Recently,
the Korean government specified the medical industry as the one of the
key leading industries driving the Korean economy in the future, and the
government has accordingly provided a blueprint for the financial and
political backing of the industry. Globalization of the medical and health-
care service industry sector is of particular interest in Korea nowadays; in
the global environment the sharing of information and visions is vital.
The recent global economy downturn has caused severe difficulties
in the entire Korean economy; this only reinforces the need for the
development of new technologies and new markets, which is more
important than ever
Providing a timely vision of the future of the medical industry, KIMES
2010 attracted 1045 exhibitors from 35 countries. Unaffected by today’s
global shifts, the expectation for KIMES to play its role as a platform
for further development of the industry is as high as ever. The organ-
isers of KIMES are confident that tough conditions can yield rare
opportunities of high potential - future success is often founded in
difficult times like the present.
Many Korean medical product providers launched their newly devel-
oped products at KIMES this year. The various exhibit categories at
KIMES this year included: consultation; clinical examination; hospi-
tal accommodation; emergency room equipment; radiology; medical
information systems; surgical equipment; oriental medicine; pharma-
ceuticals, physiotherapy equipment; obesity therapies; general health-
care; ophthalmic and dental equipment; and many others.
In addition, there were more than 40 academic and practical semi-
nars during the 4 days of the exhibition, providing the opportunity for
KIMES visitors to have a chance to listen to or participate in high level
discussion and perspectives and insights on emerging trends.
The 27th edition of KIMES will take place in Seoul, Korea in March 2011.
scientific literature review: hospital management
On this page IHE presents a few key
abstracts from the clinical literature
about hospital management, selected
by our editorial board.
Computerised physician order
entry as a new technology for
patients’ safety.
Concern about patient safety is a priority in the
quality policy of health systems. In the phar-
macotherapeutic process, from prescription
to administration of drugs, failures that cause
unwanted effects in patients may occur. This
is especially common in patients with multi-
ple pathologies and polypharmacy, common
in medical specialities services. It is essential to
analyse and identify the causes that trigger med-
ical errors to prevent their occurrence. In this
context, computerised physician order entry is
an attractive tool for ensuring patients safety.
Villamañán E, Herrero A, Alvarez-Sala R. Med Clin
(Barc). 2010 Apr 29.
Different usage of the same
oncology information system in two
hospitals in Sydney - lessons go
beyond the initial introduction.
The experience of clinicians at two public hos-
pitals in Sydney, Australia, with the introduc-
tion and use of an oncology information system
(OIS) was examined to extract lessons to guide
the introduction of clinical information systems
in public hospitals. Semi-structured interviews
were conducted with 12 of 15 radiation oncolo-
gists employed at the two hospitals. The person-
nel involved in the decision making process for
the introduction of the system were contacted
and their decision-making process revisited. The
transcribed data were analysed using NVIVO
software. Themes emerged included implementa-
tion strategies and practices, the radiation oncol-
ogists’ current use and satisfaction with the OIS,
project management and the impact of the OIS
27
on clinical practice. The hospitals had contrast-
ing experiences in their introduction and use of
the OIS. Hospital A used the OIS in all aspects of
clinical documentation. Its implementation was
associated with strong advocacy by the Head of
Department, input by a designated project man-
ager, and use and development of the system by
all staff, with timely training and support. With
no vision of developing a paperless information
system, Hospital B used the OIS only for booking
and patient tracking. A departmental policy that
data entry for the OIS was centrally undertaken
by administrative staff distanced clinicians from
the system. All the clinicians considered that the
OIS should continuously evolve to meet changing
clinical needs and departmental quality improve-
ment initiatives. This case study indicates that
critical factors for the successful introduction of
clinical information systems into a hospital envi-
ronment were an initial clear vision to be paper-
less, strong clinical leadership and management
at the departmental level, committed project
management, and involvement of all staff, with
appropriate training. Clinician engagement is
essential for post-adoption evolution of clinical
information systems.
Yu P, Gandhidasan S, Miller AA. Int J Med Inform
2010 Jun;79(6):422-9.
A critical appraisal of physician-
hospital integration models.
The economic environment and the current
healthcare debate have prompted a critical reeval-
uation of previous and current physician-hospital
integration models. Even though the independ-
ent, self-employed, private practice, medical staff
remains the most common model, surgical spe-
cialists such as vascular surgeons are increasingly
being employed and integrated into healthcare
delivery systems. The degree of integration varies
from minimal to full integration or full employ-
ment. This review defines the forces driving these
changes and analyses the strengths and weak-
nesses of each employment model from the phy-
sicians’ point of view. Strategies for the success-
ful implementation of a 21st century integrative
employment model are discussed.
Satiani B, Vaccaro P. J Vasc Surg. 2010 Apr;51(4):
1046-53.
Implementing an electronic
change-of-shift report using
transforming care at the bedside
processes and methods.
Bedside nurses are well positioned to make
changes that positively affect operations and
practice. Using Transforming Care at the
Bedside processes and methods, the authors
describe the clinical nurse-led development,
testing and implementation of an electronic
template and process for change-of-shift report.
Outcomes included a reduction in time spent
in change-of-shift reports, reduced end-of-shift
overtime and a more standardised process,
Apr/May 2010
and staff who perceived improved information
quality and were satisfied with the process.
Nelson BA, Massey R. J Nurs Adm. 2010
Apr;40(4):162-8.
Human factors engineering
in healthcare systems:
the problem of human error
and accident management.
This paper discusses some crucial issues associ-
ated with the exploitation of data and informa-
tion about healthcare for the improvement of
patient safety. In particular, the issues of human
factors and safety management are analysed in
relation to exploitation of reports about non-
conformity events and field observations. A
methodology for integrating field observation
and theoretical approaches for safety studies is
described. Two sample cases are discussed in
detail: the first one makes reference to the use of
data collected in the aviation domain and shows
how these can be utilised to define hazard and
risk; the second one concerns a typical ethno-
graphic study in a large hospital structure for the
identification of most relevant areas of interven-
tion. The results show that, if national authorities
find a way to harmonise and formalise critical
aspects, such as the severity of standard events,
it is possible to estimate risk and define audit-
ing needs, well before the occurrence of serious
incidents, and to indicate practical ways forward
for improving safety standards.
Cacciabue PC, Vella G. Int J Med Inform 2010
Apr;79(4):e1-17.
Effect of point-of-care computer
reminders on physician behaviour:
a systematic review.
The opportunity to improve care using com-
puter reminders is one of the main incentives
for implementing sophisticated clinical infor-
mation systems. A systematic review was con-
ducted to quantify the expected magnitude of
improvements in processes of care from com-
puter reminders delivered to clinicians during
their routine activities. The MEDLINE, Embase
and CINAHL databases (to July 2008) were
searched and the bibliographies of retrieved
articles were scanned. Studies were included
in the review if they used a randomised or
quasi-randomised design to evaluate improve-
ments in processes or outcomes of care from
computer reminders delivered to physicians
during routine electronic ordering or chart-
ing activities. The results were that computer
reminders produced much smaller improve-
ments than those generally expected from the
implementation of computerised order entry
and electronic medical record systems. Fur-
ther research is required to identify features of
reminder systems consistently associated with
clinically worthwhile improvements.
Shojania KG et al. CMAJ. 2010 Mar 23;182(5):
E216-25.
 Apr/May 2010 28
Enteroscopy:
yesterday, today and tomorrow
The small bowel is the most difficult segment of the gastrointestinal tract to inves-
tigate. The present review describes the evolution of enteroscopy, from the first
complete enteroscopy in 1971 through the current balloon-assisted and overtube-
guided methods to likely future development directions aiming for enteroscopic
perfection.
by Dr Tom G. Moreels
The wireless videocapsule was released in
2000 and has opened the last ‘black box’ of
the gastrointestinal tract, enabling complete
endoscopic visualisation of the small bowel
[1]. Since then numerous new developments
from various companies have emerged, with
improvements in image quality, number
of images recorded per second and length
of battery life. In addition the software to
read the images is becoming ever faster and
smarter, and newer developments focus upon
the design of an “interventional” capsule ena-
bling tissue sampling, directed medication
delivery and functional evaluation of the
small bowel.
Parallel to the development of the diagnostic
wireless videocapsule, conventional enteros-
copy was also subjected to a new evolution in
order to perform all conventional endoscopic
interventions throughout the small bowel. An
overview of the endoscopic developments to
explore the small bowel is given below.
Yesterday’s enteroscopy
Already in the 1970s complete enteroscopy
using a conventional fibre endoscope was
shown to be possible [2]. By means of the rope-
way method, a long fibre endoscope was pulled
down the gastrointestinal tract after a rope
loaded with a weight travelled from mouth to
anus along with gastrointestinal peristalsis.
The sonde type method involved a long thin fib-
erscope with an inflatable balloon at its distal
tip. The scope was inserted through the nose
into the stomach from where it was further
progressed beyond the pylorus using a con-
ventional endoscope. Then the balloon at the
tip of the fiberscope was inflated to serve as a
bolus that was acted on by intestinal peristalsis
to carry the fiberscope down the small intestine
[3]. Although both the ropeway and sonde type
method were effective to visualise the entire
small bowel, and gave the possibility of tissue
sampling, the procedures were very inconven-
ient and could last several days.
ENdoscopy
In the 1980s intraoperative enteroscopy became
available as a feasible alternative that is still used
today, although it requires a surgical approach
through laparotomy. It can be performed via
the oral route or the anal route but often enter-
otomy is necessary [4]. Because of its invasive-
ness the technique is generally reserved as a
last-choice approach.
At the same time push enteroscopy was devel-
oped during the 1990s and rightfully replaced
the previous inconvenient and invasive
enteroscopy methods [5]. Longer conven-
tional endoscopes were developed to proceed
beyond Treitz’s angulus. Push enteroscopy
allows endoscopic evaluation of the proxi-
mal jejunum through the oral route. Because
of the flexibility of the enteroscope and the
tortuous length of the small bowel, complete
enteroscopy is not possible. The pushing force
used to progress the enteroscope throughout
the small bowel results in stretching of the
jejunum, thus hampering further progress and
causing patient discomfort.
The introduction of a semi-rigid overtube
allows deeper intubation of the jejunum
because it helps to straighten the enteroscope
and avoids jejunal stretching [6]. The use of
an overtube was an important development,
Figure 1: Fujinon Double-Balloon Enteroscope.
leading to a major improvement in insertion
depth and an increase in the yield of push
enteroscopy. However, overtube-guided push
enteroscopy only allows intubation of the
jejunum without complete enteroscopy [7].
Today’s enteroscopy
Although both intraoperative enteroscopy
and overtube-guided push enteroscopy are
still in use, new developments have emerged
which have given rise to improved enteros-
copy performance. The concept of balloon-
assisted enteroscopy is a second major break-
through in the evolution of the endoscopic
disclosure of the small bowel. In 2001 the
Japanese endoscopist Hirohito Yamamoto
revolutionised the concept of overtube-
guided enteroscopy by adding an inflatable
latex balloon at the distal end of the flexible
overtube, allowing better mucosal grip of the
overtube, stabilising its position within the
intestinal lumen. In addition, a second inflat-
able latex balloon was added to the distal end
of the enteroscope. With this self-made dou-
ble-balloon model, he was able to intubate
the entire small bowel through the oral route
[8]. Since 2003 the double-balloon entero-
scope has been commercially available from
Fujinon [Figure 1].
Following the success of double-balloon
enteroscopy, the Olympus company devel-
oped another system of balloon-assisted
enteroscopy that became commercially
available in 2007, namely single-balloon
enteroscopy that is largely comparable to
double-balloon enteroscopy. It consists of a
latex-free balloon-loaded overtube lacking
the balloon at the distal end of the endoscope
[Figure 2].

Figure 2: Olympus Single-Balloon Enteroscope.
Both balloon-assisted methods are based
upon the push-and-pull principle [9]. It is
a stepwise progression of the enteroscope
through the small intestine with the bal-
loon-loaded overtube used as a straighten-
ing device, allowing stable position within
the intestinal lumen. The extra balloon at
the distal end of the endoscope in the dou-
ble-balloon system allows better anchoring
of the endoscope within the lumen, whereas
the single-balloon system allows faster
progression of the endoscope through-
out the small bowel. Both balloon-assisted
methods allow complete intubation of the
small bowel within a reasonable procedure
time, although often a combined approach
through the mouth and the anus is neces-
sary to complete enteroscopy. In addition,
all conventional endoscopic interventions,
ranging from mucosal tissue sampling, local
hemostasis, polypectomy and balloon dila-
tion, can now be performed throughout the
length of the small bowel thanks to balloon-
assisted enterosopy. Moreover, excluded gas-
trointestinal segments after previous small
bowel surgery have come within endoscopic
reach, allowing ERCP procedures in patients
with Roux-en-Y reconstruction of the small
bowel [10]. These important advantages
have led to a rapid spread of both balloon-
assisted enteroscopy systems in endoscopy
suites throughout the world.
A novel alternative balloon-assisted method
is the NaviAid balloon-guided enteroscopy,
developed by Smart Medical Systems and dis-
tributed in Europe by Pentax. It consists of a
standard enteroscope loaded with a stabilising
latex-free inflatable balloon at the distal end
of the endoscope and an advancing balloon-
catheter mounted on the outer perimeter of
the endoscope. The principle is comparable
to double-balloon enteroscopy, without an
overtube. Preliminary results reveal that this
technique allows deep intubation of the small
29
bowel, but complete enteroscopy has not been
achieved [11]. The results of multicenter trials
are awaited in order to determine the true clini-
cal value of this new device.
Next to balloon-assisted enteroscopy, Spirus
Medical adapted the overtube resulting in the
development of the EndoEase discovery small
bowel overtube. This spiral overtube enteroscopy
allows rapid and deep intubation of the small
bowel through the oral route [12]. The endo-
scope remains in a stable position and by rotat-
ing the overtube with its raised helices, the small
bowel is pulled backwards over the endoscope.
It seems to be a feasible, rapid method, however
mucosal and transmural traction lesions have
been reported. Comparative studies between
balloon-assisted enteroscopy and spiral over-
tube-guided enteroscopy are awaited.
...wireless video capsule
endoscopy on the one hand and
balloon-assisted or overtube-
guided enteroscopy on the other,
will remain “yin and yang”
techniques, complementing
each other’s imperfections....
Tomorrow’s enteroscopy
Both wireless video capsule enteroscopy on the
one hand and balloon-assisted and overtube-
guided enteroscopy on the other are undergo-
ing significant development processes, since
no single method is ideal. Although wireless
video capsule enteroscopy allows complete
visualisation of the small bowel without dis-
comfort, it remains a merely diagnostic pro-
cedure with significant level of false negative
results. On the other hand, balloon-assisted
and overtube-guided enteroscopy are invasive
and time-consuming techniques with a lower
chance of complete enteroscopy, allowing all
conventional endoscopic interventions within
the small bowel.
The aims of each of the current develop-
ment activities are a higher yield, reduced
patient discomfort, no complications and
better interventional options, which would
represent the ideal, perfect objective. How-
ever, it is unlikely that both approaches will
ever come together in one final, perfect
endoscopic tool for the investigation and
treatment of small bowel pathology. It looks
as though, over the next few years at least,
wireless video capsule enteroscopy and bal-
loon-assisted and overtube-guided enteros-
copy will remain the “yin and yang” of small
Apr/May 2010
bowel visualisation, perfectly complementing
each other’s imperfections.
References
1. Moreels TG. History of endoscopic devices for
the exploration of the small bowel. Acta Gastro-
enterol Belg 2009;72:335-337.
2. H iratsuka H, Hasegawa M, Ushiromachi K,
Endo T, Suzuki S, Nishikawa F. Endoscopic
diagnosis in the small intestine. Stomach Intes-
tine 1972;7:1679-1685.
3. T ada M, Akasaka Y, Misaki F, Kawai K. Clinical
evaluation of a sonde-type small intestinal fib-
erscope. Endoscopy 1977;9:33-38.
4. B osseckert H, Schramm H, Lungershausen G,
Machnik G. Oral intraoperative enteroscopy for
diagnosis of multiple jejunal ulcers. Endoscopy
1981;13:7-8.
5. F outch PG, Sawyer R, Sanowski RA. Push-enter-
oscopy for diagnosis of patients with gastroin-
testinal bleeding of obscure origin. Gastrointest
Endoscopy 1990;36:337-341.
6. S himizu S, Tada M, Kawai K. Development of a
new insertion technique in push-type enteros-
copy. Am J Gastroenterol 1987;82:844-847.
7. Wilmer A, Rutgeerts P. Push enteroscopy. Tech-
nique, depth, and yield of insertion. Gastroin-
test Clin N Am 1996;6:759-776.
8. Yamamoto H, Sekine Y, Sato Y, Higashizawa T,
Miyata T, Iino S, Ido K, Sugano K. Total enter-
oscopy with a nonsurgical steerable double-
balloon method. Gastrointest Endosc 2001;
53:216-220.
9. G erson LB, Flodin JT, Miyabayashi K. Bal-
loon-assisted enteroscopy: technology and
troubleshooting Gastrointest Endosc 2008;68:
1158-1167.
10. M  oreels TG, Hubens GJ, Ysebaert DK, Op de
Beeck B, Pelckmans PA. Diagnostic and thera-
peutic double-balloon enteroscopy after small
bowel Roux-en-Y reconstructive surgery.
Digestion 2009;80:141-147.
11. Adler SN, Bjarnason I, Metzger YC. New bal-
loon-guided technique for deep small intestine
endoscopy using standard endoscopes. Endos-
copy 2008;40:502-505.
12. Akerman PA, Agrawal D, Cantero D, Pangtay J.
Spiral enteroscopy with the new DSB overtube:
a novel technique for deep peroral small-bowel
intubation. Endoscopy 2008:40:974-978.
The author
Tom G. Moreels
Antwerp University Hospital
Department of Gastroenterology & Hepatology
Wilrijkstraat 10
B-2650 Antwerp, Belgium
Tel. +32-3-821 4974
E-mail: tom.moreels@uza.be
Comments on this article?
Feel free to post them at
www.ihe-online.com/comment/enteroscopy
 Apr/May 2010 30 PRODUCT NEWS

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point-of-care in Innova Vision software, at the lowest possible based on gradient ROIs and it is now possible to
dose in the industry. The software dynamically add and remove datasets while working on an
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initiated. This provides clinical benefits in the central touch mounting options to meet space requirements,
treatment of patients and contributes to a redu- screen at the the system has an exclusive tilt lockout that helps
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The innovative Advantage Workstation Volume- charting, lab, intranet and HIS applications
Share 4 from GE Healthcare is a complete interven- to the bedside. The system facilitates the
tional suite that gives interventional radiologists creation of concise and complete electronic
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Meters for X-ray service and QA
The Solo range of products from Unfors is a
line of meters specifically developed for qual-
ity assurance and service of diagnostic X-ray
machines. Designed for specific X-ray modali-
ties to provide the user with essential features
and high precision adapted to fit a defined
need, the Unfors Solo products share the core
technology of the market leader Unfors Xi.
Thanks to its intuitive user interface and built-
in intelligence, users can rapidly learn how to
use the system and can focus on interpreting
the measured data instead of focusing on how
to obtain the data. Not only does the ease of use
of the system save time but, more importantly,
it minimizes the risk of user errors. Depend-
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dose, dose rate, pulses, time, mA and mAs are
simultaneously measured, with options such
as direct HVL measurements and waveform
display being further enhancements.
Unfors
Billdal, Sweden
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POC test for Clostridium difficile
Providing results to health-
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C. difficile Toxin A/B test
from Oxoid is a valuable
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rapid detection of Clostrid-
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Extremely easy to use, the
test provides accurate and
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immunocompromised patients who have recently
received antibiotic therapy are most at risk of C. dif-
ficile-associated diarrhoea (CDAD), and infection
can spread quickly throughout hospital wards and
PRODUCT NEWS
other healthcare institutions. Early diagnosis is
recognized as one of several factors (including
surveillance, education and infection control
FRONT COVER PRODUCT
measures) that combine to prevent the spread Ultrasound imaging with
of CDI. The Xpect Clostridium difficile Toxin elastography
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C. difficile toxins A and B.
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sNowhere is the processing of CR cassettes more
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the wireless, cassette- With its Aixplorer product, the SuperSonic
sized DRX-1 detector Imagine company has developed a unique
from Carestream for ultrasound system with an innovative medi-
instant, high-quality cal platform that can measure and visualise
DR images. With the tissue elasticity. It is well known that manual
DRX-Mobile Retrofit palpation of tissue is part of a routine medical
Kit, images captured exam.Today, it is essential to obtain additional
at the point of care information on tissue elasticity since this can
are available in sec- have a correlation with pathology. Quantitative
onds and can be for- values for tissue elasticity can provide more
warded to multiple information about a lesion; more information
network destinations via wireless communications or leads to enhanced diagnostic confidence. The
cable plug-in, so clinicians can make rapid diagnoses Aixplorer system uses the proprietary Sonic-
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ogy also improves patient positioning and comfort tecture that is extremely rapid and flexible and
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by most DR-based systems. This makes it ideal for data up to 200 times faster than conventional
confined spaces, remote locations and imaging of ultrasound technology, the Aixplorer is fast
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that have already implemented a DRX-1 System or in real time, a color coded map which repre-
a DRX-Evolution suite can use one of their existing sents tissue elasticity expressed in kilopascals.
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Carestream Health (red). With a cutting edge compact design,
Rochester, NY, US intuitive control and touch panels, ultra light-
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Multi-channel ECG
The new EPG 6 VIEW Plus system from Progetti
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tests, and has a pacemaker-detection function.
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Blood flow monitor
The CardioTrace system from Advanced Glo-
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PRODUCT NEWS
common health markers, strengthening the
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Ultra-clean operating theatres and
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Jointly developed with the
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Combined PET - MRI scanner
With the installation of the first system that
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33 Apr/May 2010
EyeGard™ is the
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• Adult and pediatric sizes
• Gentler adhesive also available
U.S.A. 813-889-9614 • Fax 813-886-2701
www.ihe-online.com & search 45556
which give anatomical information (without
any of the ionizing radiation associated with
CT X-ray), together with PET images giv-
ing functional information, is synergistic in
diagnostic efficacity and precision. Until now,
PET and MRI investigations were carried out
separately, on two separate instruments and
for scheduling reasons, often on two different
days for the same patient. The results of such
separate examinations are difficult to corre-
late since the patient can never have exactly
the same position or orientation in the two
separate scanners. There are many reasons for
combining PET and MR scanners together.
The most straightforward are the excellent
soft tissue contrast, the elimination of the
extra radiation from the CT (used to provide
both anatomical and attenuation-correction
information) and the multifunctional imag-
ing ability (thanks to a wide spectrum of
MR sequences and techniques) that comple-
ments the functional molecular information
from the PET. The new system are currently
being evaluated in oncology, neurology and
cardiology patients.
Philips Healthcare
Eindhoven, The Netherlands
www.ihe-online.com & search 45576
 Apr/May 2010 34 PRODUCT NEWS

completeness of annotations.
FRONT COVER PRODUCT Calendar of events
Agfa Healthcare June 1-3, 2010 Tel. +33 492 947 600
Urology workstation Mortsel, Belgium Hospital Build Middle East Exhibi- Fax +33 492 947 601
www.ihe-online.com & search 45569 tion and Congress 2010 www.escardio.org/congresses/
Dubai, United Arab Emirates esc-2010
Tel. +971 4 3365161
Fax +971 4 3364021 September 14-15, 2010
Fetal doppler system e-mail: hospitalbuild@iirme.com MHealth 2010

The FM-200 fetal doppler system from Shenzhen www.hospitalbuild-me.com Dubai, UAE
Tel. +44 20 7067 1830
Biocare features a signal June 7-9, 2010 www.m-healthconference.com
strength indicating func- UKRC 2010
tion so that the probe can Birmingham, UK September 15-17, 2010
Tel. +44 20 7307 1410 Medical Fair Asia 2010
be located easily. The sys-
e-mail: conference@ukrc.org.uk Suntec Singapore
tem is equipped with a www.ukrc.org.uk Tel: + 65 6332 9620
physiological and system Fax: +65 6332 9655 / 6337
alarm function, with the June 10-13, 2010 e-mail:
15th Congress of the European medicalfair-asia@mda.com.sg
Thanks to its new dynamic flat detector tech- alarm limit ranges being
Hematology Association www.medicalfair-asia.com
nology, the new UROSKOP Omnia system : lower 50 - 120 bpm and Barcelona, Spain
allows the urologist to cover the entire kidney, the upper range 160 bpm - 240 bpm. Portable Tel. +31 70 3455563 October 5-7, 2010
ureter and bladder (KUB) tract with only one (with a user belt clamp so that it can be carried Fax +31 70 3923663 Clinical Excellence Asia
e-mail: info@ehaweb.org Marina Bay Sands, Singapore
single exposure and in exceptional image qual- conveniently) and especially designed for preg-
www.ehaweb.org www.iirme.com/clinicalasia
ity. With its curved X-ray column, the new nancy monitoring, the system has an adjustable
system allows truly unrestricted patient access volume with optional headphone use. There are June 12-15, 2010 October 9-13, 2010
from all table sides. Regardless of the type of three work modes to satisfy the requirements Euroanaesthesia 2010 23rd ESICM Annual Congress
Helsinki, Finland Barcelona, Spain
examination, the urologist does not have to of all users. The system automatically powers Tel. +32-2-743 3290 Tel. +32 2 559 03 55
reposition his patient, and the anesthesiologist off if there is a signal or probe failure that lasts Fax +32-2-743 3298 Fax +32 2 527 00 62
can always stay in place. This is very helpful, for for 2 minutes. e-mail: registration@euroanaes- e-mail: Barcelona2010@esicm.org

example in case of lateral percutaneous inter- thesia.org www.esicm.org

www.euroanaesthesia.com
ventions and increases safety , lowers costs for ShenZhen Biocare October 13-16, 2010
room equipment and infrastructure as there is Shenzhen, P.R. China June 16-19, 2010 CMEF Autumn 2010
no need to have a mobile anesthesia workplace. www.ihe-online.com & search 45568 World Congress of Cardiology Shenyang, Liaoning Province, China
Scientific Sessions 2010 Tel. +86 10 6202 8899 ext 3825
The system allows a variety of clinical applica-
Featuring the 3rd International Fax +86 20 6235 9314
tions such as transurethral and percutaneous Conference on Women, Heart e-mail:
urological interventions, urologic diagnostics Contrast media delivery system Disease and Stroke jin.liu2@ReedSinopharm.com
and even gastroenterological cases and general In addition to the development of high perform- Beijing, China http://en.cmef.com.cn/
e-mail: congress@worldheart.org
radiographic applications.Thanks to the large ance contrast media, the Guerbet company is also
www.worldcardiocongress.org November 17-20, 2010
field-of-view it’s possible to receive a real KUB committed to improving their MEDICA
image with just one single exposure. Compared presentation and delivery sys- June 16-19, 2010 Düsseldorf, Germany
with standard image intensifier systems this tems. The first bag developed CARDIOSTIM 2010 e-mail: info@medica.de
17th World Congress in Cardiac www.medica.de
means reduced examination time and less dose specifically for medical imag-
Electrophysiology & Cardiac
for the patient. Moreover, the system’s resolu- ing, the ScanBag, is based on Techniques November 28 – December 3
tion of more than 2800 X 2800 pixels exceeds the IV infusion bag concept, Nice, France RSNA 2010
that of standard image intensifier systems. The which were initially made of www.cardiostim.fr?xtor=ADI-5 Chicago, IL, USA
Tel. +1 630 571 2670
high-resolution images enable the physician to polyvinyl chloride (PVC) and June 23-26, 2010 www.rsna.org
zoom in without any quality loss and to see the later of polypropylene (PP). CARS 2010 - Computer Assisted
finest details which increases diagnostic con- Polypropylene bags are light, Radiology and Surgery December 10-12, 2010

fidence. In addition, the UROSKOP Omnia resistant, simple to use, safe to
allows for digital RAD images, saving costs as handle, and provide maximum
no cassettes are needed. asepsis, meet current envi-
ronmental requirements and
Geneva, Switzerland
Tel. +49 7742 922 434
Fax +49 7742 922 438
e-mail: office@cars-int.org
www.cars-int.org
Medifest India 2010
New Delhi, India
Tel. +91 11 30580444
e-mail: info@vantagemedifest.com
www.vantagemedifest.com

Siemens Healthcare don’t break if dropped. For all these reasons, PP

August 24-26, 2010 February 24-27, 2011
Erlangen, Germany was chosen for ScanBag. The ScanBag project was Medifest South Africa 2010 International Conference on Pre-
www.ihe-online.com & search 45567 initiated following a study of the current practices Capetown, South Africa hypertension & Cardio Metabolic
and needs of contrast media users and is based on Tel. +91 11 30580444 Syndrome

Multi-modality, vendor neutral PACS technologies widely proven in medical applica- e-mail: info@vantagemedifest.com
www.vantagemedifest.com
Vienna, Austria
Tel. +41 22 5330948
for breast imaging tions, and on technical innovations which guar- Fax +41 22 5802953
The new IMPAX for Breast Imaging module antee the compliance to current requirements in August 28 – Sep 1, 2010 e-mail:
from Agfa extends the company’s PACS solution matters of safety, convenience and environmental ESC Congress 2010 Secretariat@prehypertension.org
Stockholm, Sweden www.prehypertension.org
into breast imaging with unique new features. protection.
For example, it implements the IHE Mammog- For more events see
raphy Image profile, which solves image display Guerbet www.ihe-online.com/events/
problems typically encountered in mixed ven- Roissy, France Dates and descriptions of future events have been obtained from
dor environments, such as: orientation, size, www.ihe-online.com & search 45570 usually reliable official industrial sources. IHE cannot be held
responsible for errors, changes or cancellations.
justification, consistency of grayscale contrast and
www.ihe-online.com & search 45549
 Now that we know what doesn’t work,
can anybody tell us what does?

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