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Systemic inflammation and monocyte function after major surgeryHaveman, Jan Willem
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Systemic Inflammation and Monocyte
Function after Major Surgery
J.W. Haveman
Haveman, JW
Systemic inflammation and monocyte function after major surgery
Proefschrift Groningen, met literatuur opgave en samenvatting in het Nederlands.
ISBN: 978-90-367-3699-2 (boek)
ISBN: 978-90-367-3700-5 (digitaal)
© 2009 J.W. Haveman
All rights are reserved. No part of this publication may be reproduced, stored in a retrieval
system, or transmitted in any form of by any means, mechanically, by photocopying,
recording, or otherwise, without the written permission of the author.
Cover design and layout: J.W. Haveman
Printed by: Gildeprint Drukkerijen BV, Enschede, The Netherlands
Systemic Inflammation and Monocyte Function after
Major Surgery
Proefschrift
ter verkrijging van het doctoraat in de Medische Wetenschappen
aan de Rijksuniversiteit Groningen op gezag van de
Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op
woensdag 28 januari 2009 om 13.15 uur
door
Jan Willem Haveman
geboren op 10 februari 1974 te Assen
Promotor: Prof. dr. J.H. Zwaveling
Copromotores: Dr. A.P. van den Berg
Dr. M.W.N. Nijsten
Beoordelingscommissie: Prof. dr. C.G.M. Kallenberg
Prof. dr. R.J. Ploeg
Prof. dr. D.F. Zandstra
Paranimfen: Drs. H.C. van Calker
Dr. V.E. Hagens
Financial support for this thesis was granted by the Ambroise Paré
foundation, Groningen, The Netherlands.
Financial support for this thesis was kindly given by: Astellas Pharma BV,
Bauerfeind Benelux BV, Baxter BV, Becton Dickinson Biosciences BV,
Biomet Nederland BV, Bristol-Myers Squibb BV, Boehringer Ingelheim
BV, Cook Nederland BV, Edwards Lifesciences BV, WL Gore &
Associates BV, Graduate School GUIDE, Novartis Pharma BV and
Olympus Nederland BV.
Voor mijn ouders
CONTENTS
Chapter 1 Introduction and scope of the thesis 9
Chapter 2
The central role of monocytes in the pathogenesis of sepsis:
consequences for immunomonitoring and treatment
Netherlands Journal of Medicine 1999;55:132-141
21
Chapter 3
Low HLA-DR expression on peripheral blood monocytes predicts
bacterial sepsis after liver transplantation: relation with
prednisolone dose.
Transplantation Infectious Disease 1999;1:146-152
37
Chapter 4
Changes in laboratory values and their relationship with time after
rupture of an abdominal aortic aneurysm
Surgery Today 2008;38:1091-1101
51
Chapter 5
HLA-DR expression on monocytes and systemic inflammation in
patients with ruptured abdominal aortic aneurysms
Critical Care 2006;10:R119
71
Chapter 6
Results of streamlined regional ambulance transport and
subsequent treatment of acute abdominal aortic aneurysm
Emergency Medicine Journal 2006;23:807-810
85
Chapter 7
Multicentre aneurysm screening study (MASS).
Letter to the editor. Lancet 2003;361:1058
95
Chapter 8
Summary, general discussion and conclusions
99
Chapter 9
Samenvatting
111
Literatuur
119
Dankwoord 137
Bibliografie
141
Curriculum vitae
145
CHAPTER 1
INTRODUCTION AND SCOPE OF THE THESIS
Chapter 1
10
SYSTEMIC INFLAMMATION AFTER MAJOR SURGERY
History
The classic signs of inflammation (rubor, tumour, calor, dolor) were first described by
Celsus in the 1st century A.D. About two centuries later Galen added functio laesa of
the affected area as the fifth symptom. These signs of inflammation are still recognised
in trauma patients with skin wounds, but also appear in a more generalised pattern
following major surgery and severe infections. This is known as the systemic
inflammatory response syndrome (SIRS). Rubor results from the increased blood flow
caused by vasodilatation. In systemic inflammation, vasodilatation presents as a
decrease in systemic blood pressure with compensatory tachycardia and an increased
cardiac output. Tumour develops because of (generalised) oedema resulting from
increased capillary permeability and fluid leak. Calor is a local manifestation of
inflammation presenting as warm skin. Systemically, calor may present with fever,
caused by interleukins and toll-like receptor triggering, which elevates the set point of
the thermoregulatory center in the hypothalamus (1). Dolor is manifested as local or
generalised pain. Functio laesa presents locally as the inability to use the affected body
part. With systemic inflammation, functio laesa presents as multi-organ failure.
Surgery dates back to prehistoric times, and the first successful therapeutic
arm amputation was likely performed in ancient Egypt (2). During the middle ages,
surgical interventions were usually performed by barber-surgeons. Although most of
the surgical procedures they performed were straightforward, complication rates were
high (3). Furthermore, patients suffered considerable pain as anaesthesia was not yet
available. These two factors contributed to the negative image and low social status of
the non-academic barber-surgeons.
Important changes in medicine and in surgery as a profession were required
before major surgery would be feasible. Physicians became increasingly interested in
the field of surgery during the 18th century due in part to the increased knowledge of
pathological anatomy. At the same time, the former barber-surgeons became more
interested in medical research and began to separate themselves from the barber trade.
Introduction
11
As a result, their social standing rose (3). Ultimately, a confrontation resulted at the
University of Paris between the physicians and the surgeons, who demanded the right
to teach the science and art of surgery instead of limiting themselves to wound
treatment, setting bones, letting blood, and trimming beards. This marked the
beginning of the acceptance of surgery as an academic degree by universities.
Figure 1. View of a right foot of a mummy from ancient Egypt. The left panel shows the well healed amputation area of the big toe. The right panel shows a wooden prosthesis attached to the forefoot. (4)
New developments in the 19th century set the foundation for modern surgery.
Painless surgery was first described by Warren and Morton who removed a neck
tumour from a patient under ether anaesthesia at the Massachusetts General Hospital in
Boston. This method was adopted throughout Europe. Soon afterward, chloroform was
introduced as a general anaesthetic, followed by cocaine infiltration as a local
anaesthetic several years later. Minor surgery of the extremities became much easier to
Chapter 1
12
perform when epidural cocaine was available for the blocking of nerve trunks (5).
Although surgery could now be practised without pain, surgery related mortality was
still high due to blood loss and postoperative infection.
In 1848, Semmelweis reported that fever and septicaemia in pregnant women
could largely be prevented by hand scrubbing and washing in chlorine water before
obstetrical examination. It was only after Lister’s publications in 1867 that it became
understood that infections were caused by microbes and that infection was not a normal
stage in the wound healing process. Surgical techniques were also markedly improved
in these years: intestinal suture techniques were first performed by Dieffenbach in 1836
and further refined with sterilised fine silk thread by Kocher in 1888.
These developments resulted in several new major surgical operations in the
late 19th century. Billroth performed his first successful esophagus resection in a dog in
1871, and the first laryngectomy in 1872. He was also the first to attempt
reconstruction after partial gastrectomy by gastroduodenostomy (Billroth I; 1881) and
by gastroenterostomy distal to the ligament of Treitz (Billroth II; 1885). Sauerbruch
became a pioneer in thoracic surgery and performed the first thymectomy in a patient
with myasthenia gravis in 1912.
Many surgical procedures were introduced at the end of the 19th century and at
the beginning of the 20th century. Operations were performed with increasing success
due to a better understanding of anatomy, physiology, increased experience, and the
development of anaesthesia. Other supportive techniques were introduced soon
afterwards, for example the artificial kidney by Willem Johan Kolff in 1944, the heart-
lung machine by Gibbon in 1953, and the treatment of blood loss by blood transfusion.
The incidence of postoperative infections decreased due to the implementation of
antisepsis measures and the invention of Penicillin by Flemming in 1928 (6).
However, despite the development of surgical skills and improved methods in
the treatment of postoperative complications, mortality remained considerable. Many
patients died after the progressive failure of one or more vital organs such as the heart,
the lungs or the kidneys. Treatment aimed at replacing or restoring the function of
individual organs (such as fluid replenishment, mechanical ventilation, haemodialysis
Introduction
13
etc.) often failed to stop the fatal course of events. It became clear that more than
symptomatic treatment was needed, and that insight into the underlying
pathophysiology of the multi-organ failure syndrome would be required for effective
intervention. The central mechanism in the pathophysiology of the development and
progression of multi-organ failure is called systemic inflammation (7).
Systemic inflammation
Theoretically, the inflammatory response which follows surgery facilitates tissue
healing. With a small skin wound, platelets initiate the formation of blood clots,
thereby stopping bleeding. Activated platelets secrete mediators that attract
macrophages and fibroblasts. Chemo-attractants produced by macrophages and
fibroblasts attract and activate neutrophils and monocytes. The wound area is cleaned
by these neutrophils and an extracellular matrix is formed. After the initial phase of
inflammation, the wound is re-epithelialized followed by wound contraction and
extracellular matrix reorganization (8). The inflammatory response in patients with
small skin wounds is principally a local phenomenon, manifested by redness, swelling,
warm skin and mild pain (rubor, tumour, calor, dolor). In patients with extensive
trauma, major surgery, severe burns, pancreatitis or sepsis, the inflammatory response
generally has important systemic manifestations and has been termed the systemic
inflammatory response syndrome (SIRS). SIRS has been defined in a consensus
conference, as shown in table 1 (9).
Table 1. Criteria for SIRS
SIRS is manifested as 2 or more of the following conditions:
- Fever (> 38.0 C) or hypothermia (< 36 C)
- Tachycardia (> 90 beats/min)
- Tachypnea (>20 breaths/min) or hyperventilation (PaCO2 < 4.3 kPa)
- Leukocytes > 12 x109/L or < 4 x109/L or > 10% immature neutrophils
Chapter 1
14
SIRS can progress in an uncontrollable reaction leading to multiple organ
failure (heart, lungs, kidneys, liver and bone marrow). The pathogenesis of multiple
organ failure is complex and involves several mediators and cytokines. Tumour
necrosis factor-alfa (TNF-α) and Interleukin-1 (IL-1) play a key role (10). Activated
monocytes and macrophages are able to release massive amounts of these cytokines.
This activates the coagulation and complement pathways, and the platelets are
triggered by the release of platelet activating factor. The activated endothelium also
releases large amounts of pro-inflammatory cytokines, and the expression of adhesion
molecules is increased. Polymorphonuclear granulocytes become activated, and
through their interaction with the adhesion molecules they transmigrate through the
endothelial cells into the targeted tissue. Subsequently granulocytes release large
amounts of reactive oxygen radicals and proteases to kill the invading micro-
organisms. This induces further endothelial damage and activation resulting in an
uncontrolled cascade (11). The release of prostaglandins and nitric oxide in
combination with the endothelial damage, causes vasodilatation, capillary leakage,
generalised oedema, systemic hypotension, and, finally, multiple organ failure (12). In
the case of an infection, antibiotics should be administered and (surgical) drainage
should be performed whenever possible. Tissue perfusion should be restored by fluid
replacement and the administration of vaso-active medication. In case of respiratory
failure caused by acute respiratory distress syndrome (ARDS), patients should be
mechanically ventilated with high PEEP and low tidal volumes (13). When renal
failure occurs, renal replacement therapy by continuous venovenous hemofiltration
should be started without delay. Despite aggressive treatment, the mortality rate when
multiple organ failure occurs is high (7% for one-organ failure and 48% in three-organ
failure) (14). One reason why supportive therapy often fails to save the patient’s life is
that supportive therapy alone does not interfere with the systemic inflammation which
is driving the whole process. Since this theory was recognised, various efforts have
been made to interfere with the immunological processes in an effort to improve
outcome.
Introduction
15
Intervention in the inflammatory response
The inflammatory response which follows major surgery should facilitate tissue
healing and eliminate the invading organisms, but this mechanism can overshoot,
leading to multiple organ failure and death. Although this hypothesis is plausible,
efforts to interrupt the inflammatory cascade such as administering neutralizing
antibodies against LPS (lipopolysaccharide), anti-TNF-α, soluble TNF receptors, IL-1
receptor antagonist and high dose steroids have not been successful (15-21). There may
be several explanations for these negative results. If the inflammatory response was
already activated, it may no longer have been dependent on the initiating stimuli, such
as TNF-α and IL-1. As only single agents were tested in these trials, just one of the
many active cascades would be affected, allowing the others to continue fuelling the
reaction. A third intriguing explanation is that at the time of the intervention, patients
may no longer have been experiencing an overwhelming pro-inflammatory response
needing counteraction, but instead were exhibiting a form of immunosuppression that
would worsen with anti-inflammatory measures. In this case interventions aimed at
restoring immune capacity would have been more appropriate. A compensatory anti-
inflammatory reaction in response to the initial pro-inflammatory response has been
described to occur and would prevent the excessive tissue destruction resulting from
uncontrolled inflammation (22). Theoretically, this anti-inflammatory response could
promote a state of immunosuppression which would increase the risk of nosocomial
infections. Together with the decreased TNF-α production by monocytes, these factors
make up the compensatory anti-inflammatory response syndrome (CARS) which
follows SIRS (22). This model for systemic inflammation combined with the anti-
inflammatory response would allow for specific treatments which target the
inflammatory cascade. Two different treatment directions are indicated, depending on
the response seen in the patient. Patients with an overwhelming systemic inflammatory
response should be treated by interfering with the pro-inflammatory cascade, whereas
patients exhibiting a dominant anti-inflammatory response should be treated by
stimulating the immune response.
Chapter 1
16
Monocyte function in systemic inflammation
The exact mechanism and timing of the anti-inflammatory response was poorly
understood until recently. Monocytes play a central role in immunity and
inflammation. Hershman et al studied monocyte function in patients after major
surgery and sepsis. They discovered that a decreased expression of HLA-DR on
peripheral blood monocytes was associated with an increased risk of infectious
complications in trauma patients (23). These results were confirmed by other study
groups in patients after major surgery and sepsis (24-29). Low HLA-DR expression
impairs the immune response, which predisposes the host to generalised infections.
Decreased expression of HLA-DR by monocytes is often accompanied by functional
abnormalities, such as a low antigen presentation by monocytes to T-cells (30), a
critical step in the immune response, and by a diminished capacity to release pro-
inflammatory cytokines, such as TNF-α, IL-1, IL-6, IL-8 and interferon-gamma (IFN-
γ) (31). This state is known as monocyte deactivation, and constitutes one of the
mechanisms underlying CARS. Monitoring monocyte function by measuring HLA-DR
expression might be an important parameter to guide intervention in the inflammatory
pathway. We hypothesised that a better understanding of the pro- and counter
inflammatory response is a prerequisite for successful intervention. This thesis reflects
our efforts to better understand these processes.
LIVER TRANSPLANTATION
To investigate monocyte function in patients with sepsis we investigated patients who
underwent orthotopic liver transplantation (OLT). The first successful OLT was
performed by Starzl in 1967 (32). During the following years, the short-term mortality
remained high initially because of uncontrolled haemorrhaging during surgery,
technical problems, and acute rejection. However, due to major improvements in
surgical techniques, anaesthesiology, post-operative care, and the development of
potent immunosuppressive drugs, mortality eventually decreased, and liver
transplantation became an accepted treatment option for end-stage liver disease.
Introduction
17
Unfortunately, the incidence of serious infections remained high and was the principle
cause of death during the first months after transplantation (33,34). Although
immunosuppressive drug therapy is an important cause of these infections, there are
several other factors which contribute as well. For instance: the patient’s poor general
condition and nutritional status before surgery; the presence of intravascular, biliary,
and urinary catheters; mechanical ventilation; a large surgical wound with drains; and
the considerable blood loss that can occur during surgery and afterwards due to poor
clotting and low platelet counts. Antimicrobial drugs are important in the treatment of
these infections, but may not be sufficient when the patient’s natural protective
immune responses fail. In order to enable the immune system to initiate these
protective responses, the dosage of immunosuppressive drugs should be strongly
reduced. This might result in a dilemma, as insufficient suppression of the immune
system predisposes to rejection of the graft. The treatment in these cases depends
largely on clinical intuition as there are no presently recognized clinical parameters
which indicate immune function. Such parameters would be of great value for
calculating dosages of immunosuppressive drugs so that both over-
immunosuppression, with its attendant risk of infection, and under-
immunosuppression, leading to rejection, may be avoided. To address this issue in our
thesis, we note that sepsis was generally preceded by a strong decrease in the
expression of HLA-DR on monocytes. Whereas the return of HLA-DR expression to
normal values accompanies recovery from sepsis and survival, persistently low values
occur in patients who subsequently die from sepsis. As previously discussed, a variety
of conditions impact immunoresponsiveness and monocyte function in OLT patients
including age, pre-transplant illness, nutritional status, co-existing diseases, and the
type and dosage of immunosuppressive drugs. To further investigate the inflammatory
response and monocyte function following major surgery, but without many of the
confounding factors encountered in OLT patients, we studied a second, much more
homogeneous group of patients.
Chapter 1
18
RUPTURED ABDOMINAL AORTIC ANEURYSMS
Patients with ruptured abdominal aortic aneurysms (RAAA) represent a homogeneous
patient group (previously healthy, non-immunosuppressed) with a clearly defined
catastrophic event, followed immediately by surgery. In RAAA patients, haemorrhagic
shock is the primary cause of death both intra-operatively and during the 24 hours
following surgery. After this initial post surgical phase, the most frequent cause of
death is multiple-organ failure. In fact, more patients die from multiple organ failure
than hemorrhagic shock (35,36). Almost all patients who survive surgery develop a
systemic inflammatory response syndrome (SIRS), responsible for the development of
multi-organ failure (37). The aim of our study was to describe HLA-DR expression on
monocytes in RAAA patients after surgery and to establish whether HLA-DR
expression correlated with the occurrence of secondary infections and death. In this
‘clean’ model of post-surgical systemic inflammation, we aimed to establish whether
RAAA patients die from an overwhelming systemic inflammatory response or from
secondary infections with monocyte deactivation and a predominant compensatory
anti-inflammatory response. To achieve this, we analysed several clinical and
immunological variables.
An abdominal aortic aneurysm is a serious medical condition associated with a
high mortality. It is the tenth leading cause of death in men aged 65 to 74 years old,
and its incidence is on the rise (38-40). The management of patients with AAA consists
of surgical repair with an aortic graft. Endovascular treatment (stenting) was more
recently introduced for selected cases. Hospital mortality for the elective repair of
AAAs larger than 5.5 cm is reported to be as low as 2% in some centres (41,42). This
low mortality is in contrast with the in hospital mortality associated with RAAAs,
which ranges from 30% to 70% with surgical repair (43-47).
The advantage of the recently established elective endovascular repair of
abdominal aortic aneurysm (EVAR) is the lower incidence of systemic complications
(48,49) and a lower hospital mortality (50), compared with open repair. Results for
EVAR in symptomatic non-ruptured and ruptured AAAs are promising (51). However,
Introduction
19
the survival benefit of avoiding the trauma of surgery might be off-set by the negative
influence of the time delay that results from waiting for the required CT-scan.
Furthermore, the impact of long-term complications on mortality after EVAR is
unknown and EVAR is frequently not feasible in patients with ruptured AAA (51-53).
AIMS AND OUTLINE OF THE PRESENT THESIS
The concept of systemic inflammation is well established in surgical patients. The aim
of this study was to describe this response in patients after major surgery with special
emphasis on the role of the monocyte. Our studies focused on patients following liver
transplantation and patients with a RAAA. These two groups are highly relevant since
they show a high incidence of secondary systemic complications, with progression to
multiple organ failure and death.
Chapter 2 describes new insights in the pathophysiology of sepsis. The role of
monocytes in the inflammatory response is described in detail. Furthermore, possible
new interventions based on the patient’s immune status are outlined. Liver
transplantation patients are studied in chapter 3. The purpose of this study was to
describe the role of HLA-DR expression on monocytes in infectious complications and
mortality. Our hypothesis was that a low HLA-DR expression on monocytes is
associated with sepsis and mortality. The effect of immunosuppression on monocyte
function was also investigated. In postoperative OLT patients this might be especially
relevant since patients in whom the anti-inflammatory response predominates might
benefit from reduced immunosuppression therapy.
As explained above, patients who have undergone surgical repair of a ruptured
aortic aneurysm are also relevant to the study of the systemic inflammatory response.
Systematic data on the organ responses in terms of biochemical parameters of
patients after RAAA have only rarely been described. Therefore, we studied the typical
biochemical response in RAAA patients in chapter 4. The impact of several parameters
on outcome is also described. Although the role of several different cytokines in
patients after RAAA has been described in a number of studies, the clinical
Chapter 1
20
significance of biochemical parameters is not always clear. In chapter 5 we describe
pro- and anti-inflammatory cytokines and HLA-DR expression on monocytes in
RAAA patients. We hypothesised that a low HLA-DR expression was associated with
a high mortality in these patients. As multiple organ failure is the most frequent cause
of death in our patient population, we evaluated if this was from an ongoing systemic
inflammatory response or from immunosuppresion and secondary infections as is seen
in patients with CARS.
The treatment and outcome of RAAA patients admitted to the University
Medical Center Groningen are described in chapter 6. This study will show how the
streamlined management of patients directly before surgery, during surgery, and after
surgery impacts hospital mortality in patients with symptomatic AAAs.
The Multicentre Aneurysm Screening Study (MASS) has investigated whether
screening men aged 65 to 74 for AAA has an effect on AAA related mortality.
Screening resulted in a significant survival benefit (54). Screening has also been found
to be cost-effective (55). In chapter 7 a letter to the editor in response to the MASS
study is presented, stressing that although screening men seems to improve survival,
measures to improve survival in RAAA patients by prompt and surgery according to
liberal inclusion criteria should not be overlooked.
CHAPTER 2
The central role of monocytes in the pathogenesis of
sepsis: consequences for immunomonitoring and
treatment
JW Haveman1, AC Muller Kobold2, JW Cohen Tervaert2,
AP van den Berg2,3, JE Tulleken4, CGM Kallenberg2,
TH The2
1 Department of Surgery
2 Department of Clinical Immunology 3 Department of Gastroenterology and Hepatology
4 Department of Intensive and Respiratory Care Unit
University Medical Center Groningen, The Netherlands
Netherlands Journal of Medicine 1999;55:132-141
Chapter 2
22
ABSTRACT
Despite important advances in critical care medicine during the last two decades, the
mortality rate of sepsis has remained high, probably because the pathogenesis of sepsis
is still incompletely understood. Recent studies have shown that sepsis is a bimodal
entity. The first phase is characterized by the systemic release of pro-inflammatory
cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-8, and
by activation of the complement and coagulation cascades. In the second phase, anti-
inflammatory mediators such as transforming growth factor-β (TGF-β), IL-10 and
prostaglandin E2 (PGE2) may be released in an effort to counteract ongoing
inflammation. Depending whether the pro- or anti-inflammatory response
predominates, sepsis results in a systemic inflammatory response syndrome (SIRS), or
a compensatory anti-inflammatory response syndrome (CARS). So far, most efforts to
intervene in the immunopathogenesis of sepsis have been directed at the pro-
inflammatory response. None of these interventions has been shown to improve the
prognosis of sepsis, possibly because many patients were already in a state in which
anti-inflammatory responses dominated. Recently, it has been shown that decreased
expression of HLA-DR on monocytes in patients with sepsis constitutes a marker for
CARS. We suggest that HLA-DR expression on monocytes might constitute a useful
indicator of the immunological status of the individual patient with sepsis and a guide
for treatment. Patients with CARS, as manifested by low HLA-DR expression, might
benefit from immunostimulants, while patients with SIRS and normal or high
monocyte HLA-DR expression should receive treatment directed to interfere with pro-
inflammatory pathways.
HLA-DR on monocytes in sepsis
23
INTRODUCTION
Sepsis is a leading cause of acute hospital admissions, and, in addition, often
complicates the clinical course of patients hospitalized for other reasons. Sepsis is
defined by a microbiologically documented infection that is associated with a systemic
response, consisting of hyper- or hypothermia, an increased or decreased white blood
cell count, tachycardia and tachypnea (56). Despite modern antimicrobial therapy and
intensive care facilities, the mortality rate of sepsis remains high at 30–40%, and
morbidity in survivors may be considerable. The incidence of sepsis is rising, because
of increasing numbers of old patients and of patients with complicated conditions,
including major trauma, extensive surgery, and immunosuppressive treatment.
The immune system plays a pivotal role in the pathogenesis of sepsis. In this
review we will discuss new insights in this syndrome, with special emphasis on the role
of HLA-DR expression on monocytes as a prognostic marker and as a guide to direct
im munomodulatory therapy.
PATHOGENESIS OF SEPSIS
Traditionally, sepsis was considered to be an overwhelming and persistent,
inflammatory response of the immune system to a bacterial infection. This response is
initiated by bacterial toxins, such as the endotoxin of gram-negative organisms and the
lipoteichoic acid-peptoglycan complex of gram-positive bacteria. In gram-negative
sepsis, binding of lipopolysaccharide (LPS) to the CD14 receptor on the cell
membrande results in activation of monocytes and macrophages. In addition, LPS may
bind to soluble CD14, and this complex subsequently interacts with, and activates,
endothelial, and smooth muscle cells (57). It is not completely clear how gram-positive
bacteria activate monocytes, but both CD14-dependent mechanisms may play a role
(11).
Chapter 2
24
Figure 1. A simplified scheme of the pro-inflammatory response of sepsis designated as SIRS. After bacterial toxin release monocytes (mono´s) and macrophages (M) produce massive amounts of TNF-α, IL-1, IL-6, IL-8 and reactive oxygen species (ROS), platelet activating factor (PAF), and nitric oxide (NO). Together with endothelial activation this initiates a cascade of reactions, which leads ultimately to endothelial damage, capillary leakage, edema, vasodilatation and systemic hypotension. In order to prevent sepsis, septic shock, multi organ failure (MOF) and eventually death, the left side of the figure shows potentially pharmacologic interventions. Anti LPS; anti TNF; soluble TNF receptor; IL-1-RA (receptor antagonist); PAF antagonist; nitric oxide-inhibitors (N-v-nitro-L-arginine methyl ester) (NO-inhibitors (L-NAME)).
HLA-DR on monocytes in sepsis
25
Figure 2. The pathogenesis of CARS. After the release of bacterial toxins a pro-inflammatory response follows. The anti-inflammatory response is probably mainly initiated by IL-10, TGF-β and PGE2. Monocyte deactivation follows, manifested by low antigen presenting activity and low release of pro-inflammatory cytokines, such as TNF-α, IL-1, IL-6, IL-8 and IFN-γ. Intervention in the pathophysiology of CARS is possible by administration of IFN-γ and possibly Granulocyte Macrophage–Colony Stimulating Factor (GM–CSF).
Chapter 2
26
Activated monocytes and macrophages release large amounts of TNF-α, which can be
considered to be the principal mediator that sets the septic response in motion. In
addition to TNF-α, monocytes/macrophages produce other pro-inflammatory mediators
including IL-1 and IL-6, eicosanoids, reactive oxygen species (ROS), platelet
activating factor, and nitric oxide (NO); whereas activated endothelial cells release
inflammatory mediators like IL-1, IL-6, IL-8 and NO. Bacterial cell wall products
interact with and activate the complement and coagulation cascades, damaging the
endothelial surface. During activation of endothelial cells the expression of adhesion
molecules is increased. Polymophonuclear granulocytes become activated and, via
interaction with adhesion molecules, adhere to, and transmigrate through the
endothelial monolayer. During this process, the activated granulocytes release oxygen
radicals and proteases, thereby killing micro-organisms. However, these products may
also damage endothelial cells (58). NO, prostaglandins and kinins released by
endothelial cells all cause profound vasodilatation which, in combination with
widespread endothelial damage, results in systemic hypotension, capillary leakage, and
edema. Although the inflammatory response is intended to eliminate the invading
micro-organisms, causing sepsis to deteriorate into septic shock, multiple organ
dysfunction, and death (see Figure 1) (56,59). Numerous efforts have been made to
intervene at various levels of this inflammatory cascade. Neutralising antibodies
against LPS (15), or TNF-α (16,17), soluble TNF receptors (18), IL-1 receptor
antagonists (19), platelet activating factor-antagonist (20), high-dose corticosteroids
(21), and inhibitors of the arachidonic acid pathways were all found to be effective in
animal models, but none of these agents has resulted in a clinically significant survival
benefit in humans so far (for review see (60)). No synthase-inhibitors might also form a
rational intervention in patients with sepsis. However, mortality was not reduced by
treatment of hypotensive septic patients with L-NAME (N-ω-nitro-L-arginine
methylester) (61). This failure to impact on the outcome of sepsis has been thought to
reflect the fact that these immunomodulatory agents had been administered several
hours after the onset of sepsis. At that time, the inflammatory response probably had
been fully activated, and was no longer dependent on its initial stimuli. Only single
HLA-DR on monocytes in sepsis
27
agents were tested in these trials, each directed at one of the early steps in the
pathogenesis of sepsis. Combination of agents might be required for blocking the septic
response, targeting multiple, probably more distal sites of the inflammatory cascade.
Another explanation, which does not exclude the previous one, suggests that sepsis just
is not as simple as we have always thought. Indeed, the concept that the septic response
consists only of an overwhelming inflammatory reaction, the so-called systemic
inflammatory response syndrome (SIRS), is probably not correct. It has become
evident in recent years that the inflammatory response is followed by counter-
regulatory anti-inflammatory reactions that are intended to prevent undue tissue
destruction from uncontrolled inflammation. This anti-inflammatory reaction may
become the dominant pathophysiologic abnormality, and may result in a state of
immunological anergy with an increased risk of secondary infections. Bone introduced
the term compensatory anti-inflammatory response syndrome (CARS) for this situation
(Figure 2) (22). Therefore, Bone has proposed to consider the immunologic response in
sepsis as a spectrum, with overwhelming inflammation (SIRS) on the one end,
profound immunodepression (CARS) on the other, and the mixed antagonistic response
syndrome (MARS) that has features of both extremes in between (22). Both pro- and
anti-inflammatory responses may give rise to fatal complications. This spectrum
concept of sepsis explains why immuno-interventions directed against the pro-
inflammatory response have been ineffective. Since patients were treated irrespective
of their immune status, inhibition of inflammation might have been beneficial in
patients with SIRS, but deleterious in patients with predominant CARS.
It has to be stressed that the validity of the concepts of CARS and MARS still
has to be proven. However, if this hypothesis of sepsis as a spectrum of pro- and anti-
inflammatory responses is correct, it follows that immunomodulation will be effective
only it is tailored to the immune status of the individual patient.
HLA-DR EXPRESSION ON MONOCYTES IN PATIENTS WITH SEPSIS
Monocytes and macrophages play a central role in the immune response against micro-
organisms and in the pathogenesis of sepsis, as already discussed above. The are
Chapter 2
28
essential for phagocytosis and killing of micro-organisms, production of cytokines, and
presentation of microbial antigens to T cells, thus initiating and regulating both cellular
and humoral immune responses.
It was first shown by Hershman et al. that decreased expression of HLA-DR
on peripheral blood monocytes (Figure 3) was associated with an increased risk of
infectious complications in trauma patients (23). Subsequently, these findings were
extended to various other categories of patients. Low HLA-DR expression was found
to predict sepsis in patients with thermal injury (62), patients undergoing major
abdominal surgery (24,25), neurosurgery (26), or liver transplantation (63), and in
patients on ventricular assist device awaiting cardiac transplantation (27) Table 1.
Moreover, the degree of expression of HLA-DR on monocytes in patienst with
established sepsis was shown tob e of prognostic significance. Low HLA-DR
expression on monocytes on five consecutive days was associated with a mortality rate
of 81% (31). In addition, 11 out of 12 transplant patients with sepsis and low HLA-DR
expression on monocytes, in whom immunosuppression was kept unchanged, died,
whereas all 20 patients with similarly low HLA-DR expression, in whom
immunosuppression was rapidly tapered, survived (28).
HLA-DR on monocytes in sepsis
29
Table 1. Association between HLA-DR expression and the risk of infection or death
Patient category Number of
patients
Reference Comment
Recipients of
immunosuppression because
of organ transplantation or
autoimmune disease
21 (28) Monocyte HLA-DR expression
was <20% in all patients; 0/13 om
whom immunosuppression was
kept unchanged.
Liver transplant recipients 20 Personal
experience
and (63)
Expression of HLA-DR on <50%
of monocytes preceeded sepsis in
all 7 patients
Trauma patients 69 (23) Low HLA-DR expression
correlated with development of
infections and death.
Patients undergoing elective
laparotomy
24 (25) Five patients with a low
percentage of HLA-DR
expression before and seven days
after the operation developed
surgical wound infections.
36 (24) Twelve patients with low HLA-
DR expression developed sepsis
Patients with a ventricular
assist device awaiting cardiac
transplantation
30 (27) Seven of nine patients who died
of septic MOF had low
percentage HLA-DR expression.
Neurosurgery 46 (26) Nine of ten patients with a low
percentage of HLA-DR
expression developed infectious
complications.
Chapter 2
30
Figure 3. Leukocyte activation in 2 patients with sepsis and in a healthy individual. The course of expression of HLA-DR on monocytes (Fig. 3A and C) and of plasma concentrations of interleukin 10 is shown (Fig. 3B and C). Arrows indicate the length of stay at the ICU for patient 1 and patient 2. The horizontal line represents expression of HLA-DR on monocytes at an intensity of 30% of healthy controls (N=5).
HLA-DR on monocytes in sepsis
31
Direct comparison between studies is somewhat hampered by the fact that
different parameters were used to quantify HLA-DR expression (either as the
percentage of HLA-DR-positive monocytes, or as the mean fluorescence intensity of
the HLA-DR signal of the monocyte population). Similarly, various cut-off values have
been used for what constitutes pathologically low HLA-DR expression (e.g., 20% (28),
30% (27), 50% (63). Thus, standardization of methodology and cut-off values will
become an important issue. Since many patients with low HLA-DR expression died as
a result of superinfections, Volk et al. coined the term immunoparalysis to denote this
condition. They subsequently demonstrated that the capacity for antigen presentation of
monocytes taken from patients with immunoparalysis is reduced, which is in
agreement with the role of HLA-DR in the presentation by monocytes of antigens to T
cells (30). However, it is difficult to accept that decreased antigen presentation would
predispose to bacterial infections in view of the limited importance of T cells in
antibacterial immunity. The finding that monocytes expressing low amounts of HLA-
DR also produce lower amounts of pro-inflammatory cytokines, such as TNF-α, IL-1,
IL-6, IL-8, and IFN-γ, offers a better explanation for the association between decreased
HLA-DR expression and infections (30). It followed logically that these ´deactivated´
monocytes were a marker for, and probably a mediator of, CARS. Therefore,
elucidation of the pathogenesis of monocyte deactivation, and the development of
strategies to restore normal monocyte function, have become important objectives that
may have a major impact of the treatment of sepsis.
MEDIATORS OF MONOCYTE DEACTIVATION
In cultures of monocytes that have been stimulated with LPS, high levels of the pro-
inflammatory cytokines IL-1, IL-1, IL-6, IL-8, TNF-α, GM-CSF and G-CSF can be
detected within 4–8 h (64). Production of IL-10, a cytokine with potent anti-
inflammatory effects on monocytes and on T 1 lymphocytes, peaks 24–48 h after
stimulation (64). Probably, release of IL-10 is important to downregulate the
inflammatory response. In monocytes that have been stimulated with LPS, reexposure
to LPS leads to low production of pro-inflammatory cytokines, whereas release of anti-
Chapter 2
32
inflammatory mediators such as IL-10 is increased (65). This ‘LPS desensitization’,
which is mediated by IL-10, transforming growth factor-β (TGF-β), and probably by
prostaglandin E2 (PGE2), is an other counter-regulatory mechanism intended to control
the inflammatory response (65). It has been postulated that monocyte deactivation that
occurs during sepsis is caused by IL-10 (65-68) and PGE2 (66,69). IL-10 inhibits the
release of pro-inflammatory cytokines (64), suppresses antigen presentation and
formation of free oxygen radicals (70,71), and down-regulates HLA-DR expression on
monocytes (72). Serum levels of IL-10 are increased in patients with sepsis or septic
shock compared with healthy controls (66). In a series of 32 patients undergoing major
abdominal surgery, IL-10 gene expression correlated inversely with monocyte HLA-
DR expression, which is consistent with a role for IL-10 as a mediator of the
immunosuppression associated with surgical injury (67). We longitudinally monitored
IL-10 levels in plasma and HLA-DR expression on monocytes in two patients with
sepsis, and found that CARS was associated with increased plasma IL-10 levels and
low HLA DR expression, and that normalisation of these parameters coincided with
clinical recovery (see Figure 2) (73).
Other mediators may be involved in the pathogenesis of monocyte
deactivation in addition to IL-10. TGF-β is a cytokine with profound inhibitory effects
on the immune system and on haematopoiesis. It lowers TNF-α production by
monocytes after LPS stimulation (65), and prevents upregulation of HLA-DR
expression on human fibroblasts by IFN-γ (74). The in-vivo sifnificance of TGF-β is
uncertain, however, since serum levels of TGF-β were found to belower in patients
with sepsis and septic shock than in healthy controls (66).
PGE2 has an inhibitory effect on a variety of monocyte functions, and is one of
the mediators of LPS desensitation. It is a potent inhibitor of the expression on Ia, the
rat equivalent of HLA-DR, on rat macrophages (75). PGE2 levels are increased in
patients with sepsis (66,69). Moreover, the production of PGE2 by monocytes in
patients with sepsis is higher than in healthy controls (69). Yet PGE2 does not decrease
the antigen-presenting capacity of monocytes (76,77). These data suggest that IL-10 is
HLA-DR on monocytes in sepsis
33
the principal mediator of monocyte deactivation, and that TGF-β and PGE2 may be of
secondary importance.
In vitro stimulation by IFN-γ at least partially reverses IL-10 or TGF-β
induced monocyte deactivation (78). Moreover, incubation with IFN-γ of monocytes
taken from patients with sepsis restored the expression of HLA-DR to normal levels,
and partially corrected LPS-stimulated TNF-α secretion (79). Furthermore, it was
recently reported that administration of IFN-γ in vivo in patients resulted in
normalisation of the reduced HLA-DR expression (79). GM-CSF also upregulates the
expression of HLA-DR on monocytes and stimulates the production of TNF-α and IL-1
in vitro (80). These observations suggest that IFN-γ and, probably, GM-CSF may be
valuable in ameliorating the state of immunodeficiency in patients with CARS, thereby
reducing the risks of secondary infections and death.
MONOCYTE HLA-DR EXPRESSION: A GUIDE FOR INDIVIDUALIZING
SEPSIS TREATMENT?
The insight that sepsis is no a homogeneous disorder, but a spectrum of immunological
changes, ranging from overwhelmin inflammation to profound immunodeficiency, has
given rise to calls for a more individualized treatment approach (22,81). Thus,
antimicrobial and general supportive treatment should be supplemented by
immunodulatory interventions that are specifically tailored to correct the
immunological disturbances in the individual patient. This concept is attractive, but
requires the availability of reliable parameters to guide this treatment. Serial measures
of cytokines and other mediators might be an indicator of the pro-/anti-inflammatory
state of the immune system (78). Van Dissel et al measured cytoken levels in patients
admitted because of fever, and found that the IL-10/TNF-α ratio was 1.7 times higher
in patients with a fatal outcome compared to those who survived. Interestingly, the
ratio of these cytokines was more predictive than the level of either cytokine alone
(82).
The expression of HLA-DR on monocytes may be and alternative parameter to
guide immuno-intervention. Monitoring HLA-DR expression has the advantage that it
Chapter 2
34
may provide an extimate of the ‘net’ biological effect of pro- and anti-inflammatory
stimuli. We have previously reported that high plasma levels of IL-10 in patients with
sepsis were associated with low HLA-DR expression, and that clinical recovery was
associated with normalisation of HLA-DR expression and decreases IL-10 levels (73).
More studies will be necessary to determine which marker(s) provide the best
prognostic information.
The validity of the concept of individualized immuno-intervention was
recently tested by Döcke et al (79). IFN-γ was administered for a median 6 days to 10
patients with sepsis and CARS as evidenced by low HLA-DR expression (79,83). The
degree of HLA-DR expression on monocytes was rapidly upregulated in all patients,
increasing from a median of 27% before, to 62% on day 1 after treatment, and it
remained at this level in most patients. Normalisation of HLA-DR expression was
associated with a significant increase in plasma levels of TNF-α and IL-6. The small
number of patients treated, and the uncontrolled nature of the study, make it impossible
to draw conclusions on the clinical efficacy of this intervention. It is clear, however,
that this approach of immuno-intervention is worth pursuing.
CONCLUSIONS AND FUTURE DIRECTIONS
The ultimate goal in the treatment of septic patients is to improve outcome. Recent
advances in antimicrobial therapy and supportive intensive care have, to a large extent,
failed to achieve this goal. Direct intervention in the immunological response is a new
and promising approach, but a variety of immune-modulating agents have not been
effective in reducing mortality. Sepsis is not a homogeneous entity, but can be regarded
as a spectrum of pro- and anti-inflammatory responses. It seems reasonable that
immuno-intervention should be tailored to the immunopathological condition of the
individual patient. The degree of HLA-DR on peripheral blood monocytes appears to
be a good parameter in defining the immune status of patients with sepsis: low HLA-
DR expression is associated with immunological energy due to predominance of anti-
inflammatory responses, that might require intervention with immunostimulants such
as IFN-γ or GM-CSF. Normal HLA-DR expression is observed in patients with an
HLA-DR on monocytes in sepsis
35
inflammatory response, who might benefit by measures interfering with the pro-
inflammatory cascade. It is now time to test the concept of immuno-intervention as
based on HLA-DR expression in randomized clinical trials. Given the complex
pathophysiology of sepsis it would be surprising if, even in the subgroups of patients
with SIRS or CARS, a single agent would be effective in all patients. Therefore,
intervention at multiple levels of the pro- or anti-inflammatory cascades may be
required for optimal results. Parameters such as HLA-DR expression on monocytes
may be useful to guide this treatment. Ultimately, increased insight in the pathogenesis
of sepsis, and the growing number of new tools for immuno-intervention will lead to
improved outcome for patients with sepsis.
ACKNOWLEDGEMENTS
We would like to thank Mr. Jan Brouwer for his artistic input in figures 1 and 2.
36
CHAPTER 3
Low HLA-DR expression on peripheral blood monocytes
predicts bacterial sepsis after liver transplantation:
relation with Prednisolone intake
JW Haveman1, AP van den Berg2,3, JMM van den Berk4,
G Mesander2, MJH Slooff1, LHFM de Leij2,
TH The2
1 Department of Surgery
2 Department of Clinical Immunology 3 Department of Gastroenterology and Hepatology
University Medical Center Groningen, The Netherlands 4 Department of Internal Medicine, University Hospital Nijmegen, The Netherlands
Transplantation Infectious Disease 1999;1:146-152
Chapter 3
38
ABSTRACT
Bacterial sepsis remains a frequent complication after liver transplantation. We
previously reported the results of a pilot study that suggested that low expression of
HLA-DR on monocytes is a predictive marker for the occurrence of sepsis. We have
studied the value of this marker in an additional cohort of patients, and have analyzed
the relation of HLA-DR expression with the use of immunosuppressive agents. 20
adult liver transplantation patients were prospectively monitored during the first 4
weeks after transplantation. All were treated according to standard protocols. The
percentage of monocytes expressing HLA-DR was measured by flow cytometry. In
addition, the effects of incubation of monocytes with prednisolone in vitro on the
expression of HLA-DR was determined in 7 healthy volunteers. Seven patients
developed bacterial sepsis after a median 15 (range 10–20) days after transplantation.
HLA-DR expression was significantly lower in these patients on days 7, 14, 21, and 28
after transplantation compared with non-septic patients. The percentage of HLA-DR
positive monocytes was 30% or less, 3 (1–8) days before onset of sepsis. On day 7
after transplantation, HLA-DR expression on 50% or less of monocytes had a positive
predictive value for sepsis of 71%, whereas the negative predictive value was 85%.
Patients who developed sepsis received significantly more prednisolone. Incubation
with prednisolone in vitro lowered the expression of HLA-DR in a dose-dependent
manner. We conclude that low HLA-DR expression on monocytes is a marker for a
high risk of subsequent sepsis in liver transplantation patients. This high risk may be
(at least partly) related to the dose of prednisolone.
HLA-DR expression in liver transplantation
39
Sepsis remains an important cause of morbidity and mortality after liver
transplantation, despite improvements in antibiotic treatment and supportive care
(84,85). Immunosuppressive agents probably constitute the most important underlying
cause of the increased susceptibility for infections in these patients, but other factors
such as poor nutritional status, hepatic failure, surgical trauma, uremia, multiple blood
transfusions and viral infections also have a negative influence on the
immunocompetence (86). Drug-induced immunosuppression is the only one of these
factors that can be easily modified in order to prevent over-immunosuppression with its
attendent risk of severe infections. To date, drug dosage still depends on clinical
intuition, as no good parameter is available for identification of patients at high risk of
developing septic complications.
HLA-DR expression on monocytes might be a useful marker of an increased
risk of infection. Low HLA-DR expression on monocytes is associated with an
increased risk of infections in patients with trauma (23) or thermal injury (62), patients
undergoing major abdominal (24,25) or neurosurgery (87), and in patients with a
ventricular assist device awaiting cardiac transplantation (27). We have previously
reported that low HLA-DR expression preceeded clinical signs of sepsis in a small
series of liver-transplant patients (63). Here we present an extension of that study,
confirming the usefulness of HLA-DR expression on monocytes. Moreover, we present
evidence that low HLA-DR expression and sepsis may be related to the dose of
prednisolone.
PATIENTS AND METHODS
Patients
We prospectively monitored 20 adult liver transplant recipients during the first 4 weeks
after transplantation. Results in 9 of these patients have been reported previously (63).
All patients were treated according to standard protocols, without knowledge of the
results of flow-cytometric analysis. Demographic data and details on the operative
procedure are shown in Table 1. The nutritional status was determined before
Chapter 3
40
transplantation by clinical examination by two investigators. This method has been
shown to be as accurate as laboratory testing (88).
Baseline immunosuppression and rejection treatment
Standard immunosuppression consisted of ‘high-dose’ prednisolone (1.25–1.5 mg/kg/d
during the first week, tapering to 0.4–0.5 mg/kg/d at day 28), azathioprine (125 mg/d),
and cyclosporine A (target trough levels 200–250 mg/l), combined with a one-week
induction course of cyclophosphamide, as reported previously (89) in 12 patients. The
remaining patients took part in a randomized trial comparing tacrolimus with
cyclosporin A, both combined with ‘low-dose’ prednisolone (1.5 mg/kg on day 1,
tapered to 0.3 mg/kg at day 7 and 0.2 mg/kg at day 28). Target trough levels of
tacrolimus ranged between 10 and 15 ng/ml (6 patients), whereas trough levels of
cyclosporin A ranged between 200 and 300 ng/ml (two patients). The selection of
patients for this comparative trial did not depend on the risk of infection after
transplantation, or on the expression of HLA-DR on monocytes. In case of abnormal
liver tests a Doppler-ultrasound examination was performed to exclude vascular or
biliary tract problems. A liver biopsy was taken to confirm the diagnosis of rejection.
Firstline rejection treatment consisted of methylprednisolone pulses of 1 g
intravenously on 3 successive days; steroid-resistent rejection was treated with anti-
thymocyte globulin (90).
Infection prophylaxis, monitoring, and treatment
All patients received selective bowel decontamination consisting of colistine,
tobramycine, and amphotericin B until the bile drain had been clamped and full oral
intake had been resumed, as described before (91). In addition, systemic antibiotic
prophylaxis was given for 48h, consisting of cefotaxim with tobramycin, or, in case of
renal failure, imipenem monotherapy. In cases of fulminant liver failure or
retransplantation, amphothericine B was given intravenously in a dose of 0.25 mg/kg
for the first 10 postoperative days as a prophylactic measure against fungal infections.
All patients received low-dose oral acyclovir against herpes simplex virus infections.
HLA-DR expression in liver transplantation
41
No prophylaxis was given against CMV or PCP. In case of fever or suspected
infections 2 or 3 blood cultures were taken, in addition to urine and sputum cultures.
Bile, ascites, aspirates from fluid collections or abcesses, and catheter tips were also
cultured. Treatment of infections consisted of antibiotics and surgical drainage when
necessary. In case of severe infections or CMV disease, prednisolone was lowered to
10 mg/d and azathioprine to 50 mg/d.
HLA-DR expression on monocytes
EDTA anticoagulated blood was taken before transplantation, and on days 7, 14, 21,
and 28 post-transplantation. Monoclonal antibodies against CD-14 antigen (anti CD-
14-PE (phycoerythine), Immuno Quality Products, Groningen, The Netherlands) were
used to set a lifegate for monocytes. The percentage of HLA-DR+ monocytes was
determined using anti-HLA-DR FITC (fluoresceine isothiocyanate) (Becton Dickinson
Immunocytometry Systems, San Jose, CA), with an IgG2a isotype control (isotype
control IgG2a FITC, Immuno Quality Products); in the last 11 patients the signal
intensity of fluorescence was also determined. For sequential analysis the flow
cytometer was calibrated by using QC windowsTM microbeads as a standard curve
(Flow Cytometry Standards Corporation (FCSC), San Juan, Puerto Rico).
In vitro monocyte incubation with prednisolone
To determine the effect of prednisolone on HLA-DR expression by monocytes in vitro
we incubated whole blood from 7 healthy volunteers, diluted 1:10 with RPMI, with
increasing concentrations of prednisolone. After 24h of incubation at 37°C, monocytes
were stained by monoclonal antibodies and analyzed by flow cytometry as described
above.
Definitions
Sepsis, septic shock, sepsis syndrome, and multi-organ failure were defined following
the criteria of Bone (92). Sepsis was defined as a systemic response to a
microbiologically confirmed infection consisting of hypothermia or hyperthermia (core
Chapter 3
42
or rectal temperature, <35.5 or >38.0°C), tachypnea (respiration >20 breaths/min; if
mechanically ventilated, minute ventilation >10 l/min), and tachycardia (heart rate >90
beats/min).
Statistical analysis
Data are given as median (range). Patient characteristics were compared with the
Fisher’s exact test or in case of continuous data the Mann–Whitney U-test. HLA-DR
expression was compared with the Mann–Whitney U-test and with the Wilcoxon
signed rank test or Friedman’s test. For detection of correlations we used Spearman’s
rank correlation test. A P-value of 0.05 was considered to indicate statistical
significance.
HLA-DR expression in liver transplantation
43
RESULTS
Patients
Seven of the 20 patients experienced an episode of sepsis during the first 4 weeks after
orthotopic liver transplantation (OLT). No significant differences were found regarding
demographic, surgical or postoperative characteristics between patients with and
without sepsis (Table 1).
Table 1. Patient characteristics
Patients with sepsis (n=7)
Patients without sepsis (n=13)
P
Demographic characteristics Sex (male/female) 5/2 8/5 NS Age (yrs) 47 (34-60) 36 (18-61) NS Acute/elective procedure 1/6 1/12 NS Re-transplantation 0 2 NS Child Pugh (A/B/C) 1/1/5 0/5/8 NS Nutritional status (normal/moderate/poor)
5/2/0 5/5/3 NS
SBP 1 5 NS Surgical data Cold ischemic time (min) 760 (369-960) 730 (376-864) NS Warm ischemic time (min) 58 (36-89) 58 (31-76) NS Operative time (min) 520 (440-900) 703 (515-840) NS Blood loss (l) 9 (7-23) 9 (2-35) NS Post operative data Graft function (good/IPF/PNF)
5/2/0 10/3/0 NS
Immune suppressive regimen (1/2/3)
6/0/1 6/6/1 NS
prednisolone dose on day 7 (mg/d)
100 (80-100) 50 (10-100) 0.016
Other infections 6 5 NS CMV infection 2 0 NS Acute rejection 3 2 NS Died 2 0 NS Data represents number of patients or median (range). SBP = spontaneous bacterial peritonitis. Graft function: IPF = immediate poor function, PNF = primary non-function. Immune suppressive regimen: 1 = cyclophosphamide induction therapy, high-dose prednisolone, cyclosporine A and azathioprine, 2 = low-dose prednisolone and tacrolimus, 3 = low-dose prednisolone and cyclosporine A. NS, nonsignificant.
Chapter 3
44
Sepsis was first diagnosed 15 (10–20) days after transplantation. Three
patients developed sepsis with cholangitis, one of them developed sepsis syndrome
caused by Staphylococcus aureus; two had sepsis, one of these caused by S. aureus and
the other by CNS (coagulase-negative Staphylococcus). Two patients had peritonitis,
one with combined infection of S. aureus and Citrobacter, and one developed septic
shock due to infection with Serratia and S. aureus. Two patients died in the sepsis
group. Patient #7 (see Figure 2) died due to a liver rupture resulting in massive blood
loss and catheter sepsis with CNS. Patient #3 died because of fulminant sepsis and
multi-organ failure (MOF) caused by S. aureus.
HLA-DR expression on monocytes and sepsis
Figure 1 shows HLA-DR expression on monocytes in patients with and without sepsis.
Patients who suffered sepsis had a significantly lower HLA-DR expression on
monocytes on day 7 (P=0.013), day 14 (P<0.001), day 21 (P=0.004), and day 28
(P=0.010) after transplantation. In both patients with fatal outcome HLA-DR
expression on monocytes was lower than 30%, and remained so until death, whereas in
all patients who survived sepsis, expression of HLA-DR on monocytes rose during
recovery. On days 21 and 28 it was significantly higher than on day 14 (P=0.039 and
P=0.042, respectively). Figure 2 shows that in all patients with sepsis, low HLA-DR
expression was already present 3 days (1–8) before onset of sepsis. Five of the seven
patients with less than 50% HLA-DR positive monocytes on day 7 developed sepsis
(positive predictive 71%), whereas 11/13 patients with HLA-DR expression on more
than 50% of all monocytes on day 7 remained free from septic complications (negative
predictive value 85%).
The percentage of HLA-DR positive monocytes and the fluorescence intensity
of the positive signal as determined in the 46 samples taken during the second part of
the study were strongly correlated (r=0.60, P<0.001). Signal intensity was low before
onset of sepsis in the 2 patients with this complication.
HLA-DR expression in liver transplantation
45
Figure 1. HLA-DR expression on monocytes in patients with and without sepsis during the first month after transplantation. Box plots show the median, 10th, 25th, 75th, and 90th percentiles. Open circles indicate outliers.
Figure 2. HLA-DR expression in seven patients with sepsis. The horixontal axis in the middle of the figure indicates the onset of sepsis. The shaded area indicates mean ±2 SD in non-septic patients.
Chapter 3
46
Prednisolone, white blood cell, and monocytes counts in relation to HLA-DR
expression
Prednisolone dosage was significantly higher at day 7 after transplantation in patients
who developed sepsis compared to those without sepsis (1.33 mg/kg/d (1.25–1.45) vs.
0.60 mg/kg/d (0.18–1.61) respectively, P= 0.022). Differences in prednisolone dosage
were no longer significant 2 weeks or more after transplantation, probably as a result of
our tendency to taper prednisolone in patients with severe infections.
Incubation of monocytes from healthy volunteers with prednisolone in vivo did
not reduce the percentages of HLA-DR positive monocytes (P=0.134). However, the
amount of HLA-DR per monocyte, as reflected by the intensity of HLA-DR
fluorescence signal, decreased in a dose-dependent fashion (Figure 3).
Total numbers of monocytes and white blood cells did not differ in patients
who suffered a septic episode from those in patients without sepsis. Furthermore, there
were no significant correlations between the white blood cell counts or the numbers of
monocytes on the one hand, and HLA-DR expression on monocytes on the other hand
(r=-0.132, P=0.253, and r=-.253, P=0.241, respectively).
HLA-DR expression and other complications
Two patients suffered from a CMV infection. In these patients HLA-DR expression
was comparable with patients not experiencing this complication. Patients with other
infections or technical complications did not show a lower or higher percentage of
HLA-DR positive monocytes. Five patients suffered from acute rejection during the
first 4 weeks after transplantation. Three of these patients also experienced sepsis,
either shortly after (patient #3, Figure 2) or before onset of rejection. One of these
(patient #7) developed rejection 2 days after onset of sepsis when HLA-DR expression
was still very low (16%).
HLA-DR expression in liver transplantation
47
Figure 3. Effect of incubation with prednisolone on HLA-DR expression of monocytes taken from healthy volunteers.
DISCUSSION
In this study we show that HLA-DR expression on monocytes is a reliable prognostic
marker for sepsis during the first month after liver transplantation. All seven patients
who suffered from sepsis had a low percentage of HLA-DR positive monocytes (15%,
7–30) before onset of sepsis. On day 7 after transplantation, expression of HLA-DR on
50% or less of monocytes had a positive predictive value for sepsis of 71%, and a
negative predictive value of 85%. These data indicate that monitoring of HLA-DR
expression will identify patients at a high risk of developing septic complications. To
increase the reliability of this parameter, a repeated measurement of HLA-DR
expression on subsequent days might be necessary.
As shown in Figure 1, OLT patients who developed sepsis did not have lower
HLA-DR expression before transplantation. Moreover, demographic and surgical
characteristics did not differ between both groups. Although large studies have shown
that a poor pretransplant nutritional status (86,93,94) and spontaneous bacterial
Chapter 3
48
peritonitis (95) are associated with high post-transplant infection rate and mortality, it
remains difficult to determine the risk of sepsis in the individual patient. Monitoring of
HLA-DR could be helpful in adapting immunosuppression to the needs of the
individual patient. Sepsis occurred in 6 of the 12 patients on the high-dose steroid,
CsA-based regimen, and in only one of the 8 patients on low-dose prednisolone,
generally tacrolimus-based immunosuppression. The baseline conditions, difficulty of
surgery, and graft function were comparable in these groups. This leaves
immunosuppression as the most probable determinant of cause of the difference in the
incidence of sepsis. There is no strong evidence that CsA as a primary
immunosuppressant is, by itself, associated with a higher risk of infection than
tacrolimus (96). The high doses of prednisolone coadministered in the cyclosporin A
regimen may be of greater importance. Patients with sepsis received significantly more
prednisolone on day 7 after transplantation. Moreover, incubation of whole blood with
prednisolone in vitro led to a dose-dependent decrease of HLA-DR expression on
monocytes. Concentrations used in this experiment are comparable with concentrations
in OLT patients, i.e. 10-8 –10-6 (96). This suggests that decreasing of steroids in
patients with low HLA-DR expression could lower risk of sepsis and might improve
prognosis. In this respect data from Oehling et al. are highly relevant. These workers
showed that oral glucocorticoid therapy in bronchial asthma was associated with an
increased frequency of respiratory tract infections. In addition, HLA-DR expression on
monocytes was lower in patients receiving glucocorticoids compared with those who
did not receive oral glucocorticoid therapy (96). Although intensive steroid treatment
undoubtly increases the risks of sepsis, we do not think that low HLA-DR expression
was just a marker for intensive steroid therapy, because half of the patients in the high-
dose steroid group had persistently normal HLA-DR expression, whereas several
patients in the low-dose prednisolone group had low expression.
Volk et al. reported that prednisolone and azathioprine could belowered in
transplant patients with sepsis and low HLA-DR expression without precipiting
rejection (28). The fact that two of our patients suffered from acute rejection shortly
after sepsis, one of them at a time when only 16% of monocytes were HLA-DR
HLA-DR expression in liver transplantation
49
positive, suggests that it may not be realistic to expect that a single parameter might be
able to indicate the risks of both infection and rejection.
A causal relationship between low monocyte HLA-DR expression and severe
bacterial infections remains to be elucidated. HLA-DR serves as a scaffold on which
monocytes present peptides derived from exogeneous antigens to CD4+ T cells. T cells
do not play an important role in the defense against bacteria except for those that can
survive intracellularly, and it is difficult to envisage howreduced antigen presentation
would predispose to sepsis. Alternatively, low HLA-DR expression might ‘just’ be a
very early and sensitive marker of as yet subclinical infection. In agreement with this
hypothesis, Randow et al. have shown that repeated LPS stimulation induces monocyte
deactivation and down-regulates HLA-DR expression (65). This theory is difficult to
reconcile with the predictive value of low monocyte HLA-DR expression for sepsis in
patients undergoing elective major surgery (24,25). Thus, we favor the hypothesis that
low HLA-DR expression is a marker of generalized monocyte dysfunction. In
agreement with this, monocytes expressing low amounts of HLA-DR have been shown
to have reduced capacity for synthesis of pro-inflammatory cytokines like TNF-α, IL-1,
IL-6, IL-8, and IFN-γ (30). What causes this monocyte dysfunction and down-
regulation of HLA-DR remains to be determined. Both IL-10 and TGF-β have been
shown to down-regulate HLA-DR expression (72,74). Our study shows that
corticosteroid treatment may be another important factor.
If low HLA-DR expression on monocytes is indeed an indicator of a high risk
of sepsis, prompt reduction of steroids or treatment aimed at improving monocyte
function may prevent development of sepsis. Both IFN-γ and GM-CSF have been
shown to improve monocyte function in vitro and in vivo, but IFN-γ might precipitate
rejection. In contrast, GM-CSF has been administered to liver transplant recipients with
severe infections, apparently without causing rejection, and might therefore an
attractive agent for immunomodulation (97). Randomized studies are required to test
this hypothesis.
50
CHAPTER 4
Changes in Laboratory Values and their Relationship
with Time after Rupture of an Abdominal Aortic
Aneurysm
JW Haveman1, CJ Zeebregts1, ELG Verhoeven1,
AP van den Berg2,3, JJAM van den Dungen1, JH Zwaveling4,
MWN Nijsten1
1 Department of Surgery
2 Department of Clinical Immunology 3 Department of Gastroenterology and Hepatology
University Medical Center Groningen, The Netherlands 4 Department of Intensive Care, University Hospital Maastricht
Surgery Today 2008;38:1091-1101
Chapter 4
52
ABSTRACT
Purpose
Many laboratory values are abnormal after surgery for a ruptured abdominal aortic
aneurysm (RAAA). However, these changes have not been comprehensively evaluated.
We analysed the changes in routine laboratory values and how these changes were
related to outcome in a consecutive series of RAAA patients.
Methods
All patients who underwent surgery for an RAAA between January 1990 and June
2003 at our hospital were included in this study. We analysed laboratory data acquired
during the first week for all patients and at discharge for survivors. We categorised 29
different measurements into six categories based on the related pathological process,
including: haematology and coagulation, metabolism, systemic inflammation, renal
function, liver function, and electrolytes.
Results
A total of 290 patients underwent RAAA surgery, with a hospital mortality of 34%.
Haemorrhage was the most common cause of early death, whereas multiple-organ
failure (MOF) was the most common cause of death several days after surgery. Most
laboratory values deviated from normal at multiple time points and they differed
significantly between survivors and non-survivors.
Conclusions
Both survivors and non-survivors of RAAA surgery displayed characteristic time-
dependent laboratory abnormalities. Awareness of these responses may help us predict
patients prone to complications.
Changes in laboratory values in RAAA
53
INTRODUCTION
Despite major improvements in emergency care, anaesthesiology, surgical equipment,
graft materials and postoperative intensive care management, hospital mortality after
surgical repair of ruptured abdominal aortic aneurysms (RAAAs) remains high and
variable (30%-70%) (43-45,47,98). Multiple-organ failure (MOF) is the major cause of
death in the intensive care unit (ICU) after successful RAAA repair (99,100).
Consequently, there are many associated laboratory abnormalities. However, data on
laboratory values and their specific time course after RAAA repair have not been
comprehensively described in the literature. Identification of common patterns as they
occur in patients who follow a benign course and those who will die could be of great
consequence. As such, one or more of these laboratory values may serve as an indicator
for the development of complications and adverse outcome, whereby unnecessary
diagnostic or therapeutic interventions may be avoided. We conducted this study to
evaluate the time-dependent changes in routine laboratory values during the first week
after RAAA repair. For this purpose we performed two comparisons: First, to find out
which values differed from the normal reference values and at what time; and second,
to find out which values differed between survivors and non-survivors and at what
time. We included essentially all routinely measured laboratory values, which were
arbitrarily grouped into six basic physiologic categories.
Chapter 4
54
PATIENTS AND METHODS
Study Design
We retrospectively analysed all patients who underwent open repair for RAAA in our
tertiary referral centre between January, 1990 and June, 2003. Survival data on this
population was published previously (35). Patients who underwent endovascular
treatment were excluded. From June 2003 onward the number of AAAs treated with
endovascular aneurysm repair (EVAR) increased rapidly. Therefore, no patients who
underwent open repair of an RAAA was included after 2003, since the results might
have been biased by excluding patients who were haemodynamically stable and
anatomically normal (101).
RAAA was diagnosed only if retroperitoneal or intraperitoneal blood, or both,
was identified during the operation. Consequently, all acute non-ruptured aneurysms
without retro- or intraperitoneal blood were excluded from the analysis. Acute
physiology and chronic health evaluation II (APACHE-II) scores were calculated in
patients who survived surgery. The APACHE-II score is based on 12 physiological and
laboratory parameters as well as on age and previous health status, measured in the first
24h of ICU admission. The APACHE-II score ranges from 0 to 71, and mortality rates
increase with an increasing APACHE-II score (102). The number of transfusions of red
blood cells (RBCs) and platelet concentrates were also recorded during the first 24h.
Laboratory Data
The laboratory values studied and their reference values are presented in Table 1.
Laboratory data were measured daily, from day 0 (representing the day of surgery). If
more than one laboratory measurement a day was available, the mean of these values
was calculated before further analysis. In the group of survivors, the laboratory values
available within 5 days of hospital discharge were recorded.
The laboratory values were grouped into the following categories: Haematology and
coagulation: activated partial thromboplastin time (APTT), fibrinogen, haemoglobin,
platelet count, prothrombin time (PT), and white blood cell count. Systemic
inflammation: C-reactive protein (CRP). Metabolic: bicarbonate, pCO2, pH, lactate,
Changes in laboratory values in RAAA
55
glucose and pO2. Renal: creatinine and urea. Liver: albumin, alanine aminotransferase
(ALAT), alkaline phosphatase (AP), aspartate aminotransferase (ASAT), direct
bilirubin, total bilirubin, gamma glutamyl transferase (gGT), and lactate dehydrogenase
(LDH). Electrolytes: calcium, chloride, magnesium, phosphate, potassium and sodium.
Definitions of Outcome Parameters
In addition to ICU-stay and length of stay in hospital, all reoperations were
recorded. The main outcome measure was hospital mortality. In patients who died, the
following major complications were recorded: haemorrhagic shock, sigmoid necrosis,
abdominal infection, infected aortic graft, and organ failure according to the Sequential
Organ Failure Assessment (SOFA)-definitions (103). The SOFA score measures the
failure of six organ systems, respectively defined as the neurological, haemodynamic,
respiratory, renal, liver, and coagulation systems. Organ failure was defined as a SOFA
score ≥ 2 with regard to the relevant organ system (103).
Chapter 4
56
Table 1. Reference values of laboratory measurements
Laboratory measurements Reference values Activated partial thromboplastin time (APTT) 26-36 seconds Alanine-amino transferase (ALAT) 0-30 U/L Albumin 37-47 g/L Alkaline phosphatase (AP) 13-120 U/L Aspartate aminotransferase (ASAT) 0-40 U/L Bicarbonate (HCO3
-) 21-28 mmol/L Bilirubin - direct - total
0-5 mol/L 3-26 mol/L
Calcium 2.25-2.75 mmol/L Chloride 98-107 mmol/L C-reactive protein (CRP) < 5 mg/dL Creatinine 62-106 mol/L Fibrinogen 1.7-3.5 g/L Gamma glutamyl transferase (gGT) 0-65 U/L Glucose 4.0-5.4 mmol/L Haemoglobin (Hb) - male - female
8.7-10.6 mmol/L 7.5-9.9 mmol/L
Lactate 0.5-2.2 mmol/L Lactate dehydrogenase (LDH) 114-235 U/L Magnesium 0.74-1.48 mmol/L pCO2 (arterial) 4.6-6.0 kPa pH (arterial) 7.35-7.45 Phosphate 0.65-1.30 mmol/L Platelet count (PC) 150-350 x 109/L pO2 (arterial) 9.5-13.5 kPa Potassium 3.6-4.8 mmol/L Prothrombin time (PT) 11-16 seconds Sodium 132-144 mmol/L Urea 3.3-6.7 mmol/L White blood cell count (WBC) 4-10 x 109/L
Changes in laboratory values in RAAA
57
Statistics
Data are expressed as means with standard deviation (SD) or median and interquartile
range (IQR) in case of skewed distribution. Differences between categorical variables
were tested with a Chi-square analysis. To calculate differences between continuous
variables, Student’s t-test (normal distribution) or Mann-Whitney U test (skewed
distribution) were used. P values <0.05 were regarded as significant. Since the main
purpose of our study was to define all laboratory abnormalities at different time points,
we did not perform Bonferroni's correction for multiple testing. Receiver operating
characteristic (ROC) curves were made for all laboratory values on postoperative day
(POD) 1. Laboratory values measured on POD 1 after surgery were included in a
multivariate logistic regression analysis when the area under the ROC curve was > 0.6.
Chapter 4
58
RESULTS
Patients
The clinical characteristics of the 290 patients are summarised in Table 2. The mean
age was 71 (±8) years. The mean APACHE-II score was 18 (±7) on ICU admission,
being 23 (±8) for patients who died after surgery vs. 16 (±6) for those discharged from
hospital (p<0.001). Intra-operative mortality was 11% (31/290) and hospital mortality
was 34% (100/290), including the 31 patients who died intra-operatively. Table 3
shows the main causes of death in relation to the times of death of the 100 non-
survivors. Haemorrhagic shock was the most common cause of death during, and in the
first hours after surgery, whereas MOF with or without abdominal sepsis was the most
common cause of death ≥24h after surgery.
Laboratory Data
We analysed 29 laboratory measurements in the 290 RAAA patients, with a total of
49 726 laboratory values. For the survivors, we recorded 261 median laboratory values;
namely, 29 measurements done on 8 days plus the day of discharge. In 122 (47%) of
the 261 medians, these values were not within the reference value range. For the non-
survivors we recorded 126 (54%) of 232 medians; namely, 29 measurements done on 8
days. There were significant differences between the survivors and non-survivors in 95
(41%) of the 232 medians that were compared. These abnormalities were clearly time-
dependent in the survivors and non-survivors. Deviations from the normal range and
differences between survivors and non-survivors were evaluated according to the six
categories defined in figures 1, 2, and 3. Electrolytes and some of the data not
displayed in the figures are shown in Table 4.
The following data are not discussed in this article: chloride and sodium,
APTT, ALAT, AP, ASAT, and direct bilirubin. This is because chloride and sodium
values were not clinically different between survivors and non-survivors, APTT has a
similar pattern to PT (Figure 1), ALAT and ASAT have a similar pattern to LDH
(Figure 3), AP has a similar pattern to gGT (Figure 3), and direct bilirubin has a similar
pattern to total bilirubin.
Changes in laboratory values in RAAA
59
Table 2. Clinical characteristics of the 290 patients who underwent repair of a ruptured
abdominal aortic aneurysm
Survivors
N = 190
Non-survivors
N = 100 P-value
Demographic characteristics
Age (yrs) 70 (±8) 73 (±7) 0.001
Gender (male) 161 (85%) 87 (87%) NS
Risk factors
Platelet count before surgery
(x 109/L) 195 (±95) 161 (±102) 0.024
Serum creatinine before
surgery (μmol/L) 131 (±100) 148 (±129) NS
Suprarenal clamping 6 (3%) 12 (12%) 0.02
No. of RBC transfusions
during surgery 8 (±7) 14 (±12) <0.001
No. of platelet concentrate transfusions during surgery
.17 (±.47) .27 (±.64) NS
APACHE-II 16 (±6) 23 (±8) < 0.001
Postoperative data
Re-operations 34 (18%) 39 (39%) 0.007
Sigmoid resection 11 (6%) 19 (19%) 0.005
Rebleeding 11 (6%) 13 (13%) NS
ICU length of stay (days)
9 (±14)
10 (±14)
NS
Hospital length of stay (days) 26 (±28) 10 (±14) < 0.001
RBC: red blood cell unit, APACHE-II: Acute Physiology and Chronic Health Evaluation, ICU: intensive care unit
Chapter 4
60
Table 3. Main causes of death in relation to time in the 100 non-survivors of a ruptured
abdominal aortic aneurysm
Main cause Time of death
(days)*
Number of deaths according to phase
Intra-operative
<24h at ICU
≥ 24h
Haemorrhagic shock 0.2 (±0.4) 31 5
Brain death 4 1
Sigmoid necrosis with MOF 6 (±7.9) 1 10
Renal failure (no RRT) 6.7 (±3.5) 3
Pneumonia 9 1
Pulmonary embolism 10.5 (±7.8) 2
Gastro-intestinal bleeding 10.5 (±6.4) 2
Multiple-organ failure † 13.5 (±11.1) 5 18
Abdominal sepsis with MOF 17 (±6.2) 7
Cardiogenic shock 17.3 (±5.7) 4
Respiratory failure 21.6 (±8.1) 5
Infected aortic graft with MOF 37 (±33.8) 5
Total 31 11 58
When there were multiple causes of death, the prime cause was selected. RRT: renal replacement therapy. * Mean (± standard deviation) or the day the patient died † Multiple-organ failure without sepsis. MOF: Multiple-organ failure
Changes in laboratory values in RAAA
61
In the haematology and coagulation category, the following differences were
seen: Haemoglobin was decreased in both groups, but it was lower at all times in the
non-survivors. The platelet count dropped in the first days after surgery and failed to
recover in non-survivors. Leukocyte counts were slightly increased, with no clear
time-dependent changes or differences between survivors and non-survivors.
Fibrinogen dropped initially and then increased after 2 days to supra-normal values,
which were slightly higher in the survivors. PT increased immediately after the
operation in the non-survivors. At discharge almost all the laboratory values in the
haematology and coagulation category had returned to normal in the survivors, except
for haemoglobin, which was still low (Figure 1, Table 4).
As a measurement that reflects systemic inflammation, CRP increased
immediately, to much higher levels in the non-survivors peaking on PODs 3 and 4. The
median CRP remained above the reference value until discharge in the survivors
(Figure 1).
In the metabolic category, the following differences were seen: pH and
bicarbonate showed a marked metabolic acidosis, which recovered during the first
week after surgery and was more pronounced in the non-survivors throughout this
period. Analogously, lactate levels increased immediately, to much higher levels in the
non-survivors. Lactate was almost never measured at the time of discharge. The pO2-
levels were initially elevated and returned to normal after 2 days, with no differences
between survivors and non-survivors. Glucose levels were elevated in the survivors
and non-survivors, especially in the first 2 days. No differences or changes were noted
in pCO2 levels (Figure 2, Table 4).
In the renal category, both creatinine and urea were persistently elevated from
POD 1 to POD 7 in the non-survivors, whereas in the survivors, creatinine remained
low and urea was only slightly elevated after surgery, but returned to normal by the
time of discharge (Figure 2, Table 4).
In the liver category, the following changes were seen: LDH was increased in
both groups, both more so in the non-survivors from day 2 onwards. There was a time-
Chapter 4
62
dependent rise in gGT, which was largely within the reference values. Remarkably, the
rise in gGT was higher in survivors than in non-survivors, which persisted until
discharge. In fact, of all the laboratory values analysed, gGT was the only one that
showed a larger deviation from the reference values in survivors than in non-survivors.
Total bilirubin increased gradually above the reference values during the first week,
especially in the non-survivors. Albumin decreased immediately after surgery and
remained unchanged during the first week, with lower levels in the non-survivors
(Figure 3).
In the electrolyte category the following differences were seen: Calcium was
lower in the non-survivors from POD 2 to POD 6. Magnesium was higher in the non-
survivors from POD 5 to POD 7. Phosphate was higher in the non-survivors from day
0 to POD 4 (Table 4).
The area under the ROC curve was more than 0.6 in nine laboratory
measuremernts; namely, APTT, total bilirubin, creatinine, lactate, phosphate, pH,
potassium, PT, and urea. In addition to these laboratory values, age, APACHE-II score,
number of RBC transfusions during surgery and suprarenal clamping and platelet count
before surgery were included in the multivariate analysis because of significant
differences, as outlined in Table 2. After stepwise logistic regression analysis, age,
APACHE-II score, number of RBC transfusions during surgery and serum potassium
level remained significant and were identified as an independent predictor of death
after RAAA. The odds ratios with a 95% confidence interval were as follows: age, 1.07
(1.02-1.13); number of RBC transfusions, 1.05 (1.01-1.10); APACHE-II score, 1.16
(1.09-1.23); and potassium, 2.64 (1.41-4.95)
To classify the various time-dependent laboratory abnormalities in RAAA
patients, we summarised them in Figure 4. Five major pathological processes were
responsible for important laboratory derangements. Important laboratory abnormalities
were seen after RAAA surgery in all patients, but they were more pronounced in the
non-survivors.
Changes in laboratory values in RAAA
63
Figure 1. Haematology and inflammatory measurements in the 290 patients who underwent surgery for a ruptured abdominal aortic aneurysm. * p<0.05, open squares=survivors (n=190) and closed squares=non-survivors (n=100). D, laboratory values in survivors at discharge. Hb, haemoglobin; PT, prothrombin; CRP, C-reactive protein
Chapter 4
64
Figure 2. Renal and metabolic measurements in the 290 patients who underwent surgery for a ruptured abdominal aortic aneurysm. * p<0.05, open squares=survivors (n=190) and closed squares=non-survivors (n=100). D, laboratory values in survivors at discharge.
Changes in laboratory values in RAAA
65
Figure 3. Liver function test measurements in the 290 patients who underwent surgery for a ruptured abdominal aortic aneurysm.* p<0.05, open squares=survivors (n=190) and closed squares=non-survivors (n=100). D, laboratory values in survivors at discharge, but this was not available for lactate. LDH, lactate dehydrogenase; gGT, gamma-glutamyltransferase
Chapter 4
66
Figure 4. Pathological processes in the 290 patients who underwent surgery for a ruptured abdominal aortic aneurysm.Summary of patterns and duration of the different pathological responses leading to abnormalities in laboratory values
Changes in laboratory values in RAAA
67
DISCUSSION
We confirmed distinct laboratory responses in all patients who underwent RAAA. The
laboratory data were more abnormal in the non-survivors than in the survivors,
although they were often outside the reference range in the survivors as well. To our
knowledge, this is the first study to chart these changes comprehensively. The main
goal of our study was to perform univariate analysis of all routine laboratory
measurements at different time-points. Many of the univariate comparisons revealed a
significant difference with a two-sided p-value of < 0.05. When using a p-value of
0.05 as a matter of chance, we would expect 5% or 12 comparisons out of the 232
comparisons between survivors and non-survivors to be significant. In reality, we
found that not 12, but 95 of the 232 comparisons showed a significant difference,
underscoring that many laboratory values differ between survivors and non-survivors.
This study did no aim to identify prospective measurements that predict death, but if
we focus only on day 0 or POD 1, the following variables were differed significantly
between survivors and non-survivors: Hb, fibrinogen, pH, PT, lactate, creatinine, urea,
phosphate, and potassium. The most apparent reasons for the differences in these
values were blood loss and diffuse intravascular coagulation, accounting for Hb,
fibrinogen and PT; lactic acidosis, accounting for pH and lactate; and acute renal
failure, accounting for creatinine, urea, phosphate, and potassium.
Although our main purpose was univariate analysis, we also performed
multivariate analysis, after which age, APACHE-II score, RBC transfusions during
surgery, and potassium remained an independent predictor for outcome. Age,
APACHE-II score, and blood-loss reflected by RBC transfusions during surgery are
well known independent predictors of mortality in many surgical patients. The fact that
potassium remains the only independent biochemical value that predicts outcome also
underscores the limitations of multivariate analysis in this study of 29 biochemical
values. For multivariate analysis, Altman suggests that multiple regressions should not
be applied to small data sets, and that the number of tested variables should be no more
than the square root of the sample size or than the sample size divided by 10 (104).
This explains why only a few values on POD 1 were independent predictors of
Chapter 4
68
outcome with multivariate analysis in our series. It may also underscore the strong
interrelationship of the laboratory values measured. Obviously, our data set did not
allow multivariate analysis at multiple time points after POD 1.
We chose to aggregate the laboratory responses according to the six categories
in this study. Obviously, there will be extensive overlap when artificial classifications
are used. For example, the white blood cell count may be a haematological measure or
an inflammatory measure. Similarly, albumin can be regarded as a measure of
metabolic or inflammatory liver dysfunction. The categories we chose are strongly
related to the causes of death as patients suffer, and subsequently die of massive
haemorrhage, mainly during and within 24h after surgery, whereas inflammatory
response and MOF occur more than 24h after surgery (Table 3).
Haematology and Coagulation
Several laboratory variables showed that non-survivors suffered from more extensive
bleeding than survivors, as underscored by the multivariate relationship between RBC
transfusions and mortality. Severe coagulation disturbances were also seen more
frequently in non-survivors post-surgery, leading to relatively high mortality within the
first 24 hours (Table 3). The pre-operative platelet count was lower in the non-
survivors than the survivors, as reported in other studies (105,106). Fibrinogen, and PT
were also significantly more disturbed in the non-survivors, as reported in several other
studies on RAAA patients (105,107,108). A low postoperative platelet count reflects
intra-operative blood loss and disseminated intravascular coagulation (DIC). The
increasing platelet count seen later in the non-survivors was probably the result of
ongoing systemic inflammation (109). Rebleeding occurred relatively infrequently in
this cohort of RAAA patients, since only 8% (24/290) of our patients required
reoperation for this complication.
Systemic Inflammation
CRP, a commonly used marker of inflammation, was increased in the survivors and
non-survivors, indicating severe systemic inflammation. Non-survivors had a more
severe and longer duration of severe inflammation (Figure 1). Accordingly, CRP was
Changes in laboratory values in RAAA
69
significantly higher in the non-survivors on PODs 3 and 4. The serum concentration of
CRP correlates with the clinical course of infection (110). The platelet count decreased
after surgery and remained low in the non-survivors, primarily as a result of systemic
inflammation (109). Serum albumin is also decreased as a result of redistribution and
down-regulation in severe inflammation and is associated with poor outcome in
critically ill patients (111).
Metabolism
Aortic cross-clamping causes ischaemia and reperfusion injury to distal tissues (112).
The massive blood transfusions and haemorrhage in RAAA patients augment the tissue
damage. The ischaemia reperfusion injury is reflected by lactate acidosis and elevated
enzymes (Figures 2 and 3). Serum lactate is an important prognostic value in critically
ill patients, trauma patients and RAAA patients immediately after the operation (113-
117). Accordingly, the serum lactate levels were higher on day 0 to POD 4 in the non-
survivors, indicating more profound tissue hypoperfusion. These metabolic and acid-
base abnormalities take a long time to recover, as shown by the course of pH post-
surgery.
Acute Renal Failure
Acute renal failure (ARF) characteristically developed within 2 days and was reflected
by a significant increase in serum creatinine and urea. Gordon et al reported an
incidence of ARF of 15% in 91 patients who underwent RAAA surgery (118). ARF is
associated with high mortality, ranging from 38-87%, in RAAA patients (108,118-
121). Preoperative renal dysfunction is also associated with a poor outcome (122-124).
Liver Failure
Liver failure was reflected by a late increase in LDH, gGT, and bilirubin (Figure 3). In
ICU patients in general, liver failure develops late in the MOF cascade (125). Sprung et
al. reported poor outcome in patients undergoing elective AAA repair if they had liver
function test abnormalities (126). In a limited number of acute AAA patients, it is also
associated with high mortality (127). Durrani et al reported a 3% incidence of liver
Chapter 4
70
failure after RAAA repair (128). We cannot explain why gGT was one of the only two
measurements that deviated more from the reference values in the survivors than the
non-survivors. The isolated increase in bilirubin without other liver function
abnormalities in these patients may be the result of haemolysis of transfused blood and
resorption of the retroperitoneal haematoma that exists in almost all patients (129).
Electrolytes
The differences in electrolytes were less pronounced. One possible explanation for this
is that electrolytes depend heavily on infusion rates or renal replacement therapy. The
differences in phosphate and potassium were probably attributable to the higher rate of
renal failure in the non-survivors (130). The fact that only potassium emerged from the
multivariate analysis as an independent laboratory predictor of mortality on POD 1 is
of little consequence since the median potassium levels in survivors and non-survivors
differed by only 0.2 mmol/L and both were within the reference values.
In general, when the surviving patients were discharged from hospital after
about 1 month, most of their laboratory values had normalised, the most notable
exceptions being a decreased haemoglobin value, a mildly increased CRP value, and
discrete liver enzyme abnormalities.
In conclusion, RAAA patients show well-defined laboratory responses after
surgery, starting with haematological and coagulation abnormalities, and followed by
inflammatory, metabolic, renal, and finally liver derangement. These abnormal values
are more prominent in non-survivors, although survivors also show a wide range of
laboratory abnormalities. We believe that recognition of these abnormalities is
important since it may help to identify and predict post-operative complications early.
CHAPTER 5
HLA-DR expression on monocytes and systemic
inflammation with ruptured abdominal aortic aneurysms
JW Haveman1, AP van den Berg2,3, ELG Verhoeven1,
MWN Nijsten1, JJAM van den Dungen1, TH The2,
JH Zwaveling1
1 Department of Surgery
2 Department of Clinical Immunology 3 Department of Gastroenterology and Hepatology
University Medical Center Groningen, The Netherlands
Critical Care 2006;10:R119
Chapter 5
72
ABSTRACT
Introduction
Mortality from ruptured abdominal aortic aneurysms (RAAA) remains high. Severe
systemic inflammation, leading to multi-organ failure, often occurs in these patients. In
this study we describe the level of HLA-DR expression in a consecutive group of
patients following surgery for RAAA and compare results between survivors and non-
survivors. A similar comparison is made for IL-6 and IL-10 levels and Sequential
Organ Failure Assessment (SOFA) scores.
Methods
This is a prospective observational study. Patients with RAAA were prospectively
analysed. Blood samples were collected on days 1, 3, 5, 7, 10 and 14. The fraction of
CD-14 positive monocytes expressing HLA-DR was measured by flowcytometry. IL-6
and IL-10 levels were measured by ELISA.
Results
The study included 30 patients with a median age of 70 years, of which 27 (90%) were
men. Six patients died from multiple organ failure, all other patients survived. The
SOFA scores were significantly higher in non-survivors on days 1 through 14. HLA-
DR expression on monocytes was significantly lower on days 3, 5, 7, 10 and 14 in non-
survivors. IL-6 and IL-10 levels were significantly higher in non-survivors on day 1
and days 1 and 3, respectively.
Conclusion
HLA-DR expression on monocytes was decreased, especially in non-survivors. All
patients with RAAA displayed a severe inflammatory and anti-inflammatory response
with an increased production of IL-6 and IL-10. Poor outcome is associated with high
levels of IL-6 and IL-10 and a high SOFA score in the first three days after surgery,
while low levels of HLA-DR expression are observed from day three after RAAA
repair.
Systemic inflammation and HLA-DR in RAAA
73
INTRODUCTION
Mortality in patients following repair of a ruptured abdominal aortic aneurysm
(RAAA) remains high (30% to 70%), despite important advances in emergency
medicine, anaesthesiology, surgery and intensive care (43-47). The postoperative
course of patients after RAAA repair is almost always characterized by systemic
inflammation, sometimes leading to multiple-organ failure, a prolonged intensive care
unit (ICU) stay and a high mortality (99,100,131). Down-regulation of HLA-DR
expression on monocytes has been reported in different groups of surgical patients and
has been associated with septic complications and increased mortality
(12,23,24,29,79). We studied the expression of HLA-DR on monocytes in patients
following surgery for RAAA, taking into account levels of IL-6 and IL-10 and
Sequential Organ Failure Assessment (SOFA) scores. The primary aim of this study
was to describe the level of HLA-DR expression in these patients and to establish, if
possible, whether low HLA-DR expression was associated with increased mortality as
a result of secondary infections.
MATERIALS AND METHODS
Patients and design of the study
Patients with RAAA who survived surgery were prospectively analysed and included
in the study. Patients who underwent endovascular treatment were excluded. Cases
were only classified as RAAA when an aortic aneurysm and retroperitoneal or
intraperitoneal blood were present. The study was approved by our Medical Ethics
Committee. Written informed consent was obtained from a family member.
For each patient, one healthy employee of the laboratory served as normal
control.
On days 1, 3, 5, 7, 10 and 14, 10 ml of EDTA blood was withdrawn from the
patient and HLA-DR expression on monocytes was analysed immediately. For IL-6
and IL-10 measurements blood was kept on ice, centrifuged at 1,655 g at 4°C for 10
minutes and stored at -80°C until analysis.
Chapter 5
74
Acute Physiology and Chronic Health Evaluation (APACHE)-II scores were
calculated on ICU admission (102). The SOFA score was measured daily after surgery
(103). ICU-acquired infections were defined according to the criteria issued by the
Centres for Disease Control and Prevention. All infections were recorded
prospectively. Sepsis was defined according to Bone and colleagues (56).
Laboratory analysis
C-reactive protein (normal value <5 mg/dl) and white blood cell count (normal value 4
to 10 × 109/l) were measured every day.
IL-6 and IL-10 were measured by ELISA in 26 patients (21 survivors and five
non-survivors), using a monoclonal antibody against human IL-6 (Sanquin,
Amsterdam, the Netherlands) or IL-10 (BD Pharmingen, Alphen a/d Rijn, the
Netherlands).
The percentage of CD-14 positive monocytes expressing HLA-DR was
measured by flow-cytometry. Monoclonal antibodies against CD-14 antigen (anti-CD-
14-PE, Immuno Quality Products, Groningen, the Netherlands) were used to set a gate
for monocytes. The percentage of HLA-DR on monocytes was determined using anti-
HLA-DR fluorescein isothiocyante (Becton Dickinson Immunocytometry Systems,
San Jose, CA, USA), with an IgG2a isotype control (IgG2a FITC, Immuno Quality
Products). A live gate was set using forward and sideward scatter characteristics. A
monocyte gate was set by the CD-14+ group. Data were analysed using Cell Quest
software (Becton-Dickinson).
Statistics
Data are given as median with interquartile range. Differences between categorical
variables were tested with Chi-square analysis. The Mann-Whitney U or Kruskal-
Wallis test was performed to calculate differences in continuous variables. For
detection of correlation we used Spearman's rank correlation test. The rank correlation
coefficients were averaged after z-transformation. P values < 0.05 were regarded as
statistically significant.
Systemic inflammation and HLA-DR in RAAA
75
RESULTS
Patients
During the course of the study 46 patients with RAAA were admitted to our Hospital.
All patients were operated upon. Sixteen patients were not included in this study: six
were endovascular treated, five died during surgery, four patients were not included
because of absence of one of the primary investigators (JWH or APvdB), and for one
patient no informed consent was obtained.
Of the remaining 30 patients, the median age was 70 (64 to 75) years and 27
patients (90%) were men. Six patients died and 24 survived until hospital discharge.
Clinical characteristics of survivors and non-survivors are shown in Table 1. The non-
survivors were significantly older, had a higher APACHE-II score and more sigmoid
necrosis was observed. Blood-loss, lowest systolic blood pressure and suprarenal
clamping did not significantly differ between survivors and non-survivors.
Table 2 displays the intra- and postoperative complications of the non-
survivors. The six non-survivors died on days 2, 3, 4, 12, 21 and 30 after RAAA repair.
In three of these patients the sigmoid colon had to be resected because of ischemic
necrosis. Two patients had a culture proven infection. All patients died from multiple-
organ failure.
The SOFA score did not differ significantly between survivors and non-
survivors upon arrival in the ICU, but was significantly higher on days one through 14
in the non-survivors (Figure 1).
C-reactive protein and white blood cell count
The median C-reactive protein level increased postoperatively. In non-survivors and
survivors C-reactive protein (mg/dl) was 84 versus 31 on day 1, 283 versus 190 on day
3, 212 versus 157 on day 5 and 167 versus 159 on day 7. The median white blood cell
count (× 109/l) was 9.6 versus 10.0 on day 1, 7.8 versus 9.5 on day 3, 7.9 versus 9.4 on
day 5 and 12.6 and 10.0 on day 7 in non-survivors and survivors, respectively. All
differences were non-significant.
Chapter 5
76
Table 1. Characteristics of the survivors and non-survivors.
Survivors (N=24)
Non-survivors (N=6)
P
Demographic characteristics Age 68 (64-72) 78 (73-79) <.01 Sex (male) 21 (88%) 6 (100%) NS Intra-operative data
Lowest systolic RR (mmHg)
77 (53-90) 65 (23-79) NS
Blood-loss (litres) 3.8 (1.6-5.4) 4.8 (2.0-12.9) NS Suprarenal clamping (yes)
5 (21%) 2 (33%) NS
Post-operative data APACHE-II score 13 (9-16) 19 (16-23) .01 Re-operations (total) 10 4 NS - Sigmoid resection - Rebleeding - Lower leg amputation
2 (8%) 0
1 (4%)
3 (50%) 0 0
0.04 NS NS
Infectious complications (total patients)
7 2 NS
- Septic shock - Abdominal infection - Pneumonia - CVC infection - Wound infection
(17%) 3 (13%) 4 (17%) 2 (8%)
0
2 (33%) 1 (4%)
0 0
1 (4%)
NS NS NS NS NS
Renal replacement therapy 4 (17%) a 2 (33%) b NS Hydrocortisone treatmentc 3 (13%) 1 (17%) NS ICU length of stay (days)
7 (2-16) 8 (3-23) NS
Hospital length of stay (days)
20 (11-33) 8 (3-23) NS
Data are given as medians with interquartile range, or absolute number of patients with percentage of the total population. NS = non-significant. CVC infection; Central venous catheter related infection. a All patients had a full recovery of renal function at hospital discharge.b In an additional 2 patients renal replacement therapy was indicated but not performed because it was considered futile. c Hydrocortisone treatment was initiated for relative adrenal insufficiency.
Systemic inflammation and HLA-DR in RAAA
77
Table 2. Clinical data in the six non-survivors.
Age Died on day
Resuscitation during surgery
Blood-loss
(L)
Complications Organ failure Infectious complication
79
2 - 7.0 Respiratory and renal
-
80 3 - 9.5 Sigmoid necrosis, ischemic lower legs
Respiratory, cardiovascular and renal
-
74
4 - 2.0 Respiratory, cardiovascular and renal
-
79 12 - 2.5 Sigmoid necrosis Respiratory, hepatic, cardiovascular and renal
Enterococi in blood culture
79 21 - 3.0 Wound infection Respiratory, cardiovascular and renal
Proteus mirabilis in wound and blood
76 30 + 25.0 Sigmoid necrosis
Respiratory, cardiovascular and renal
-
Chapter 5
78
Figure 1. SOFA score after surgery for RAAA patients.The SOFA score was significantly (as indicated by*) higher in non-survivors than survivors from day 1 post-surgery onwards.
Systemic inflammation and HLA-DR in RAAA
79
Cytokine production
IL-6 and IL-10 were elevated in all RAAA patients post-surgery (Figures 2 and 3).
Median IL-6 was significantly higher in non-survivors versus survivors on day 1;
median (interquartile range) 543 pg/ml (90 to 701) versus 122 pg/ml (39 to 137), p =
0.03. IL-10 was significantly higher on days 1 and 3 postsurgery in the non-survivors
(p = 0.03 for both days).
HLA-DR expression on monocytes
On day one after surgery HLA-DR expression on monocytes was comparable in
survivors and non-survivors, and significantly lower than the 76% to 96% observed in
healthy controls. In survivors, HLA-DR expression rose to normal levels, whereas it
decreased further and remained low in non-surviving patients. Percentages of
monocytes expressing HLA-DR were significantly lower on days 3, 5, 7, 10 and 14 in
the patients who died (Figure 4) compared to survivors. No significant differences were
found between HLA-DR expression in the patients who developed infections (two non-
survivors and seven survivors) and those who did not develop infections.
HLA-DR expression on days 1, 3, 5, 7, 10 and 14 had a significant negative
correlation with the SOFA score on these subsequent days. After z-transformation,
mean r = -0.416, 95% confidence interval (CI; -0.56 to -0.25), p < 0.01. The correlation
coefficient between HLA-DR expression and IL-6 was r = -0.055, 95% CI (-0.26 to
0.15), p = 0.60. The correlation coefficient between HLA-DR expression and IL-10
was r = -0.078, 95% CI (-0.28 to 0.13), p = 0.47.
Chapter 5
80
Figure 2. IL-6 after RAAA repair. Levels of IL-6 (normal value < 20 pg/ml) were significantly higher on day one in nonsurvivors. *p < 0.05.
Figure 3. IL-10 after RAAA repair. Levels of IL-10 (normal value < 10 pg/ml) were significantly higher on days one and three in non-survivors. *p < 0.05.
Systemic inflammation and HLA-DR in RAAA
81
DISCUSSION
This study shows that, in the first days after RAAA repair, patients develop a
generalised increase in immunoregulatory cytokines as reflected by elevated levels of
IL-6 and IL-10. HLA-DR expression on monocytes is reduced and remains
consistently low in non-survivors, while it returns to normal levels in survivors. Early
high levels of IL-6 and IL-10 and subsequently reduced HLA-DR were all associated
with multiple-organ failure and death.
Several studies have shown that a severe inflammatory response is associated
with multiple organ failure and poor outcome in RAAA patients (23,132,133). It is
believed that, in RAAA patients, haemorrhagic shock, surgical trauma and ischemia
reperfusion injury all contribute to this overwhelming inflammatory response. Blood-
transfusions and surgery for sigmoid necrosis may also modulate the inflammatory
response (134,135). Our study confirms the presence of such an inflammatory response
by demonstrating an increased production of IL-6. Furthermore, the SOFA score was
significantly higher in the non-survivors from day 1 through day 14, with an increase in
difference compared to survivors from day three (Figure 1). The anti-inflammatory
cytokine IL-10 was significantly higher on days 1 and 3 in the non-survivors. Our
findings are in accordance with a study described by Lekkou and colleagues (136) who
studied 30 patients with severe sepsis and noted that HLA-DR expression was lower in
non-survivors. Furthermore, these authors also found an initial high level of IL- 6 in
non-survivors and high IL-10 on days 3, 10 and 13. The association of an initial high
level of IL-6 with organ failure and poor outcome is confirmed in patients with sepsis,
after trauma and AAA patients (137-140). The initial increase in IL-10 levels is also
described in patients after orthopaedic trauma and pancreatitis (141,142). The initial
hyperinflammatory state followed by immunoparalysis, expressed as a prolonged
increase in IL-10, could not be confirmed in these patientgroups. In patients with septic
shock, Monneret and colleagues described a significantly lower HLA-DR expression
and higher IL-10 in non-survivors (143). Caille and colleagues (144) described that
HLA-DR expression was low in septic shock but not decreased in patients with
haemorrhagic shock. One might conclude that our data from RAAA patients are in
Chapter 5
82
contrast with these findings. However, Caille and colleagues described patients with
trauma and postpartum haemorrhage; these patients do not suffer from an additional
ischemia reperfusion injury. RAAA patients experience haemorrhagic shock and
ischemia reperfusion injury simultaneously.
Figure 4. HLA-DR expression on monocytes after RAAA repair. The expression of HLA-DR on monocytes (normal range 76% to 96%) of patients after RAAA is sharply and significantly decreased from day three post-surgery onwards. a,p = 0.04; b,p = 0.02; c,p < 0.01.
The causal relationship between low HLA-DR expression and poor outcome in
ICU patients remains an interesting point of discussion. In patients with sepsis, low
HLA-DR expression is associated with monocyte deactivation, an anti-inflammatory
cytokine profile, infectious complications and death (22,30). In patients with RAAA
we could only partially confirm these findings. As shown in Figure 4, a decrease in
HLA-DR expression on monocytes is associated with a poor outcome. However, the
presence of a sustained anti-inflammatory response in these patients is difficult to
Systemic inflammation and HLA-DR in RAAA
83
envisage, considering the fact that IL-10 levels are low from day three post-surgery,
following an initial rise. In our series, only two non-survivors developed culture-
proven infection. One of these patients had necrosis of the sigmoid colon and the other
developed a wound infection in the presence of extensive organ failure. The majority of
the patients died from multiple organ failure, not from overwhelming infection due to
functional immunosuppression (Table 2). In theory, early death from multiple organ
failure may have prevented the onset of severe infection, but this remains speculative.
Low HLA-DR expression in the non-survivors might also be the result of their older
age, although this correlation could not be confirmed (145,146). Alternatively, low
HLA-DR expression may not be causally related to mortality. As such, HLA-DR
expression may be no more than a coincidental finding. Bloodloss and sigmoid
resection may also significantly alter the immune response and HLA-DR expression,
although no significant differences were found between these factors in survivors
versus non-survivors.
What can we do to improve the survival of RAAA and other surgical patients?
Since blood-loss and duration of surgery are related to the development of multiple
organ failure, meticulous technique will increase the chances of survival. The recent
advances in endovascular surgery are promising (48,50,51), although long-term
durability is unknown (147-150). Because of the shortcomings of endovascular
surgery, RAAA patients with a severe inflammatory response after open surgery will
continue to be presented to the ICU and a significant number of them will not survive.
In theory, hydrocortisone might also lead to a better outcome in RAAA patients. In
patients with sepsis and relative adrenal insufficiency, hydrocortisone suppletion
improves prognosis (151). In addition Keh and colleagues (152) showed that
hydrocortisone restored haemodynamic stability and modulated the immunological
response. These effects might also benefit RAAA patients since adrenal insufficiency
can be identified in a significant amount of them (153). The clinical effect of
hydrocortisone suppletion in RAAA patients needs to be evaluated further.
Our study has its limitations, mainly because of the small patient numbers and
the relatively low percentage of non-survivors. On the other hand, these low numbers
Chapter 5
84
were enough to reach statistical significance on HLA-DR expression. This is probably
related to the fact that RAAA patients present as an homogenous group with a well-
defined insult, as reflected in similar values for blood-loss, lowest systolic blood
pressure and suprarenal clamping.
Conclusion
Patients with RAAA displayed a severe inflammatory response post-surgery,
with markedly increased immunoregulatory cytokines. HLA-DR expression was low in
non-survivors from the day of surgery onwards. In contrast to survivors, in whom
levels returned to normal values, it remained low. Organ failure was present in non-
survivors from day 1 and was the primary cause of death. A relationship between
impaired monocyte function and death from infectious causes was not apparent in our
series. More likely, the severe initial insult in non-survivors is probably responsible for
both their low HLA-DR expression on monocytes and their onset of fatal multiple
organ failure.
Acknowledgements
The authors thank Geert Mesander and Johan Bijzet for their assistance in laboratory
analysis and Wim J Sluiter for statistical advice. This study was financially supported
by the Ambroise Paré foundation.
CHAPTER 6
Results of streamlined regional ambulance transport and
subsequent treatment of acute abdominal aortic
aneurysm
JW Haveman, A Karliczek, ELG Verhoeven, IFJ Tielliu,
R de Vos, JH Zwaveling, JJAM van den Dungen,
CJ Zeebregts, MWN Nijsten
Department of Surgery
University Medical Center Groningen, The Netherlands
Emergency Medicine Journal 2006;23:807-810
Chapter 6
86
ABSTRACT
Objective
To describe the triage of patients operated for non-ruptured and ruptured abdominal
aortic aneurysms (AAAs) before the endovascular era.
Design
Retrospective single-centre cohort study.
Methods: All patients treated for an acute AAA between 1998 and 2001 and admitted
to our hospital were evaluated in the emergency department for urgent AAA surgery.
All time intervals, from the telephone call from the patient to the ambulance
department, to the arrival of the patient in the operating theatre, were analysed.
Intraoperative, hospital and 1-year survival were determined.
Results
160 patients with an acute AAA were transported to our hospital. Mean (SD) age was
71 (8) years, and 138 (86%) were men. 34 (21%) of these patients had symptomatic,
non-ruptured AAA (SAAA) and 126 patients had ruptured AAA (RAAA). All patients
with SAAA and 98% of patients with RAAA were operated upon. For the patients with
RAAA, median time from telephone call to arrival at the hospital was 43 min
(interquartile range 33–53 min) and median time from arrival at the hospital to arrival
at the operating room was 25 min (interquartile range 11–50 min). Intraoperative
mortality was 0% for SAAA and 11% for RAAA (p = 0.042), and hospital mortality
was 12% and 33%, respectively (p = 0.014).
Conclusions
A multidisciplinary unified strategy resulted in a rapid throughput of patients with
acute AAA. Rapid transport, diagnosis and surgery resulted in favourable hospital
mortality. Despite the fact that nearly all the patients were operated upon, survival was
favourable compared with published data.
Regional transport and treatment of acute AAA
87
As untreated ruptured abdominal aortic aneurysm (AAA) has an almost 100%
mortality, rapid diagnosis and treatment are essential goals. Nevertheless, several
recent series report a hospital mortality >50% for patients with acute AAAs
(44,45,47). These figures include only patients who arrive alive at the hospital.
Therefore, total mortality for acute AAA may approximate 80–90% (43,154,155).
Delay in treatment might significantly influence mortality; therefore, measures to
reduce time to surgery can be valuable in decreasing mortality. Very few studies
describe the delay to surgery (107,156-158). AbuRahma et al describe a mortality of
73% in patients operated after a delay of >2h, whereas patients who were operated
within 2h had a mortality of 48% (p=0.05) (107). Both transportation by ambulance
and intrahospital management protocol have an influence on delays to surgery.
This study aims to present the results of a strategy of direct ambulance
transport to our tertiary referral centre when acute AAA was suspected, followed by
minimal diagnostics and emergency surgery for nearly all patients.
MATERIALS AND METHODS
Patients
This is a retrospective cohort study of consecutive patients undergoing emergency
surgery for acute AAA at a university centre. All patients admitted alive to our hospital
with acute AAAs between 1998 and 2001 were included in the study. Patients were
identified from the ambulance database, hospital and medical records using the
International Classification of Diseases—Ninth Revision codes and the search terms
aneurysm, aorta and aortic surgery.
A rural and stable population provides the referral base for our hospital.
Information on survival was retrieved from hospital databases.
Definitions
Acute AAA was defined as any AAA requiring treatment within 24h. Patients were
classified as having an acute symptomatic, non-ruptured AAA (SAAA) or ruptured
AAA (RAAA), according to the absence or presence of discontinuation of the integrity
of the aortic wall with blood extravasation as shown on computerised tomography or as
Chapter 6
88
found during surgery. Haemorrhagic shock was defined as a systolic blood pressure
≤100 mm Hg before surgery. Hospital mortality was calculated for all patients who
reached the operating theatre alive. Patients treated with emergency endovascular
repair during the same period were excluded.
Transport time was defined as the time from telephone call to the ambulance
service to arrival in the emergency room. Intrahospital delay was defined as time from
arrival of the patient in the emergency department to arrival in the operating theatre.
Total delay to surgery was defined as the sum of transport time and intrahospital delay.
Distance of transport was defined as the distance from the home address of the patient
to our hospital.
Management strategy
When ambulance personnel suspected that the patient had a ruptured aneurysm, our
hospital was alerted, so that an experienced vascular surgeon and a radiologist were
present when the patient arrived. At the same time, the operating room was alerted. The
ambulance personnel inserted two intravenous lines and initiated fluid resuscitation
only in the case of shock (ie, systolic blood pressure ≤100 mm Hg) with altered mental
state. On arrival, the diagnosis was confirmed by physical examination, ultrasound and,
more recently, computerised tomography to evaluate emergency endovascular repair as
a treatment option. For a patient in haemodynamic shock with a palpable aneurysm, no
ultrasound was carried out and the patient was immediately transported to the operating
theatre. Until aortic clamping was carried out in the operating theatre, we accepted a
systolic blood pressure of ≤100 mm Hg, to reduce retroperitoneal blood losses or to
prevent free rupture in the peritoneal cavity. Patients who had a cardiac arrest during
transport or in the emergency room but were successfully resuscitated were also
offered surgery. Exclusion criteria for surgery were prolonged cardiac arrest despite
resuscitation, advanced Alzheimer’s disease and a poor Karnofsky performance score
(159) (≤40; ie, the patient is disabled and requires special care and help), or severe
cardiovascular disease associated with a New York Health Association-IV performance
score. If the clinical picture was unclear or unknown, the patient was still offered
surgery.
Regional transport and treatment of acute AAA
89
Surgery was performed with at least one experienced vascular surgeon present.
In the operating theatre, a rapid sequence induction of anaesthesia and intubation was
carried out after prepping and draping the abdomen. After surgery, all patients
remained intubated and mechanically ventilated and were transferred to a tertiary
intensive care unit (ICU). This ICU is staffed with nurses in a 1.5:1 patient–nurse ratio,
with onsite doctors dedicated solely to the ICU for 24h a day and supervised by
certified intensivists.
Statistics
Data are reported as mean and standard deviation (SD), or as median with interquartile
ranges for skewed data. The Student’s t test was used to compare normally distributed
continuous variables, and the Mann–Whitney U test was used for continuous variables
with a skewed distribution. Differences between categorical variables were tested by χ2
analysis. Cumulative survival was calculated using Kaplan–Meier analysis. The log
rank test was used to compare survival curves between patients with SAAA and those
with RAAA. p Values <0.05 were regarded as significant.
RESULTS
Patient population
During the study period, 160 patients with acute aneurysms were operated upon: 34
with SAAA and 126 with RAAA. An additional 15 patients who received emergency
endovascular treatment for their acute AAA were excluded. Table 1 describes the
demographics of this population. Age and sex did not differ between patients with
SAAA and RAAA; nor did comorbidity profiles between these two groups.
All 34 patients presenting to the emergency department with a SAAA were
operated upon. In total, 126 patients with RAAA were evaluated for surgery, of which
only three (2.4%) patients did not undergo surgery, because of severe cardiovascular
disease with a New York Health Association-IV performance score.
Chapter 6
90
Table 1. Demographic data of the patients operated for symptomatic aneurysms. All patients
N=160
SAAA
N=34
RAAA
N= 126
p
Demographic characteristics
Age (y), mean ± SD 71 ± 8 71 ± 7 71 ± 8 NS
Male sex, n (%) 138 (86%) 29 (85%) 109 (87%) NS
Cerebrovascular disease 18 (11%) 2 (6%) 16 (12%) NS
Chronic obstructive pulmonary disease
37 (23%) 7 (21%) 30 (24%) NS
Chronic renal failure 12 (8%) 3 (9%) 9 (7%) NS
Congestive heart failure 17 (11%) 4 (12%) 13 (10%) NS
Coronary artery disease 62 (39%) 15 (44%) 47 (37%) NS
Diabetes mellitus 15 (9%) 3 (9%) 12 (10%) NS
Hypertension 50 (31%) 11 (32%) 39 (31%) NS
SD = Standard Deviation; SBP = Systolic blood pressure in the emergency department; IQR = Interquartile Range
Transport time and intrahospital delay
Median transport time for the 34 patients with SAAA was 43 min (interquartile range
33–52 min). The median distance of transport (between patient pick-up and hospital)
was 22 km (16–31 km). Median intrahospital delay was 160 min (53–452 min).
Median transport time of the 126 operated patients with RAAA was 43 min
(33–53 min). The median distance of transport was 22 km (4–30 km). Median
intrahospital delay was 25 min (11–50 min). Median total delay to surgery was 67 min
(52–102 min; table 2). Of these patients, 66% were referred by a general practitioner or
directly by the ambulance services, and 34% were referred from another hospital.
The diagnostic investigation was different in patients with SAAA and RAAA:
an ultrasound or computed tomography scan was used in 76% and 51%, respectively
(p=0.007).
Regional transport and treatment of acute AAA
91
Table 2. Blood pressure at arrival emergency department, delay to surgery, diagnostic approach, level of aortic clamping and length of stay of patients operated for symptomatic aneurysms. All patients
N=160
SAAA
N=34
RAAA
N= 126
p
Systolic blood pressure at arrival
Cardiac arrest
RR 20-60 mmHg
RR 60-100 mmHg
RR >100 mmHg
8 (5%)
31 (19%)
65 (41%)
56 (35%)
0
0
7 (21%)
27 (79%)
8 (6%)
31 (25%)
58 (46%)
29 (23%)
NS
<.01
NS
NS
Delay to surgery (minutes)
Transport time 42 (33-49) 43 (33-52) 43 (33-53) NS
Intrahospital delay 29 (12-61) 160 (53-452) 25 (11-50) <.001
Diagnostic work-up
Physical examination only 70 (43%) 8 (24%) 62 (49%) .007
Ultrasound 40 (25%) 8 (24%) 32 (25%) NS
Computerised tomography 65 (41%) 23 (68%) 42 (33%) <.001
Intra-operative data
Suprarenal clamping (yes) 8 (5%) 0 8 (6%) NS
Length of stay (days), median (IQR)
Intensive care 3 (1-8) 2 (1-3) 4 (2-10) .001
Hospital 12 (8-18) 9 (7-11) 14 (9-21) .001
IQR, interquartile range; NS, not significant; RAAA, ruptured AAA; SAAA, symptomatic, non-ruptured AAA.
Outcome
Overall intraoperative mortality was 0 for patients with SAAA and 14 (11%) for
patients with SAAA (p=0.042). Thirty-day and hospital mortality was 3 (9%) and 4
(12%), respectively, for SAAA. Thirty-day and hospital mortality for patients with
RAAA was 38 (30%) and 42 (33%), respectively (p=0.011 and 0.014). Haemorrhagic
Chapter 6
92
shock was observed in 7 (21%) patients with SAAA versus 97 (77%) patients with
RAAA. None of the patients with SAAA and eight with RAAA had a cardiac arrest
during ambulance transport or in the emergency department. Four of these patients died
intraoperatively, two died in the ICU and another two patients survived until discharge
from hospital. Of these two patients, one died after 4 months; the other is still alive
after >5 years of follow-up. One-year mortality was 6 (18%) for SAAA and 54 (43%)
for RAAA, see figure 1 (p=0.008; log rank). Follow-up was complete in all patients.
Figure 1. Kaplan-Meier curve of the 1-year survival in patients with SAAA and RAAA.
DISCUSSION
This study shows that a unified strategy for the treatment of patients with acute AAAs
is associated with a hospital mortality of 12% and 35%, for SAAA and RAAA,
respectively, despite offering surgery to >95% of all patients. We infer that the
combined transport time and intrahospital delay of only 67 min has contributed to this
relatively favourable outcome.
The survival curves for SAAA and RAAA suggest that longer-term survival is
similar, which reflects the similar effect of associated comorbidities.
Regional transport and treatment of acute AAA
93
In the literature, hospital mortality for patients operated for RAAA ranges
from 20% to 70% (44,45,160-162). This wide range is partly explained by selection
bias, with some centres having restrictive and others liberal indications for surgery.
This, however, is not the only explanation, as in some series (160,161,163-165) in
which surgery was offered to an average of 73% (95% confidence interval (CI) 72% to
74%) of the patients with
ruptured aneurysms, the cumulative hospital mortality was 40% (95% CI 38% to 41%).
The average time of 43 min between the emergency call and arrival of patients
at our emergency department reflects the efficiency of our transport system and the size
of our catchment area in the northern Netherlands. In addition, the fact that the
paramedics alert the hospital before their arrival and that the vascular surgeon and the
radiology staff are in hospital at the time of the patients’ arrival reduces intrahospital
delay.
Many other factors affect outcome after acute AAA. Another important
determinant of outcome is the experience and the specialty of the operating surgeon,
with worse survival reported for less experienced surgeons or for general surgeons than
for vascular surgeons (123,166,167). Postoperative treatment also affects outcome.
Sandison et al (168) observed marked differences in mortality between two ICUs that
received patients operated by the same surgical team. Thus, the availability of a well-
staffed surgical ICU may also have been beneficial for the prognosis of our patients.
Comparison of results between hospitals and surgeons is confounded by
patient selection, modality of patient transport, distances, surgical experience,
postoperative care, definition of symptomatic aneurysms and of haemodynamic
stability. The retrospective design of our study limits the inferences that may be drawn.
However, our extensive search for patients with symptomatic aneurysms (including
hospital, doctor and emergency services records), the regional pattern of referral and
the completeness of our follow-up provide an insight to the results that may be
obtained with a unified strategy of aggressive management of patients with
symptomatic aneurysms.
Chapter 6
94
The clinical implications of our findings may vary depending on the setting in
which treatment of acute AAAs is performed. As geographical conditions that
determine the distance that patients should travel vary widely, the effectiveness of
measures to limit transport delay may also vary. Faster means of transportation and a
protocol for the management of these patients are strategies to improve results.
An additional approach may be the implementation of an endovascular
programme for the treatment of symptomatic aneurysms. In elective AAA repair,
endovascular treatment has shown reduced organ dysfunction and lower 30-day
mortality than in open AAA repair (48,50), although long-term survival is comparable
(149,150). Endovascular treatment for symptomatic AAAs showed promising results;
however,
suitability was low (169). Furthermore, a potential hazard of this approach is the
inevitable delay to surgery caused by the necessary computed tomography. Therefore,
the effectiveness of emergency endovascular procedures in the treatment of RAAA
needs confirmation in prospective clinical trials.
Further studies on the management of acute AAA should include a description
of the protocols used, and report the delays involved as well as the number and type of
patients who were denied surgical treatment.
CONCLUSION
In an environment and an ambulance system that has short delays of transportation, a
unified strategy of treatment of acute AAA provides hospital survivals comparable to
the best reported in the literature, despite a policy of offering surgery to most patients.
ACKNOWLEDGEMENTS
We thank CS Cinà for his valuable comments on this article.
CHAPTER 7
Letter to the editor
With regard to:
The Multicentre Aneurysm Screening Study Group.
The Multicentre Aneurysm Screening Study (MASS) into
the effect of abdominal aortic aneurysm screening on
mortality in men: a randomised controlled trial.
Lancet 2002;360:1531–39.
JW Haveman, A Karliczek, ELG Verhoeven,
JJAM van den Dungen, MWN Nijsten
Department of Surgery, University Medical Center Groningen, The Netherlands
Lancet 2003;361:1058
Chapter 7
96
Sir
The Multicentre Aneurysm Screening Study (MASS) Group do not address the
potential effect of measures to improve survival in patients with ruptured abdominal
aortic aneurysm (54). If surgery is withheld from these patients they will die.
Nevertheless, surgery is frequently withheld from these patients: P Basnyat and
colleagues found that 100 of 233 patients with ruptured abdominal aortic aneurysm
who reached hospital alive were denied surgery (160).
It is difficult to predict the outcome of surgery for ruptured abdominal aortic
aneurysm when a patient is still at the emergency department, whereas, as Kniemeyer
and coworkers found, a much more realistic prognosis can be made for those patients
who are alive 48h after surgery (170). Since 1990 we have implemented a policy of
immediate surgery in nearly all patients with suspected ruptured abdominal aortic
aneurysm. When we are notified of such a patient, a vascular surgeon is immediately
called. Surgery is initiated in almost every patient, even those in shock. Surgery is not
done in patients who are moribund or in those with a poor performance score. In 265
consecutive patients (mean age 71 [SD 8] years), surgery was started 25 (IQR 11–50)
min after arrival at hospital. 30-day mortality was 33%, which is similar to 38% in
MASS, whereas most published studies report mortality rates that range from 30% to
70%. We believe these differences are likely to be related to different treatment
policies, including variation in delay to surgery (107).
Although the required effort for screening seems considerable, the MASS
Group previously reported that prevention of ruptured abdominal aortic aneurysm by
screening is cost-effective (55). Now that cost-effectiveness arguments favour
preventive screening for abdominal aortic aneurysm, it would be relevant to see any
data the MASS Group have about the cost-effectiveness of emergency treatment.
When an integral programme for prevention of death from ruptured abdominal
aortic aneurysm is designed, guidelines for prompt treatment should be included.
Patients who develop ruptured abdominal aortic aneurysm despite the presence of a
screening programme should not suffer because of an overly fatalistic view about their
Letter to the editor of the lancet
97
outcome. We believe that prompt and liberal treatment for ruptured abdominal aortic
aneurysm could be as cost effective as screening.
Chapter 7
98
CHAPTER 8
Summary, general discussion and conclusions
Chapter 8
100
SUMMARY
Chapter 1 introduces the concept of systemic inflammation after major
surgery. The understanding of (systemic) inflammation in the context of surgery
throughout previous centuries is described. Chapter 1 also describes the two patient
groups studied: patients who had undergone orthotopic liver transplantation (OLT) on
the one hand, and patients with ruptured abdominal aortic aneurysms (RAAA) on the
other. The concept of the Systemic Inflammatory Response Syndrome (SIRS) is
reviewed, and the role of monocyte function after OLT and RAAA is explored.
In chapter 2 the pathogenesis of sepsis is described with a focus on the role of
monocytes, immunomonitoring and treatment. In this review article, the two phase
theory of sepsis is presented. The first phase represents the inflammatory response
leading to the activation of monocytes with a systemic release of pro-inflammatory
cytokines like TNF-, IL-1 and IL-6. The first phase is generally described as the
Systemic Inflammatory Response Syndrome (SIRS). The second phase represents the
anti-inflammatory phase with the release of anti-inflammatory cytokines as IL-10, and
is referred to as the Compensatory Anti-inflammatory Response Syndrome (CARS).
Despite enormous effort, most randomised controlled trials investigating a single drug-
intervention in sepsis did not show an improvement in survival. The intervention drugs
used in these trials were almost always designed to counteract the inflammatory
response, which is the first phase. The anti-inflammatory response may already have
been in effect at the time the drugs were administered, which may account for the lack
of successful intervention seen in these studies. In this chapter we elaborated on the
role of HLA-DR expression on monocytes as a parameter for the inflammatory
response. A normal or high HLA-DR expression on monocytes corresponds with SIRS
while a low HLA-DR indicates CARS. The expression of HLA-DR may be used as an
indicator for immunomodulation. In patients exhibiting a predominantly systemic
inflammation, anti-inflammatory interventions may improve prognosis, while patients
with sepsis and low HLA-DR expression may benefit from immunostimulation.
Sepsis following orthotopic liver transplantation (OLT) is a complication that
causes significant morbidity and mortality. Chapter 3 describes a prospective
Summary, discussion and conclusions
101
observational study of 20 adult OLT patients. HLA-DR expression on monocytes was
monitored during the first 4 weeks after transplantation. The seven patients who
developed sepsis had a significantly lower HLA-DR expression on monocytes, both
before and after they developed sepsis. In the two patients with sepsis who died, HLA-
DR expression remained low, while in the five septic patients who recovered, HLA-DR
expression returned to normal values. The patients who developed sepsis had received
significantly more prednisolone than the patients who did not. Incubation with
prednisolone in vitro lowered the expression of HLA-DR in a dose-dependent manner.
Low HLA-DR expression on monocytes appears to be a reliable risk marker for
impending sepsis in OLT patients. The level of risk may be, at least in part, related to
the dose of prednisolone. If HLA-DR is treated as a risk indicator for sepsis, treatment
aimed at improving monocyte function or a reduction in steroids should be promptly
initiated in those patients who show a low expression of HLA-DR to prevent the
development of sepsis.
Laboratory values are routinely determined after the surgical repair of a
ruptured abdominal aortic aneurysm (RAAA). In chapter 4 we present the results of a
retrospective analysis of the course of all routinely determined laboratory values in 290
RAAA patients. The purpose of the study was to describe the ‘normal or benign’
course of RAAA patients who survive until hospital discharge and to identify factors
that distinguished them from the non-survivors. Both the survivors and the non-
survivors showed a wide range of laboratory abnormalities after surgery. The
laboratory results were grouped into six categories (haematology and coagulation,
systemic inflammation, metabolic, renal, liver, and electrolytes). The categories we
chose are strongly related to the causes of death. For example, the patients who die of
massive haemorrhage usually do so within the first 24 hours following surgery,
whereas systemic inflammation and MOF develop more than 24 hours after surgery.
We believe that recognition of the associated laboratory abnormalities is important as it
may help in the early prediction and identification of post-operative complications.
Chapter 5 describes systemic inflammation and HLA-DR expression on
monocytes in RAAA patients in a prospective observational study. Thirty patients were
Chapter 8
102
included and analysed consecutively. The primary outcome parameter was hospital
mortality. Mortality was higher in older patients, patients with a higher APACHE-II
(Acute Physiology and Chronic Health Inquiry) score, and the vital need for suprarenal
clamping. The Sequential Organ Failure Assessment score (SOFA) was significantly
higher in non-survivors from day 1 through day 14 after surgery. IL-6 and IL-10 were
transiently higher on days 1 and 3 in non-survivors. HLA-DR expression on monocytes
dropped after surgery in both survivors and non-survivors. However, in non-survivors
HLA-DR expression was significantly lower from day 3 through day 14 after surgery
compared with the survivors. Low HLA-DR expression was associated with multiple
organ failure and death, although death from secondary infections was not seen in our
patients. We conclude that shock and surgery lead to an overwhelming inflammatory
response which sets the stage for fatal multiple organ failure.
Rapid surgical intervention is one of the most important principles in the
clinical management of patients with RAAA. Chapter 6 describes the importance of a
multidisciplinary approach with clear protocols and dedication to the treatment of these
patients. Our treatment protocol consisted of rapid transport by ambulance to the
emergency department while accepting a low systolic blood pressure. During transport,
the hospital was notified of imminent arrival of a patient with a possible RAAA. Only
three of the 126 patients with ruptured abdominal aortic aneurysms were denied
surgery. The average intrahospital delay was 25 minutes. Hospital mortality was 33%.
Despite our liberal policy of offering surgery to almost every patient, hospital mortality
was comparable to the best reported in the literature.
The multicentre aneurysm screening study group has investigated the potential
benefit of screening men aged 65-74 years for an abdominal aneurysm. In chapter 7,
we emphasize that guidelines for the prompt treatment of ruptured aortic aneurysms
should also be included when screening programs are implemented. Patients who
develop a ruptured AAA despite the presence of a screening program should not be
denied treatment due to an overly fatalistic view on their outcome. In our opinion,
immediate surgery for RAAA patients is as cost effective as a screening program.
Summary, discussion and conclusions
103
GENERAL DISCUSSION AND CONCLUSIONS
Our results show that both OLT and RAAA patients develop an intense
inflammatory response and depressed HLA-DR expression after surgery which is
associated with high morbidity and mortality. Therefore, understanding the
inflammatory response after major surgery is relevant and may provide opportunities to
improve outcome in these patients.
The implications for understanding the pathophysiology of SIRS
The previously postulated SIRS/CARS sequence of events is depicted in the
left panel of figure 1. A catastrophic event causes an inflammatory reaction that is
followed by a counter-inflammatory response that theoretically should restore the
balance of health. We also see these two phases in the OLT patients’ inflammatory
response, but here they occur against the background of immunosuppression present as
a result of pre-existing illness and immunosuppressive drugs.
Figure 1. left panel the ‘normal’ pro- and anti-inflammatory response, illustrated by a mildly enhanced pro- and subsequently a counter-inflammatory response which re-establishes equilibrium. The right panel shows the response in a patient with an overwhelming counter-inflammatory response which can be counteracted by early intervention (i.e. decreasing immunosuppressants).
Chapter 8
104
In OLT patients, the intensity of the pro-inflammatory phase may be less
intense as a result, and the counter-inflammatory phase becomes more pronounced than
in other patients. This might explain the high incidence of sepsis related complications
in our patient cohort. A timely reduction in immunosuppression (indicated by the arrow
in the right panel of figure 1) might be effective in preventing these infections, as
discussed below.
To complicate matters, our observations in RAAA patients seriously challenge
the SIRS/CARS concept of events. We did not see the development of any
opportunistic infections which are the classical clinical manifestation of
immunodeficiency. Instead, patients died from the complications of multiple organ
failure which developed almost immediately after surgery. Additionally, our data (and
those of others) show that the pro and counter inflammatory responses co-exist from
the start (136,171,172). This is represented in figure 2.
Whether these two types of inflammatory response contribute equally to the
development of multiple organ failure is not clear. This warrants further research as it
has important consequences for intervention.
Figure 2.The co-existing pro- and anti-inflammatory response.
Diagnostic and prognostic aspects of monocyte HLA-DR expression
Previously, HLA-DR expression on monocytes was measured to predict septic
complications after major surgery, trauma, severe burns, and for patients on a
Summary, discussion and conclusions
105
ventricular assist device awaiting cardiac transplantation (23-27,62). Most studies
showed that a persisting low HLA-DR expression was associated with poor outcome
(79,136,142,173-176), however a few others could not confirm these results (177,178).
These latter 2 studies measured HLA-DR expression on monocytes only during the
first 2 post-operative days. Our studies on OLT and RAAA patients confirmed that
HLA-DR expression on monocytes is an accurate predictor of outcome. Low HLA-DR
expression on monocytes was present 1-8 days before the onset of clinical symptoms in
all 7 patients who developed sepsis, and remained low in the 2 patients who died from
sepsis. RAAA patients with a low HLA-DR expression on monocytes had a very poor
prognosis. Non-survivors could be identified by a significantly lower intensity of HLA-
DR expression on monocytes as early as day 3, and preceding death by a median of 8
days.
The usefulness of monocyte HLA-DR expression, at least in RAAA patients,
is somewhat limited by our finding that 3 days were required before a distinction
between survivors and non-survivors could be made with any degree of statistical
significance. This observation was confirmed by Monneret et al, who showed that
HLA-DR expression on monocytes is significantly lower in the non-survivors after 3-4
days (175).
Laboratory markers such as lactate levels, platelet counts, CRP, pro-calcitonin,
or cytokine levels also show marked differences between survivors and non-survivors.
It remains to be determined which of these will serve as the most useful prognostic
markers, and whether different markers will be required for different disease processes.
Mechanism(s) of decreased HLA-DR expression
It is not known which pathophysiological mechanism is responsible for the (low) HLA-
DR expression on monocytes; for example signal transduction or mRNA secretion
might be important. A study by Fumeaux et al showed that IL-10 decreases HLA-DR
expression. In patients with septic shock, this is probably due to re-endocytosis of
HLA-DR and intracellular sequestration (179).
Chapter 8
106
Our studies did not clarify whether low HLA-DR expression is “just” a
clinically useful epiphenomenon or whether it constitutes a relevant element in the
pathophysiologic chain that underlies SIRS. In the first theory, monocytes might be
useful as surrogate markers in (immuno-)intervention studies (which by itself is
important given the large numbers of patients required in randomised studies having
survival as outcome parameter). In the second theory, monocytes (or their HLA-DR
expression) might constitute a target for intervention.
Therapeutic implications of monocyte HLA-DR expression
Our observations in OLT patients strongly suggest that it is the combination of
chronic illness, major surgery and immunosuppression that predisposes the patients to
septic complications. While the first two of these factors cannot be changed, the
intensity of immunosuppression can be easily adapted. The potential impact of such
changes is illustrated by our observation that in vitro, prednisolone decreases HLA-DR
expression on monocytes in a dose-dependent way.
Figure 3. The abrogated pro- and anti-inflammatory response by early intervention.
Consequently, monitoring HLA-DR expression provides us with the
opportunity to decrease immunosuppression pre-emptively in OLT patients at a high
risk of developing sepsis in an effort to prevent this complication and improve
outcome. Our findings justify undertaking a prospective, randomised study to
determine whether the lowering of immunosuppression guided by low monocyte HLA-
DR expression decreases the incidence of septic complications. Indeed, our
Summary, discussion and conclusions
107
observations on the effect of steroids on HLA-DR expression provides an argument for
low-dose prednisolone or even steroid-free immunosuppression regimens that may be
associated with a lower incidence of sepsis (180,181).
The therapeutic consequences of low HLA-DR expression in other categories
of patients such as those with RAAA are more difficult to envisage. As pro- and
counterinflammatory responses co-exist, immuno-intervention should probably be
aimed at lowering both these two responses. Intuitively it might be disadvantageous to
“block” inflammation, thereby leaving counter-inflammation unopposed. Measures
directed at both components of the response might be more beneficial (Figure 3).
After Ronco et al. showed that a high ultrafiltration rate leads to a better
prognosis in ICU patients with renal failure (182), the early initiation of renal
replacement therapy in septic ICU patients became more accepted (183-186). Other
investigators showed that high cutoff haemofiltration leads to lower levels of IL-6 and
IL-1ra, which had a beneficial effect on leukocyte proliferation, polymorphonuclear
function, and the amount of norepinephrine administered (187-189). Furthermore,
selective extracorporeal immunoabsorption lowers LPS, IL-6, and C5a levels, and
leads to an increase in HLA-DR expression on monocytes. However, the effect on
outcome in patients with sepsis has not yet been established (190).
Hydrocortisone suppletion might also be beneficial, as a significant number of
RAAA patients have relative adrenal insufficiency (153). Hydrocortisone restores
haemodynamic stability and modulates the immune response and probably improves
prognosis in patients with septic shock (151,152,191-193). One can speculate that this
effect also holds for RAAA patients. In a subgroup of RAAA patients even high dose
steroids might be beneficial. However, after the negative results of high dose steroids
in patients with sepsis and the significant increase in secondary infections in the group
of patients receiving methylprednisolone no more trials with high dose steroids were
conducted (194). Nevertheless, hypothetically there may be a two group phenomenon.
One group would have a relatively low pro- and anti-inflammatory response, and the
second group would display a high inflammatory response. The first group would have
Chapter 8
108
a good prognosis anyway, and would not benefit from the administration of
methylprednisolone as they are less susceptible to multiple organ failure to begin with.
The second group, which has the massive immune response may benefit from the
administration of high dose steroids to mitigate that response. To our knowledge, these
two groups have not been separately explored in the literature. It would be worthwhile
to investigate a two group model, although more evidence supporting this theory would
first be necessary before a study of high dose steroid treatment for patients with sepsis
can be re-initiated.
Prevention of RAAA
In order to improve prognosis for RAAA patients, the benefits of screening for
AAA need to be evaluated. The MASS study showed that screening elderly men for
AAA reduced AAA-related mortality (54). However, it is unclear if screening remains
beneficial when all the family members of an AAA patient are screened. Furthermore,
the prevention of AAA related deaths may just change the cause of death in elderly
patients without delaying it, i.e. a lower AAA related mortality may lead to more death
from myocardial infarction and cancer (195). Meticulous surgical technique and
increasing experience with endovascular repair for RAAA patients will likely also
improve outcome. Hopefully this will be confirmed in a randomised controlled trial
(196). In the meantime liberal and immediate surgery for RAAA patients is probably
the best treatment for these patients (35).
HLA-DR expression on monocytes is an important and relevant parameter in
patients following liver transplantation and ruptured abdominal aortic aneurysm repair.
Persistent low HLA-DR expression is associated with a high mortality in several
patient groups. In this situation, OLT patients may benefit from a reduction in
immunosuppressive medications, especially corticosteroids. In patients who have
undergone RAAA repair, the low HLA-DR expression on monocytes is the result of an
overwhelming pro- and anti-inflammatory response. These patients might benefit from
hydrocortisone administration in the case of relative adrenal cortical insufficiency or
Summary, discussion and conclusions
109
early high-volume venovenous haemofiltration. More knowledge on the intracellular
mechanism responsible for modulating HLA-DR expression on monocytes is necessary
to make individualised immunointervention treatment a success.
110
CHAPTER 9
Samenvatting
Chapter 9
112
Dit proefschrift: ‘Systemic Inflammation and Monocyte Function after Major Surgery’
beschrijft de ontstekingsrespons en monocyt functie na grote chirurgie. Een
ontstekingsrespons is het beste uit te leggen door te bedenken wat er gebeurt als
iemand een (snij)wond oploopt. Om te zorgen dat de wond snel geneest treden er een
aantal processen op. De bloedvaten rond de wond gaan openstaan zodat witte
bloedcellen en weefselcellen (fibroblasten) naar de wond gaan. Witte bloedcellen
ruimen onder andere het aangemaakte stolsel op en de fibroblasten zorgen voor de
wondgenezing. Doordat de bloedvaten openstaan, treedt er lokaal een verhoogde
doorbloeding op; dit is te zien aan de rode kleur rond de wond en de warme huid.
Daarnaast treedt er vaak ook enige zwelling op rond de wond omdat er ook vocht uit de
bloedvaten treedt. Door prikkeling van nabijgelegen zenuwen geeft de patiënt pijn aan.
Verder is er verminderde functie van dit gebied doordat bijvoorbeeld een gewricht stijf
wordt. Al deze mechanismen zijn erop gericht een snel herstel van de wond te
bevorderen.
Systemische inflammatie (ontsteking in het hele lichaam) heeft eigenlijk dezelfde
ontstaanswijze als een lokale ontsteking, en is er ook op gericht om sneller herstel te
bevorderen. Soms kan zo´n ontstekingsrespons echter doorschieten en maakt zo de
patiënt alleen maar meer ziek, er treedt orgaanfalen op en patiënt kan zelfs overlijden.
Een systemische onsteking treedt na elke ingrijpende gebeurtenis van het lichaam op.
Enkele voorbeelden zijn: een groot ongeval waarbij de patiënt bijvoorbeeld een
bovenbeenfractuur en letsel van de buikorganen heeft, een alvleesklierontsteking, grote
brandwonden of grote operaties zoals het uitschakelen van een aneurysma (abnormale
verwijding) van de abdominale aorta (grote buikslagader). Ook bij een infectie na
bijvoorbeeld een levertransplantatie kunnen deze processen een rol spelen. Het doel
van het onderzoek was het beschrijven van de systemische inflammatoire respons en
monocyt functie. Ons onderzoek beschrijft deze respons bij patiënten na een
levertransplantatie en patiënten die geopereerd zijn in verband met een gebarsten
aneurysma van de abdominale aorta (RAAA). Deze twee patiëntenpopulaties zijn zeer
relevant omdat zij relatief vaak systemische complicaties ontwikkelen wat kan leiden
tot multi-orgaan falen en overlijden.
Samenvatting
113
Hoofdstuk 1 is het inleidende hoofdstuk waarin kort de geschiedenis van de
heelkunde en de ontwikkeling van grote en complexere operaties wordt weergegeven.
De systemische inflammatoire respons (ontstekingsreactie) wordt beschreven, evenals
de inzichten in de huidige behandeling van patiënten na een levertransplantatie.
Doordat deze patiënten afweerremmende medicamenten (immunosuppressiva)
gebruiken om afstoting te voorkomen zijn zij zeer vatbaar voor infecties. Tenslotte
wordt in deze inleiding de behandeling van patiënten met een geruptureerd aneurysma
van de abdominale aorta besproken met daarbij de problemen en complicaties tijdens
de postoperatieve periode.
Hoofdstuk 2 bevat een overzichtsartikel over de monocytfunctie bij patiënten
met sepsis. Hierbij spelen twee belangrijke immuunreacties een rol. Ten eerste SIRS
(Systemic Inflammatory Response Syndrome): dit treedt vaak vanaf het begin op
wanneer alle afweersystemen geactiveerd zijn. Dit kenmerkt zich door koorts,
verhoogde witte bloedcellen, versnelde ademhaling en een versnelde hartslag. De
tweede respons is CARS (Compensatory Anti-inflammatory Response Syndrome): dit
treedt vaak later op en kenmerkt zich door een verminderde monocytfunctie waarbij de
HLA-DR expressie op het oppervlak van de cel verlaagd is. Als complicatie treden
hierbij vaak infecties met gisten en schimmels (opportunische infecties) op die moeilijk
te behandelen zijn en een hoge mortaliteit hebben.
Er zijn in de jaren voorafgaand aan het verschijnen van dit artikel vele
gerandomiseerde studies verricht naar geneesmiddelen die erop gericht zijn de SIRS
respons te onderdrukken. De resultaten van deze studies waren teleurstellend. Er werd
geen overlevingsvoordeel gezien van patiënten die deze middelen kregen in
vergelijking met de placebogroep. In dit artikel geven wij hier een aantal verklaringen
voor. De belangrijkste verklaring is dat de SIRS reactie vaak al enige tijd bezig is.
Hierbij kan het zo zijn dat de toegediende geneesmiddelen niet op het optimale
moment gegeven waren en dat patiënt al een onderdrukt immuunsysteem had (CARS):
het geven van geneesmiddelen die deze respons onderdrukken is dan logischerwijs niet
zinvol. In het artikel stellen wij voor om aan de hand van de HLA-DR expressie op de
Chapter 9
114
monocyt te beslissen of patiënten afweeronderdrukkende middelen moeten krijgen (bij
SIRS) of juist afweerondersteunende geneesmiddelen (bij CARS). Eerder onderzoek
suggereert namelijk dat een verlaagde expressie van HLA-DR op monocyten (lager dan
30%) geassocieerd is met een slecht werkend immuunsysteem (CARS) met daarbij een
hoog risico op opportunische infecties die een hoge mortaliteit hebben. Een normale
HLA-DR expressie (70-100%) zou geassocieerd zijn met een goed werkend
immuunsysteem. Deze patiënten zouden dus wel baat kunnen hebben bij
afweeronderdrukkende geneesmiddelen waar voorheen al veel onderzoek naar verricht
is. Deze hypothese zou echter nog wel in een gerandomiseerde studie onderzocht
moeten worden.
Hoofdstuk 3 beschrijft een studie bij 20 levertransplantatiepatiënten.
Levertransplantatiepatiënten worden postoperatief behandeld met hoge doseringen
immunosuppressiva. Deze worden gegeven om afstoting van de donorlever te
voorkomen. Bij deze patiënten werd door middel van bloedafname en laboratorium
analyse de HLA-DR expressie op monocyten bepaald; direct voor de transplantatie en
op dag 7, 14, 21 en 28 na transplantatie. Deze studie laat zien dat 7 patiënten na de
operatie een infectie opliepen waarbij zij voldeden aan de criteria voor sepsis, dat wil
zeggen een bewezen infectie met een systemische ontstekingsreactie. Wanneer de
patiënten met en zonder sepsis worden vergeleken blijkt dat de patiënten met sepsis een
significant lagere HLA-DR expressie op monocyten hadden 3 tot 8 dagen voordat zij
septisch werden. Twee van de zeven patiënten met sepsis kwamen te overlijden. Verder
kregen de patiënten met sepsis een significant hogere dosering prednisolon. In vitro
incubatie van monocyten met prednisolon liet een dosis gerelateerde daling van de
HLA-DR expressie op monocyten zien. Deze resultaten suggereren dat het verlagen
van de immuunsuppressiva bij patiënten met een lage HLA-DR expressie op
monocyten, zou kunnen leiden tot minder infecties met sepsis.
Hoofdstuk 4 beschrijft het verloop van 29 laboratoriumbepalingenwaarden bij
290 patiënten met een RAAA in de eerste week na de operatie en bij ontslag. Van deze
290 patiënten overleden er 100 tijdens de ziekenhuisopname (34%). Bijna alle
laboratoriumwaarden waren postoperatief afwijkend. Er werden diverse verschillen
Samenvatting
115
tussen patiënten die overleefden en patiënten die niet overleefden gevonden, waarbij de
laatstgenoemde groep altijd het sterkste afweek van de referentiewaarde. De 29
laboratorium waarden werden verder onderverdeeld in 5 categorieën: hematologie en
stolling, systemische inflammatie, metabool, nierfalen en leverfalen. Daarnaast werden
alle elektrolyten geanalyseerd. De laboratoriumwaarden passend bij hematologie en
stolling waren direct postoperatief het meest afwijkend, waarna deze bij de patiënten
die overleefden het snelst normaliseerden. Hierna volgden de laboratoriumwaarden
passend bij systemische inflammatie, nierfalen, metabool, en leverfalen. Kennis van
deze respons postoperatief kan belangrijk zijn voor het vroegtijdig herkennen van
complicaties.
Hoofdstuk 5 beschrijft de systemische inflammatie en monocytfunctie bij
geopereerde RAAA patiënten. Bij 30 RAAA patiënten werd postoperatief op dag 1, 3,
5, 7, 10 en 14 de HLA-DR expressie op monocyten en het interleukine-6 en
interleukine 10 bepaald. Interleukine 6 is een cytokine dat fors verhoogd is bij
systemische inflammatie. Interleukine-10 is verhoogd bij een anti-inflammatoire
respons (CARS). De ziekenhuismortaliteit was 20% (6 patiënten). De resultaten van
deze studie laten zien dat de HLA-DR expressie op monocyten significant lager was bij
de overleden patiënten op dag 3, 5, 7, 10 en 14. Interleukine-6 was significant hoger bij
de overleden patiënten op dag 1. Interleukine-10 was signifant hoger bij de overleden
patiënten op dag 1 en 3 na de operatie. Patiënten ontwikkelden geen opportunische
infecties. Hieruit concludeerden wij dat de overleden RAAA patiënten een forse
systemische ontstekingsrespons ontwikkelden, zich uittend in een verlaagde HLA-DR
expressie op monocyten en een verhoogd interleukine-6 en interleukine-10 na de
operatie. Deze patiënten overleden voornamelijk ten gevolge van multi-orgaan falen.
Hoofdstuk 6 beschrijft de resultaten van 160 patiënten met een acuut
aneurysma van de abdominale aorta, waarbij 34 patiënten een symptomatisch niet-
geruptureerd AAA (SAAA) hadden en 126 een RAAA. De hele zorgketen vanaf het
telefoontje naar de ambulance tot aan het ontslag naar huis of overlijden is in kaart
gebracht en geanalyseerd. Wanneer een patiënt met een verdenking RAAA wordt
aangekondigd komt direct de vaatchirurg naar de spoedeisende hulp, net als de
Chapter 9
116
dienstdoende radioloog voor een echo of CT-scan en tot slot de anaesthesist. Daarnaast
wordt de operatie kamer in gereedheid gebracht. Alle patiënten met een SAAA en 98%
van de patiënten met een RAAA werden geopereerd. De ziekenhuismortaliteit was
12% vs 33% voor respectievelijk SAAA en RAAA. De mediane totale tijd tussen het
telefoontje naar de ambulance en start van de operatie was 67 minuten voor patiënten
met een RAAA. Onze studie laat een significant lagere mortaliteit zien in de SAAA
groep ten opzichte van de RAAA patiënten. SAAA patiënten hebben weer een hogere
mortaliteit dan electief geopereerde patiënten. Verder is in deze studie de mortaliteit
van RAAA patiënten in vergelijking met de literatuur goed.
Hoofdstuk 7 is een ingezonden brief naar aanleiding van de Multicentre
Aneurysm Screening Study (MASS). De MASS is een onderzoek bij ruim 67.000
mannen tussen de 65 en 74 jaar die middels een echografie gescreend werden op een
AAA. Wanneer de diameter van het aneurysma groter was dan 5.5 cm werden zij
verwezen naar de vaatchirurg om geopereerd te worden om zo een geruptureerd
aneurysma te voorkomen. De andere helft van de studiepopulatie werd niet gescreend.
De resultaten van deze studie laten zien dat aneurysma-gerelateerd overlijden lager was
in de gescreende groep ten opzichte van de niet gescreende controle groep. In onze
ingezonden brief die gepubliceerd is in the Lancet, hebben wij benadrukt dat ondanks
het feit dat er gescreend wordt er nog steeds patiënten met een RAAA naar het
ziekenhuis verwezen zullen worden. Ondanks het feit dat de mortaliteit bij RAAA
patiënten hoog is (literatuur 30-70%) pleiten wij ervoor om al deze patiënten te
opereren tenzij de patiënt een zeer slechte performance score heeft. Deze benadering is
gebaseerd op het feit dat het in de acute setting erg lastig is de postoperatieve
mortaliteit voor de individuele patiënt te voorspellen. De literatuur geeft weinig inzicht
in hoeveel patiënten met een RAAA niet geopereerd worden en dus overlijden. Zoals
ook in hoofdstuk 6 is beschreven zien wij in onze serie waarbij bijna alle patiënten
geopereerd werden goede resultaten met weinig overleden patiënten.
De belangrijkste resultaten van dit proefschrift worden samengevat in
Hoofdstuk 8. Dit proefschrift laat zien dat patiënten na een levertransplantatie en met
een geruptureerd aneurysma postoperatief een forse ontstekingsrespons ontwikkelen.
Samenvatting
117
Een verlaagde HLA-DR expressie op monocyten was in beide groepen geassocieerd
met een hoge mortaliteit. Er is echter ook een belangrijk verschil tussen beide groepen:
patiënten na een levertransplantatie krijgen immunosuppressiva en hebben hierbij een
verhoogde kans op het ontwikkelen van opportunistische infecties. Dit geldt niet voor
patiënten met een geruptureerd aneurysma. Hoewel deze patiënten wel een verlaagde
HLA-DR expressie op monocyten hebben, konden wij geen opportunistische infecties
bij deze patiënten waarnemen. RAAA patiënten komen te overlijden ofwel in de eerste
fase ten gevolge van het ernstige bloedverlies ofwel na enkele dagen door de uit de
hand gelopen inflammatoire respons en multi-orgaan falen.
Levertransplantatiepatiënten met een lage HLA-DR expressie op monocyten en/of
sepsis hebben waarschijnlijk baat bij het verminderen of stoppen van de
immunosuppressiva.
Chapter 9
118
LITERATUUR
Literatuur
120
1. Dinarello CA. Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed. J.Endotoxin.Res. 2004;10(4):201-22.
2. Brothwell DR, Moller-Christensen V. A possible case of amputation dated to c. 2000 BC. Man 1963;244:192-4.
3. Ellis H. A History of Surgery. London: Greenwich Medical Media Limited; 2001.
4. Nerlich AG, Zink A, Szeimies U, Hagedorn HG. Ancient Egyptian prosthesis of the big toe. Lancet 2000;356(9248):2176-9.
5. Gillison W, Buchwald H. Pioneers in Surgical Gastroenterology. Malta: Gutenberg Press Ltd; 2007.
6. Lindeboom GA. Inleiding tot de geschiedenis der geneeskunde. Rotterdam: Erasmus publishing; 1993.
7. Vincent JL, Bihari D. Sepsis, severe sepsis or sepsis syndrome: need for clarification. Intensive Care Med. 1992;18(5):255-7.
8. Singer AJ, Clark RA. Cutaneous wound healing. N.Engl.J.Med. 1999;341(10):738-46.
9. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101(6):1644-55.
10. Vincent JL. Prevention and therapy of multiple organ failure. World J.Surg. 1996;20(4):465-70.
11. Malhotra R, Bird MI. L-selectin: a novel receptor for lipopolysaccharide and its potential role in bacterial sepsis. Bioessays 1997;19(10):919-23.
12. Haveman JW, Kobold AC, Cohen Tervaert JW, van den Berg AP, Tulleken JE, Kallenberg CG et al. The central role of monocytes in the pathogenesis of sepsis: consequences for immunomonitoring and treatment. Neth.J.Med. 1999;55(3):132-41.
13. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N.Engl.J.Med. 2000;342(18):1301-8.
Literatuur
121
14. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34(2):344-53.
15. Bone RC. Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS) [see comments]. Ann.Intern.Med. 1996;125(8):680-7.
16. Abraham E, Anzueto A, Gutierrez G, Tessler S, San Pedro G, Wunderink R et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. Lancet 1998;351:929-33.
17. Cohen J, Carlet J. INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. Crit.Care Med. 1996;24(9):1431-40.
18. Fisher-CJ J, Agosti JM, Opal SM, Lowry SF, Balk RA, Sadoff JC et al. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group [see comments]. N.Engl.J.Med. 1996;334(26):1697-702.
19. Fisher-CJ J, Slotman GJ, Opal SM, Pribble JP, Bone RC, Emmanuel G et al. Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. The IL-1RA Sepsis Syndrome Study Group [see comments]. Crit.Care Med. 1994;22(1):12-21.
20. Dhainaut JF, Tenaillon A, Le TY, Schlemmer B, Solet JP, Wolff M et al. Platelet-activating factor receptor antagonist BN 52021 in the treatment of severe sepsis: a randomized, double-blind, placebo-controlled, multicenter clinical trial. BN 52021 Sepsis Study Group. Crit.Care Med. 1994;22(11):1720-8.
21. The Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N.Engl.J Med. 1987;317(11):659-65.
22. Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit.Care Med. 1996;24(7):1125-8.
23. Hershman MJ, Cheadle WG, Wellhausen SR, Davidson PF, Polk-HC J. Monocyte HLA-DR antigen expression characterizes clinical outcome in the trauma patient. Br.J.Surg. 1990;77(2):204-7.
Literatuur
122
24. Wakefield CH, Carey PD, Foulds S, Monson JR, Guillou PJ. Changes in major histocompatibility complex class II expression in monocytes and T cells of patients developing infection after surgery. Br.J.Surg. 1993;80(2):205-9.
25. Cheadle WG, Hershman MJ, Wellhausen SR, Polk-HC J. HLA-DR antigen expression on peripheral blood monocytes correlates with surgical infection. Am.J.Surg. 1991;161(6):639-45.
26. Asadullah K, Woiciechowsky C, Döcke WD, Egerer K, Kox WJ, Vogel S et al. Very low monocytic HLA-DR expression indicates high risk of infection--immunomonitoring for patients after neurosurgery and patients during high dose steroid therapy. Eur.J.Emerg.Med. 1995;2(4):184-90.
27. Hummel M, Döcke W.D., Friedel N, von BR, Hetzer R, Volk HD. Monitoring of the cellular immune system in patients with biventricular assist devices awaiting cardiac transplantation. Clin.Transplant. 1994;8(1):59-66.
28. Volk HD, Reinke P, Falck P, Briedigkeit H, v Baehr R. Diagnostic value of an immune monitoring program for the clinical management of immunosuppressed patients with septic complications. Clin.Transplant. 1989;3:246-52.
29. Haveman JW, van den Berg AP, van den Berk JM, Mesander G, Slooff MJ, de Leij LH et al. Low HLA-DR expression on peripheral blood monocytes predicts bacterial sepsis after liver transplantation: relation with prednisolone intake. Transpl.Infect.Dis. 1999;1(3):146-52.
30. Döcke W.D., Syrbe U, Meinecke A, Platzer C, Makki A, Asadullah K et al. Improvement in monocyte function - A new therapeutic approach? In: Reinhart K, Eyrich K, Sprung C, editors. Sepsis: current perspectives in pathophysiology and therapy. Berlin: Springer-Verlag; 1994. p. 437-500.
31. Volk HD, Reinke P, Krausch D, Zuckermann H, Asadullah K, Muller JM et al. Monocyte deactivation--rationale for a new therapeutic strategy in sepsis. Intensive.Care Med. 1996;22 Suppl 4:S474-S481.
32. Starzl TE, Groth CG, Brettschneider L, Penn I, Fulginiti VA, Moon JB et al. Orthotopic homotransplantation of the human liver. Ann.Surg. 1968;168(3):392-415.
33. Moreno R, Berenguer M. Post-liver transplantation medical complications. Ann.Hepatol. 2006;5(2):77-85.
34. Washington K. Update on post-liver transplantation infections, malignancies, and surgical complications. Adv.Anat.Pathol. 2005;12(4):221-6.
Literatuur
123
35. Haveman JW, Karliczek A, Verhoeven EL, Tielliu IF, de Vos R, Zwaveling JH et al. Results of streamlined regional ambulance transport and subsequent treatment of acute abdominal aortic aneurysms. Emerg.Med.J. 2006;23(10):807-10.
36. Haveman, J. W., Zeebregts, C. J., Verhoeven, E., van den Berg, A. P., Van Den Dungen, J. J., Zwaveling, J. H., and Nijsten, M. W. Time course of laboratory values after rupture of abdominal aortic aneurysm. 2007. Ref Type: Unpublished Work
37. Norwood MG, Bown MJ, Lloyd G, Bell PR, Sayers RD. The clinical value of the systemic inflammatory response syndrome (SIRS) in abdominal aortic aneurysm repair. Eur.J.Vasc.Endovasc.Surg. 2004;27(3):292-8.
38. Fowkes FG, Macintyre CC, Ruckley CV. Increasing incidence of aortic aneurysms in England and Wales. BMJ 1989;298(6665):33-5.
39. Semmens JB, Norman PE, Lawrence-Brown MM, Bass AJ, Holman CD. Population-based record linkage study of the incidence of abdominal aortic aneurysm in Western Australia in 1985-1994. Br.J.Surg. 1998;85(5):648-52.
40. Reitsma JB, Pleumeekers HJ, Hoes AW, Kleijnen J, de Groot RM, Jacobs MJ et al. Increasing incidence of aneurysms of the abdominal aorta in The Netherlands. Eur.J.Vasc.Endovasc.Surg. 1996;12(4):446-51.
41. Szilagyi DE, Smith RF, DeRusso FJ, Elliott JP, Sherrin FW. Contribution of abdominal aortic aneurysmectomy to prolongation of life. Ann.Surg. 1966;164(4):678-99.
42. Zarins CK, Harris EJ, Jr. Operative repair for aortic aneurysms: the gold standard. J.Endovasc.Surg. 1997;4(3):232-41.
43. Kantonen I, Lepantalo M, Brommels M, Luther M, Salenius JP, Ylonen K. Mortality in ruptured abdominal aortic aneurysms. The Finnvasc Study Group. Eur.J.Vasc.Endovasc.Surg. 1999;17(3):208-12.
44. Lawrence PF, Gazak C, Bhirangi L, Jones B, Bhirangi K, Oderich G et al. The epidemiology of surgically repaired aneurysms in the United States. J.Vasc.Surg. 1999;30(4):632-40.
45. Bown MJ, Sutton AJ, Bell PR, Sayers RD. A meta-analysis of 50 years of ruptured abdominal aortic aneurysm repair. Br.J.Surg. 2002;89(6):714-30.
46. Hans SS, Huang RR. Results of 101 ruptured abdominal aortic aneurysm repairs from a single surgical practice. Arch.Surg. 2003;138(8):898-901.
Literatuur
124
47. Dueck AD, Kucey DS, Johnston KW, Alter D, Laupacis A. Long-term survival and temporal trends in patient and surgeon factors after elective and ruptured abdominal aortic aneurysm surgery. J.Vasc.Surg. 2004;39(6):1261-7.
48. Prinssen M, Verhoeven EL, Buth J, Cuypers PW, van Sambeek MR, Balm R et al. A randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. N.Engl.J.Med. 2004;351(16):1607-18.
49. Boyle JR, Goodall S, Thompson JP, Bell PR, Thompson MM. Endovascular AAA repair attenuates the inflammatory and renal responses associated with conventional surgery. J.Endovasc.Ther. 2000;7(5):359-71.
50. Greenhalgh RM, Brown LC, Kwong GP, Powell JT, Thompson SG. Comparison of endovascular aneurysm repair with open repair in patients with abdominal aortic aneurysm (EVAR trial 1), 30-day operative mortality results: randomised controlled trial. Lancet 2004;364(9437):843-8.
51. Verhoeven EL, Prins TR, van den Dungen JJAM, Tielliu IF, Hulsebos RG, Van Schilfgaarde R. Endovascular Repair of Acute AAAs Under Local Anesthesia With Bifurcated Endografts: A Feasibility Study. J.Endovasc.Ther. 2002;9(6):729-35.
52. Laheij RJ, Buth J, Harris PL, Moll FL, Stelter WJ, Verhoeven EL. Need for secondary interventions after endovascular repair of abdominal aortic aneurysms. Intermediate-term follow-up results of a European collaborative registry (EUROSTAR). Br.J.Surg. 2000;87(12):1666-73.
53. Vallabhaneni SR, Harris PL. Lessons learnt from the EUROSTAR registry on endovascular repair of abdominal aortic aneurysm repair. Eur.J.Radiol. 2001;39(1):34-41.
54. Ashton HA, Buxton MJ, Day NE, Kim LG, Marteau TM, Scott RA et al. The Multicentre Aneurysm Screening Study (MASS) into the effect of abdominal aortic aneurysm screening on mortality in men: a randomised controlled trial. Lancet 2002;360(9345):1531-9.
55. The Multicentre Aneurysm Screening Study Group. Multicentre aneurysm screening study (MASS): cost effectiveness analysis of screening for abdominal aortic aneurysms based on four year results from randomised controlled trial. BMJ 2002;325(7373):1135.
56. Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 1997;112(1):235-43.
57. Ulevitch RJ, Tobias PS. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu.Rev.Immunol. 1995;13:437-57.
Literatuur
125
58. Weiss SJ. Tissue destruction by neutrophils [see comments]. N.Engl.J.Med. 1989;320(6):365-76.
59. Davies MG, Hagen PO. Systemic inflammatory response syndrome. Br.J.Surg. 1997;84(7):920-35.
60. Cohen J, Heumann D, Glauser MP. Do monoclonal antibodies and anticytokines still have a future in infectious diseases? Am.J.Med. 1995;99(6A):45S-52S.
61. Avontuur JA, Tutein NR, van BJ, Bruining HA. Prolonged inhibition of nitric oxide synthesis in severe septic shock: a clinical study. Crit.Care Med. 1998;26(4):660-7.
62. Gibbons RA, Martinez OM, Lim RC, Horn JK, Garovoy MR. Reduction in HLA-DR, HLA-DQ and HLA-DP expression by Leu-M3+ cells from the peripheral blood of patients with thermal injury. Clin.Exp.Immunol. 1989;75(3):371-5.
63. van den Berk JM, Oldenburger RH, van den Berg AP, Klompmaker IJ, Mesander G, van Son W et al. Low HLA-DR expression on monocytes as a prognostic marker for bacterial sepsis after liver transplantation. Transplantation 1997;63(12):1846-8.
64. de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de-Vries JE. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J.Exp.Med. 1991;174(5):1209-20.
65. Randow F, Syrbe U, Meisel C, Krausch D, Zuckermann H, Platzer C et al. Mechanism of endotoxin desensitization: involvement of interleukin 10 and transforming growth factor beta. J.Exp.Med. 1995;181(5):1887-92.
66. Astiz M, Saha D, Lustbader D, Lin R, Rackow E. Monocyte response to bacterial toxins, expression of cell surface receptors, and release of anti-inflammatory cytokines during sepsis. J.Lab.Clin.Med. 1996;128(6):594-600.
67. Klava A, Windsor AC, Farmery SM, Woodhouse LF, Reynolds JV, Ramsden CW et al. Interleukin-10. A role in the development of postoperative immunosuppression. Arch.Surg. 1997;132(4):425-9.
68. Sherry RM, Cue JI, Goddard JK, Parramore JB, DiPiro JT. Interleukin-10 is associated with the development of sepsis in trauma patients. J.Trauma. 1996;40(4):613-6.
69. Haupt W, Fritzsche H, Hohenberger W, Zirngibl H. Selective cytokine release induced by serum and separated plasma from septic patients. Eur.J.Surg. 1996;162(10):769-76.
Literatuur
126
70. Capsoni F, Minonzio F, Ongari AM, Carbonelli V, Galli A, Zanussi C. Interleukin-10 down-regulates oxidative metabolism and antibody-dependent cellular cytotoxicity of human neutrophils. Scand.J.Immunol. 1997;45(3):269-75.
71. Bogdan C, Vodovotz Y, Nathan C. Macrophage deactivation by interleukin 10. J.Exp.Med. 1991;174(6):1549-55.
72. de Waal Malefyt R, Haanen J, Spits H, Roncarolo MG, te-Velde A., Figdor C et al. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J.Exp.Med. 1991;174(4):915-24.
73. Muller Kobold AC, Tulleken JE, Zijlstra JG, Cohen Tervaert JW. Interleukin 10 in febrile patients and patients with sepsis [letter]. Lancet 1998;351:1587.
74. Armendariz-Borunda J., Endres RO, Ballou LR, Postlethwaite AE. Transforming growth factor-beta inhibits interferon-gamma-induced HLA-DR expression by cultured human fibroblasts. Int.J.Biochem.Cell Biol. 1996;28(10):1107-16.
75. Snyder DS, Beller DI, Unanue ER. Prostaglandins modulate macrophage Ia expression. Nature 1982;299(5879):163-5.
76. Watanabe Y, Lee S, Allison AC. Control of the expression of a class II major histocompatibility gene (HLA-DR) in various human cell types: down-regulation by IL-1 but not by IL-6, prostaglandin E2, or glucocorticoids. Scand.J.Immunol. 1990;32(6):601-9.
77. Kunkel SL, Campbell-DA J, Chensue SW, Higashi GI. Species-dependent regulation of monocyte/macrophage Ia antigen expression and antigen presentation by prostaglandin E. Cell Immunol. 1986;97(1):140-5.
78. Randow F, Docke WD, Bundschuh DS, Hartung T, Wendel A, Volk HD. In vitro prevention and reversal of lipopolysaccharide desensitization by IFN-gamma, IL-12, and granulocyte-macrophage colony-stimulating factor. J.Immunol. 1997;158(6):2911-8.
79. Döcke W.D., Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat.Med. 1997;3(6):678-81.
80. Chantry D, Turner M, Brennan F, Kingsbury A, Feldmann M. Granulocyte-macrophage colony stimulating factor induces both HLA-DR expression and cytokine production by human monocytes. Cytokine. 1990;2(1):60-7.
81. Vincent JL. Search for effective immunomodulating strategies against sepsis (commentary). Lancet 1998;351:922-3.
Literatuur
127
82. van Dissel J, van Langevelde P, Westendorp RGJ, Kwappenberg K, Frolich M. Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet 1998;351:950-3.
83. Kox WJ, Bone RC, Krausch D, Docke WD, Kox SN, Wauer H et al. Interferon gamma-1b in the treatment of compensatory anti-inflammatory response syndrome. A new approach: proof of principle. Arch.Intern.Med. 1997;157(4):389-93.
84. Singh NK, Mehta D. Bloodstream infection prevention practices. Mayo Clin.Proc. 2007;82(10):1290-1.
85. Kusne S, Fung J, Alessiani M, Martin M, Torre CJ, Irish W et al. Infections during a randomized trial comparing cyclosporine to FK 506 immunosuppression in liver transplantation. Transplant.Proc. 1992;24(1):429-30.
86. Kusne S, Dummer JS, Singh N, Iwatsuki S, Makowka L, Esquivel C et al. Infections after liver transplantation. An analysis of 101 consecutive cases. Medicine Baltimore. 1988;67(2):132-43.
87. Asadullah K, Woiciechowsky C, Döcke W.D., Liebenthal C, Wauer H, Kox W et al. Immunodepression following neurosurgical procedures. Crit.Care Med. 1995;23(12):1976-83.
88. Baker JP, Detsky AS, Wesson DE, Wolman SL, Stewart S, Whitewell J et al. Nutritional assessment: a comparison of clinical judgement and objective measurements. N.Engl.J.Med. 1982;306(16):969-72.
89. Klompmaker IJ, Haagsma EB, Gouw AS, Verwer R, Slooff MJ. Azathioprine and prednisolone immunosuppression versus maintenance triple therapy including cyclosporine for orthotopic liver transplantation. A comparative biochemical and histologic study in one center. Transplantation 1989;48(5):814-8.
90. Bijleveld CG, Klompmaker IJ, van-den-Berg AP, Gouw AS, Hepkema BG, Haagsma EB et al. Incidence, risk factors, and outcome of antithymocyte globulin treatment of steroid-resistant rejection after liver transplantation. Transpl.Int. 1996;9(6):570-5.
91. Rosman C, Klompmaker IJ, Bonsel GJ, Bleichrodt RP, Arends JP, Slooff MJ. The efficacy of selective bowel decontamination as infection prevention after liver transplantation. Transplant.Proc. 1990;22(4):1554-5.
92. Bone RC. Let's agree on terminology: definitions of sepsis. Crit.Care Med. 1991;19(7):973-6.
Literatuur
128
93. Harrison J, McKiernan J, Neuberger JM. A prospective study on the effect of recipient nutritional status on outcome in liver transplantation. Transpl.Int. 1997;10(5):369-74.
94. Selberg O, Böttcher J, Tusch G, Pichlmayr R, Henkel E, Müller MJ. Identification of high- and low-risk patients before liver transplantation: a prospective cohort study of nutritional and metabolic parameters in 150 patients. Hepatology 1997;25(3):652-7.
95. Ukah FO, Merhav H, Kramer D, Eghtesad B, Samimi F, Frezza E et al. Early outcome of liver transplantation in patients with a history of spontaneous bacterial peritonitis. Transplant.Proc. 1993;25(1 Pt 2):1113-5.
96. Hadley S, Samore MH, Lewis WD, Jenkins RL, Karchmer AW, Hammer SM. Major infectious complications after orthotopic liver transplantation and comparison of outcomes in patients receiving cyclosporine or FK506 as primary immunosuppression. Transplantation 1995;59(6):851-9.
97. Trindade E, Maton P, Reding R, de Ville d, Otte JB, Buts JP et al. Use of granulocyte macrophage colony stimulating factor in children after orthotopic liver transplantation. J.Hepatol. 1998;28(6):1054-7.
98. Visser P, Akkersdijk GJ, Blankensteijn JD. In-hospital operative mortality of ruptured abdominal aortic aneurysm: a population-based analysis of 5593 patients in The Netherlands over a 10-year period. Eur.J.Vasc.Endovasc.Surg. 2005;30(4):359-64.
99. Katz DJ, Stanley JC, Zelenock GB. Operative mortality rates for intact and ruptured abdominal aortic aneurysms in Michigan: an eleven-year statewide experience. J.Vasc.Surg. 1994;19(5):804-15.
100. Sayers RD, Thompson MM, Nasim A, Healey P, Taub N, Bell PR. Surgical management of 671 abdominal aortic aneurysms: a 13 year review from a single centre. Eur.J.Vasc.Endovasc.Surg. 1997;13(3):322-7.
101. Zeebregts CJ, Geelkerken RH, van der Palen J, Huisman AB, de Smit P, van Det RJ. Outcome of abdominal aortic aneurysm repair in the era of endovascular treatment. Br.J.Surg. 2004;91(5):563-8.
102. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13(10):818-29.
103. Vincent JL, Moreno R, Takala J, Willatts S, de Mendonca A, Bruining H et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22(7):707-10.
Literatuur
129
104. Altman DG. Practical statistisc for medical research. London: Chapman & Hall; 1991.
105. Bradbury AW, Bachoo P, Milne AA, Duncan JL. Platelet count and the outcome of operation for ruptured abdominal aortic aneurysm. J.Vasc.Surg. 1995;21(3):484-91.
106. Davies MJ, Murphy WG, Murie JA, Elton RA, Bell K, Gillon JG et al. Preoperative coagulopathy in ruptured abdominal aortic aneurysm predicts poor outcome. Br.J.Surg. 1993;80(8):974-6.
107. AbuRahma AF, Woodruff BA, Lucente FC, Stuart SP, Boland JP. Factors affecting survival of patients with ruptured abdominal aortic aneurysm in a West Virginia community. Surg.Gynecol.Obstet. 1991;172(5):377-82.
108. Harris LM, Faggioli GL, Fiedler R, Curl GR, Ricotta JJ. Ruptured abdominal aortic aneurysms: factors affecting mortality rates. J.Vasc.Surg. 1991;14(6):812-8.
109. Nijsten MW, ten Duis HJ, Zijlstra JG, Porte RJ, Zwaveling JH, Paling JC et al. Blunted rise in platelet count in critically ill patients is associated with worse outcome. Crit Care Med. 2000;28(12):3843-6.
110. Clyne B, Olshaker JS. The C-reactive protein. J.Emerg.Med. 1999;17(6):1019-25.
111. Vincent JL, Dubois MJ, Navickis RJ, Wilkes MM. Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studies and controlled trials. Ann.Surg. 2003;237(3):319-34.
112. Bown MJ, Nicholson ML, Bell PR, Sayers RD. Cytokines and inflammatory pathways in the pathogenesis of multiple organ failure following abdominal aortic aneurysm repair. Eur.J.Vasc.Endovasc.Surg. 2001;22(6):485-95.
113. Vincent JL, Dufaye P, Berre J, Leeman M, Degaute JP, Kahn RJ. Serial lactate determinations during circulatory shock. Crit Care Med. 1983;11(6):449-51.
114. Falcone RE, Santanello SA, Schulz MA, Monk J, Satiani B, Carey LC. Correlation of metabolic acidosis with outcome following injury and its value as a scoring tool. World J.Surg. 1993;17(5):575-9.
115. Manikis P, Jankowski S, Zhang H, Kahn RJ, Vincent JL. Correlation of serial blood lactate levels to organ failure and mortality after trauma. Am.J.Emerg.Med. 1995;13(6):619-22.
116. Bakker J, Gris P, Coffernils M, Kahn RJ, Vincent JL. Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am.J.Surg. 1996;171(2):221-6.
Literatuur
130
117. Singhal R, Coghill JE, Guy A, Bradbury AW, Adam DJ, Scriven JM. Serum lactate and base deficit as predictors of mortality after ruptured abdominal aortic aneurysm repair. Eur.J.Vasc.Endovasc.Surg. 2005;30(3):263-6.
118. Gordon AC, Pryn S, Collin J, Gray DW, Hands L, Garrard C. Outcome in patients who require renal support after surgery for ruptured abdominal aortic aneurysm. Br.J.Surg. 1994;81(6):836-8.
119. Barratt J, Parajasingam R, Sayers RD, Feehally J. Outcome of acute renal failure following surgical repair of ruptured abdominal aortic aneurysms. Eur.J.Vasc.Endovasc.Surg. 2000;20(2):163-8.
120. Braams R, Vossen V, Lisman BA, Eikelboom BC. Outcome in patients requiring renal replacement therapy after surgery for ruptured and non-ruptured aneurysm of the abdominal aorta. Eur.J.Vasc.Endovasc.Surg. 1999;18(4):323-7.
121. Abbott WM, Abel RM, Beck CH, Jr., Fischer JE. Renal failure after ruptured aneurysm. Arch.Surg. 1975;110(9):1110-2.
122. Chen JC, Hildebrand HD, Salvian AJ, Taylor DC, Strandberg S, Myckatyn TM et al. Predictors of death in nonruptured and ruptured abdominal aortic aneurysms. J.Vasc.Surg. 1996;24(4):614-20.
123. Ouriel K, Geary K, Green RM, Fiore W, Geary JE, DeWeese JA. Factors determining survival after ruptured aortic aneurysm: the hospital, the surgeon, and the patient. J.Vasc.Surg. 1990;11(4):493-6.
124. Halpern VJ, Kline RG, D'Angelo AJ, Cohen JR. Factors that affect the survival rate of patients with ruptured abdominal aortic aneurysms. J.Vasc.Surg. 1997;26(6):939-45.
125. Regel G, Grotz M, Weltner T, Sturm JA, Tscherne H. Pattern of organ failure following severe trauma. World J.Surg. 1996;20(4):422-9.
126. Sprung J, Levy PJ, Tabares AH, Gottlieb A, Schoenwald PK, Olin JW. Ischemic liver dysfunction after elective repair of infrarenal aortic aneurysm: incidence and outcome. J.Cardiothorac.Vasc.Anesth. 1998;12(5):507-11.
127. Hermreck AS, Proberts KS, Thomas JH. Severe jaundice after rupture of abdominal aortic aneurysm. Am.J.Surg. 1977;134(6):745-8.
128. Durrani NK, Trisal V, Mittal V, Hans SS. Gastrointestinal complications after ruptured aortic aneurysm repair. Am.Surg. 2003;69(4):330-3.
129. Kasper DL, Braunwald E, Fauci A, Hauser S, Longo D, Jameson DL. Harrison's Principles of Internal Medicine. 16ed. 2004.
Literatuur
131
130. Rose BD, Post T. Clinical Physiology of Acid-Base and Electrolyte disorders. 5ed. McGraw-Hill Professional; 2000.
131. Bown MJ, Nicholson ML, Bell PR, Sayers RD. The systemic inflammatory response syndrome, organ failure, and mortality after abdominal aortic aneurysm repair. J.Vasc.Surg. 2003;37(3):600-6.
132. Welborn MB, Oldenburg HS, Hess PJ, Huber TS, Martin TD, Rauwerda JA et al. The relationship between visceral ischemia, proinflammatory cytokines, and organ injury in patients undergoing thoracoabdominal aortic aneurysm repair. Crit Care Med. 2000;28(9):3191-7.
133. Roumen RM, Hendriks T, van-der-Ven JJ, Nieuwenhuijzen GA, Sauerwein RW, van der Meer JW et al. Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Relation with subsequent adult respiratory distress syndrome and multiple organ failure. Ann.Surg. 1993;218(6):769-76.
134. Piotrowski JJ, Ripepi AJ, Yuhas JP, Alexander JJ, Brandt CP. Colonic ischemia: the Achilles heel of ruptured aortic aneurysm repair. Am.Surg. 1996;62(7):557-60.
135. Jensen LS, Kissmeyer-Nielsen P, Wolff B, Qvist N. Randomised comparison of leucocyte-depleted versus buffy-coat-poor blood transfusion and complications after colorectal surgery. Lancet 1996;348(9031):841-5.
136. Lekkou A, Karakantza M, Mouzaki A, Kalfarentzos F, Gogos CA. Cytokine production and monocyte HLA-DR expression as predictors of outcome for patients with community-acquired severe infections. Clin.Diagn.Lab Immunol. 2004;11(1):161-7.
137. Spittler A, Razenberger M, Kupper H, Kaul M, Hackl W, Boltz-Nitulescu G et al. Relationship between interleukin-6 plasma concentration in patients with sepsis, monocyte phenotype, monocyte phagocytic properties, and cytokine production. Clin.Infect.Dis. 2000;31(6):1338-42.
138. Gebhard F, Pfetsch H, Steinbach G, Strecker W, Kinzl L, Bruckner UB. Is interleukin 6 an early marker of injury severity following major trauma in humans? Arch.Surg. 2000;135(3):291-5.
139. Nast-Kolb D, Waydhas C, Gippner-Steppert C, Schneider I, Trupka A, Ruchholtz S et al. Indicators of the posttraumatic inflammatory response correlate with organ failure in patients with multiple injuries. J.Trauma 1997;42(3):446-54.
140. Bown MJ, Horsburgh T, Nicholson ML, Bell PR, Sayers RD. Cytokines, their genetic polymorphisms, and outcome after abdominal aortic aneurysm repair. Eur.J.Vasc.Endovasc.Surg. 2004;28(3):274-80.
Literatuur
132
141. Giannoudis PV, Smith RM, Perry SL, Windsor AJ, Dickson RA, Bellamy MC. Immediate IL-10 expression following major orthopaedic trauma: relationship to anti-inflammatory response and subsequent development of sepsis. Intensive Care Med. 2000;26(8):1076-81.
142. Yu WK, Li WQ, Li N, Li JS. Mononuclear histocompatibility leukocyte antigen-DR expression in the early phase of acute pancreatitis. Pancreatology. 2004;4(3-4):233-43.
143. Monneret G, Finck ME, Venet F, Debard AL, Bohe J, Bienvenu J et al. The anti-inflammatory response dominates after septic shock: association of low monocyte HLA-DR expression and high interleukin-10 concentration. Immunol.Lett. 2004;95(2):193-8.
144. Caille V, Chiche JD, Nciri N, Berton C, Gibot S, Boval B et al. Histocompatibility leukocyte antigen-D related expression is specifically altered and predicts mortality in septic shock but not in other causes of shock. Shock 2004;22(6):521-6.
145. Le Morvan C, Cogne M, Troutaud D, Charmes JP, Sauvage P, Drouet M. Modification of HLA expression on peripheral lymphocytes and monocytes during aging. Mech.Ageing Dev. 1998;105(3):209-20.
146. Stohlawetz P, Hahn P, Koller M, Hauer J, Resch H, Smolen J et al. Immunophenotypic characteristics of monocytes in elderly subjects. Scand.J.Immunol. 1998;48(3):324-6.
147. Gorham TJ, Taylor J, Raptis S. Endovascular treatment of abdominal aortic aneurysm. Br.J.Surg. 2004;91(7):815-27.
148. Peppelenbosch N, Yilmaz N, van Marrewijk C, Buth J, Cuypers P, Duijm L et al. Emergency treatment of acute symptomatic or ruptured abdominal aortic aneurysm. Outcome of a prospective intent-to-treat by EVAR protocol. Eur.J.Vasc.Endovasc.Surg. 2003;26(3):303-10.
149. Blankensteijn JD, de Jong SE, Prinssen M, van der Ham AC, Buth J, van Sterkenburg SM et al. Two-year outcomes after conventional or endovascular repair of abdominal aortic aneurysms. N.Engl.J.Med. 2005;352(23):2398-405.
150. EVAR trial participants. Endovascular aneurysm repair versus open repair in patients with abdominal aortic aneurysm (EVAR trial 1): randomised controlled trial. Lancet 2005;365(9478):2179-86.
151. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288(7):862-71.
Literatuur
133
152. Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S et al. Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am.J.Respir.Crit Care Med. 2003;167(4):512-20.
153. Parikshak M, Shepard AD, Reddy DJ, Nypaver TJ. Adrenal insufficiency in patients with ruptured abdominal aortic aneurysms. J.Vasc.Surg. 2004;39(5):944-50.
154. Bengtsson H, Bergqvist D. Ruptured abdominal aortic aneurysm: a population-based study. J.Vasc.Surg. 1993;18(1):74-80.
155. Heikkinen M, Salenius JP, Auvinen O. Ruptured abdominal aortic aneurysm in a well-defined geographic area. J.Vasc.Surg. 2002;36(2):291-6.
156. Farooq MM, Freischlag JA, Seabrook GR, Moon MR, Aprahamian C, Towne JB. Effect of the duration of symptoms, transport time, and length of emergency room stay on morbidity and mortality in patients with ruptured abdominal aortic aneurysms. Surgery 1996;119(1):9-14.
157. Johansen K, Kohler TR, Nicholls SC, Zierler RE, Clowes AW, Kazmers A. Ruptured abdominal aortic aneurysm: the Harborview experience. J.Vasc.Surg. 1991;13(2):240-5.
158. Adam DJ, Mohan IV, Stuart WP, Bain M, Bradbury AW. Community and hospital outcome from ruptured abdominal aortic aneurysm within the catchment area of a regional vascular surgical service. J.Vasc.Surg. 1999;30(5):922-8.
159. Karnofsky DA, Abelman WH, Craver LF, Bruchenal JH. The use of nitrogen mustards in palliative treatment of carcinoma. Cancer 1948;1:634-56.
160. Basnyat PS, Biffin AH, Moseley LG, Hedges AR, Lewis MH. Mortality from ruptured abdominal aortic aneurysm in Wales. Br.J.Surg. 1999;86(6):765-70.
161. Norman PE, Semmens JB, Lawrence-Brown MM, Holman CD. Long term relative survival after surgery for abdominal aortic aneurysm in western Australia: population based study. BMJ 1998;317(7162):852-6.
162. Crawford ES. Ruptured abdominal aortic aneurysm. J.Vasc.Surg. 1991;13(2):348-50.
163. Evans SM, Adam DJ, Bradbury AW. The influence of gender on outcome after ruptured abdominal aortic aneurysm. J.Vasc.Surg. 2000;32(2):258-62.
164. Bradbury AW, Makhdoomi KR, Adam DJ, Murie JA, Jenkins AM, Ruckley CV. Twelve-year experience of the management of ruptured abdominal aortic aneurysm. Br.J.Surg. 1997;84(12):1705-7.
Literatuur
134
165. Dueck AD, Johnston KW, Alter D, Laupacis A, Kucey DS. Predictors of repair and effect of gender on treatment of ruptured abdominal aortic aneurysm. J.Vasc.Surg. 2004;39(4):784-7.
166. Dimick JB, Cowan JA, Jr., Stanley JC, Henke PK, Pronovost PJ, Upchurch GR, Jr. Surgeon specialty and provider volumes are related to outcome of intact abdominal aortic aneurysm repair in the United States. J.Vasc.Surg. 2003;38(4):739-44.
167. Pearce WH, Parker MA, Feinglass J, Ujiki M, Manheim LM. The importance of surgeon volume and training in outcomes for vascular surgical procedures. J.Vasc.Surg. 1999;29(5):768-76.
168. Sandison AJ, Wyncoll DL, Edmondson RC, Van Heerden N, Beale RJ, Taylor PR. ICU protocol may affect the outcome of non-elective abdominal aortic aneurysm repair. Eur.J.Vasc.Endovasc.Surg. 1998;16(4):356-61.
169. Kapma MR, Verhoeven EL, Tielliu IF, Zeebregts CJ, Prins TR, Van der HB et al. Endovascular treatment of acute abdominal aortic aneurysm with a bifurcated stentgraft. Eur.J.Vasc.Endovasc.Surg. 2005;29(5):510-5.
170. Kniemeyer HW, Kessler T, Reber PU, Ris HB, Hakki H, Widmer MK. Treatment of ruptured abdominal aortic aneurysm, a permanent challenge or a waste of resources? Prediction of outcome using a multi-organ-dysfunction score. Eur.J.Vasc.Endovasc.Surg. 2000;19(2):190-6.
171. Oberholzer A, Souza SM, Tschoeke SK, Oberholzer C, Abouhamze A, Pribble JP et al. Plasma cytokine measurements augment prognostic scores as indicators of outcome in patients with severe sepsis. Shock 2005;23(6):488-93.
172. Gogos CA, Drosou E, Bassaris HP, Skoutelis A. Pro- versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options. J.Infect.Dis. 2000;181(1):176-80.
173. Hynninen M, Pettila V, Takkunen O, Orko R, Jansson SE, Kuusela P et al. Predictive value of monocyte histocompatibility leukocyte antigen-DR expression and plasma interleukin-4 and -10 levels in critically ill patients with sepsis. Shock 2003;20(1):1-4.
174. Monneret G, Elmenkouri N, Bohe J, Debard AL, Gutowski MC, Bienvenu J et al. Analytical requirements for measuring monocytic human lymphocyte antigen DR by flow cytometry: application to the monitoring of patients with septic shock. Clin.Chem. 2002;48(9):1589-92.
175. Monneret G, Lepape A, Voirin N, Bohe J, Venet F, Debard AL et al. Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med. 2006;32(8):1175-83.
Literatuur
135
176. Tschaikowsky K, Hedwig-Geissing M, Schiele A, Bremer F, Schywalsky M, Schuttler J. Coincidence of pro- and anti-inflammatory responses in the early phase of severe sepsis: Longitudinal study of mononuclear histocompatibility leukocyte antigen-DR expression, procalcitonin, C-reactive protein, and changes in T-cell subsets in septic and postoperative patients. Crit Care Med. 2002;30(5):1015-23.
177. Perry SE, Mostafa SM, Wenstone R, Shenkin A, McLaughlin PJ. Is low monocyte HLA-DR expression helpful to predict outcome in severe sepsis? Intensive Care Med. 2003;29(8):1245-52.
178. Oczenski W, Krenn H, Jilch R, Watzka H, Waldenberger F, Koller U et al. HLA-DR as a marker for increased risk for systemic inflammation and septic complications after cardiac surgery. Intensive Care Med. 2003;29(8):1253-7.
179. Fumeaux T, Pugin J. Role of interleukin-10 in the intracellular sequestration of human leukocyte antigen-DR in monocytes during septic shock. Am.J.Respir.Crit Care Med. 2002;166(11):1475-82.
180. Eason JD, Nair S, Cohen AJ, Blazek JL, Loss GE, Jr. Steroid-free liver transplantation using rabbit antithymocyte globulin and early tacrolimus monotherapy. Transplantation 2003;75(8):1396-9.
181. Ramirez CB, Doria C, di FF, Iaria M, Kang Y, Marino IR. Anti-IL2 induction in liver transplantation with 93% rejection-free patient and graft survival at 18 months. J.Surg.Res. 2007;138(2):198-204.
182. Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P et al. Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet 2000;356(9223):26-30.
183. Piccinni P, Dan M, Barbacini S, Carraro R, Lieta E, Marafon S et al. Early isovolaemic haemofiltration in oliguric patients with septic shock. Intensive Care Med. 2006;32(1):80-6.
184. Honore PM, Jamez J, Wauthier M, Lee PA, Dugernier T, Pirenne B et al. Prospective evaluation of short-term, high-volume isovolemic hemofiltration on the hemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock. Crit Care Med. 2000;28(11):3581-7.
185. Ratanarat R, Brendolan A, Piccinni P, Dan M, Salvatori G, Ricci Z et al. Pulse high-volume haemofiltration for treatment of severe sepsis: effects on hemodynamics and survival. Crit Care 2005;9(4):R294-R302.
186. Cornejo R, Downey P, Castro R, Romero C, Regueira T, Vega J et al. High-volume hemofiltration as salvage therapy in severe hyperdynamic septic shock. Intensive Care Med. 2006;32(5):713-22.
Literatuur
136
187. Morgera S, Haase M, Kuss T, Vargas-Hein O, Zuckermann-Becker H, Melzer C et al. Pilot study on the effects of high cutoff hemofiltration on the need for norepinephrine in septic patients with acute renal failure. Crit Care Med. 2006;34(8):2099-104.
188. Morgera S, Haase M, Rocktaschel J, Bohler T, von HC, Vargas-Hein O et al. High permeability haemofiltration improves peripheral blood mononuclear cell proliferation in septic patients with acute renal failure. Nephrol.Dial.Transplant. 2003;18(12):2570-6.
189. Morgera S, Haase M, Rocktaschel J, Bohler T, Vargas-Hein O, Melzer C et al. Intermittent high-permeability hemofiltration modulates inflammatory response in septic patients with multiorgan failure. Nephron Clin.Pract. 2003;94(3):c75-c80.
190. Schefold JC, von HS, Corsepius M, Pohle C, Kruschke P, Zuckermann H et al. A novel selective extracorporeal intervention in sepsis: immunoadsorption of endotoxin, interleukin 6, and complement-activating product 5a. Shock 2007;28(4):418-25.
191. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K et al. Hydrocortisone therapy for patients with septic shock. N.Engl.J.Med. 2008;358(2):111-24.
192. Vincent JL. Steroids in sepsis: another swing of the pendulum in our clinical trials. Crit Care 2008;12(2):141.
193. Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008.
194. Bone RC, Fisher CJ, Jr., Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N.Engl.J.Med. 1987;317(11):653-8.
195. Mangin D, Sweeney K, Heath I. Preventive health care in elderly people needs rethinking. BMJ 2007;335(7614):285-7.
196. Hoornweg LL, Wisselink W, Vahl A, Balm R. The Amsterdam Acute Aneurysm Trial: suitability and application rate for endovascular repair of ruptured abdominal aortic aneurysms. Eur.J.Vasc.Endovasc.Surg. 2007;33(6):679-83.
DANKWOORD
Dankwoord
138
Bijna 10 jaar na de eerste publicatie is het dan zover, het proefschrift is af! Gedurende
zo´n lange periode hebben natuurlijk vele mensen bijgedragen aan 1 of meerdere
hoofdstukken uit dit boekje, die wil ik dan ook allemaal heel erg bedanken. Zonder
compleet te zijn wil ik hier een aantal personen expliciet vermelden.
Mijn promotor, prof dr JH Zwaveling. Beste Jan Harm, jij motiveerde mij om op de
chirurgische intensive care (CHIC) mijn onderzoek weer op te pakken. Ik heb altijd
veel vertrouwen van je gekregen en je hebt me altijd onvoorwaardelijk gesteund.
Daarnaast heb je mij de mogelijkheid gegeven het klinische werk op de CHIC, te
combineren met onderzoek. Na je vertrek naar Maastricht hebben we niet heel frequent
contact gehad over het onderzoek, maar je bleef je inzetten om het proefschrift tot een
goed einde te brengen.
Dr AP van den Berg. Beste Aad, als initiator van dit onderzoek en als directe
begeleider bij de lab studies ben ik je veel dank verschuldigd. Ik heb enorme
waardering voor je analytische vermogen en hulp bij het schrijven van de diverse
hoofdstukken.
Dr MWN Nijsten. Beste Maarten, dankzij jouw enthousiasme en niet aflatende energie
hebben we enkele mooie hoofdstukken geschreven. We konden bijna alles uit het ZIS
halen, wat er te halen viel. Wanneer we dit konden combineren met de juiste toon in
het manuscript hadden we zo een kraakheldere letter geschreven (hoofdstuk 7).
Prof dr CGM Kallenberg, prof dr RJ Ploeg en prof dr DF Zandstra wil ik bedanken
voor hun deelname in de leescommissie en voor hun goedkeuring van dit proefschrift.
Prof dr TH The wil ik graag bedanken voor de goede begeleiding tijdens het onderzoek
bij de klinische immunologie. Ik heb veel geleerd van uw heldere kijk op de patiënten
in relatie met de laboratorium afwijkingen.
Dankwoord
139
Dr JJAM van den Dungen, drs IFJ Tielliu, dr ELG Verhoeven en dr CJAM Zeebregts
wil ik bedanken voor hun enthousiasme in de behandeling van de RAAA patiënten en
de bijdrage aan de artikelen. Clark Zeebregts wil ik bedanken voor zijn onuitputtelijke
energie en hulp bij het schrijven van enkele lastige hoofdstukken. Als initiator van het
retrospectieve deel bij RAAA patiënten wil ik dr Anne Karliczek nog graag bedanken
voor haar inzet bij dit onderzoek.
Alle levertransplantatie chirurgen, fellow´s en hepatologen wil ik graag bedanken voor
hun enthousiasme en betrokkenheid bij de behandeling van de OLT patiënten en de
bijdrage aan dit onderzoek.
De collega´s, verpleegkundigen en staf van de CHIC wil ik enorm bedanken voor de
mooie tijd die ik daar gehad heb. Ik kreeg de mogelijkheid het klinische werk te
combineren met het onderzoek. Deze tijd heeft mij een goede basis gegeven tijdens de
opleiding en ook nog hierna.
Alle medewerkers van het laboratorium klinische immunologie wil ik graag bedanken
omdat ik daar altijd mijn gang kon gaan en van alle apparatuur en dergelijke gebruik
kon maken. Johan Bijzet en Geert Mesander hebben mij geweldig geholpen tijdens de
ELISA en flow-cytometrie.
Mijn opleiders uit de Isala klinieken in Zwolle. Eigenlijk zijn dit alle werkzame
chirurgen, echter de formele opleiders dr JE de Vries en dr EGJM Pierik wil ik graag
nog kort bijzonder bedanken. Beste Hans, het was nogal een overgang om vanuit
Groningen in Zwolle bij de chirurgie te beginnen, maar dankzij jouw begeleiding en
sturing is het een mooie en leerzame periode geworden. Beste Robert, jouw
voortvarendheid en enthousiasme werken enorm inspirerend voor de opleiding in
Zwolle.
Dr GA Patijn: beste Gijs superleuk dat je in de oppositie plaatsneemt.
Dankwoord
140
Prof dr HJ ten Duis wil ik graag bedanken voor het warme onthaal in het UMCG, de
laatste anderhalf jaar van m´n opleiding zie ik met veel vertrouwen tegemoet.
Al mijn collega´s uit Zwolle wil ik graag bedanken voor de geweldige tijd die ik daar
gehad heb. De altijd gezellige borrels en feestjes leverden altijd weer mooie momenten
op en maakte deze periode tot een onvergetelijke tijd.
Collega´s uit het UMCG: de overgang naar Groningen en de laatste loodjes voor mijn
promotie verliepen zeer soepel dankzij de uitstekende samenwerking en collegialiteit.
Mijn paranimfen Vincent Hagens en Rienk van Calker. We kennen elkaar alweer vanaf
1994, dankzij jullie is mijn studietijd een fantastische periode geweest. Daarna is het
goede contact gebleven en onze te weinige afspraken zijn altijd gezellig en lopen altijd
enkele drankjes uit. Super dat jullie m´n paranimfen willen zijn.
Lieve pap en mam, zonder jullie was het nooit zover gekomen. De basis van dit boekje
is door jullie gelegd.
Ook wil ik graag mijn schoonouders, andere familieleden en vrienden bedanken voor
hun belangstelling en steun voor mijn onderzoek.
Lieve lieve Helen, wat ben ik toch een geluksvogel!
BIBLIOGRAFIE
Bibliografie
142
1. Haveman JW. Effecten van profylactische toediening van amiodaron op de
mortaliteit na een acuut myocardinfarct en bij decompensatio cordis. Ned
Tijdschr Geneeskd Stud ed 1998;2(1):14.
2. Haveman JW, Muller Kobold AC, Cohen Tervaert JW, van den Berg AP,
Tulleken JE, Kallenberg CGM, The TH. The central role of monocytes in the
pathogenesis of sepsis: consequences for immunomonitoring and treatment.
Neth J Med 1999;55:132-141.
3. Haveman JW, van den Berg AP, van den Berk JMM, Mesander G, Slooff
MJH, de Leij LHFM, The TH. Low HLA-DR expression on peripheral blood
monocytes predicts bacterial sepsis after liver transplantation: relation with
prednisolone dose. Transplant Infect Dis 1999;1:146-152.
4. Haveman JW, Jansen PLM. Hoofdstuk Geelzucht. In: Probleemgeoriënteerd
denken in de interne geneeskunde. Een praktijkboek voor de opleiding en
kliniek. Onder redactie van S.T. Houweling, E.A.C. Beenakker, M.M. Levi,
C.D.A. Stehouwer en R.O.B. Gans. De tijdstroom, maart 2001: 27-37.
5. Haveman JW, Dullaart RPF. Hoofdstuk Dorst en polyurie. In:
Probleemgeoriënteerd denken in de interne geneeskunde. Een praktijkboek
voor de opleiding en kliniek. Onder redactie van S.T. Houweling, E.A.C.
Beenakker, M.M. Levi, C.D.A. Stehouwer en R.O.B. Gans. De tijdstroom,
maart 2001: 53-60.
6. Haveman JW, Gonera de Jong BC, Slooff MJH, Zwaveling JH
Hepatopulmonaal syndroom: therapieresistente hypoxie. Neth J Crit Care
2002;6:14-17.
7. Haveman JW, Sonneveld DJA, Uges DRA, Delwig H, Zijlstra JG. Niet-fatale
ruptuur van een cocaïnebolletje bij een man met ‘bodypacker’-syndroom. Ned
Tijdschr Geneeskd. 2002 Nov 23;146(47):2246-50.
8. Haveman JW, van Tol KM, Rouwe CW, Piers DA, Plukker JThM. Surgical
experience in children with differentiated thyroid carcinoma. Ann Surg Oncol.
2003 Jan-Feb;10(1):15-20.
Bibliografie
143
9. Haveman JW, Karliczek A, Verhoeven ELG, van den Dungen JJAM, Nijsten
MWN. Multicentre Aneurysm Screening Study (MASS). Lancet. 2003 Mar
22;361(9362):1058.
10. Haveman JW, Phan THH, Links TP, Jager PL, Plukker JT. Implications of
mediastinal uptake of 131I with regard to surgery in patients with
differentiated thyroid carcinoma. Cancer 2005 Jan 1;103(1):59-67.
11. Haveman JW, Gansevoort RT, Bongaerst AHH, Nijsten MWN. Low incidence
of nephropathy in surgical ICU patients receiving intravenous contrast: a
retrospective analysis. Intensive Care Med. 2006 Aug;32(8):1199-205.
12. Haveman JW, van den Berg AP, Verhoeven EL, Nijsten MW, van den Dungen
JJ, The HT, Zwaveling JH. HLA-DR expression on monocytes and systemic
inflammation in patients with ruptured abdominal aortic aneurysms. Crit Care.
2006;10(4):R119.
13. Haveman JW, Karliczek A, Verhoeven EL, Tielliu IF, de Vos R, Zwaveling
JH, van den Dungen JJ, Zeebregts CJ, Nijsten MW. Results of streamlined
regional ambulance transport and subsequent treatment of acute abdominal
aortic aneurysms. Emerg Med J. 2006; Oct;23(10):807-10.
14. Haveman JW, Zeebregts CJ, Verhoeven EL, van den Berg AP, van den
Dungen JJ, Zwaveling JH, Nijsten MW. Changes in laboratory values and
their relationship with time after rupture of an abdominal aortic aneurysm.
Surg Today 2008;38(12):1091-1101.
15. Haveman JW, Logtenberg SJ, Kleefstra N, Groenier KH, Bilo HJ, Blomme
AM. Surgical aspects and complications of continuous intraperitoneal insulin
infusion with an implantable pump. Langenbecks Arch Surg 2008: Epub
ahead of print.
16. Haveman JW, Jörning PJG. Een man met een verbreed mediastinum na een
trauma. Ned Tijdschr Geneeskd. In press.
17. Haveman JW, Blomme AM. Entrapment van de nervus peroneus superficialis.
Submitted.
Bibliografie
144
CURRICULUM VITAE
Curriculum vitae
146
Jan Willem Haveman werd geboren in Assen op 10 februari 1974. Hij volgde de lagere
school aan de Meester Andrea school in Diever. Na de HAVO behaalde hij zijn VWO
examen aan het Reestdalcollege in Meppel in 1994. Hierna begon hij met de studie
geneeskunde aan de Rijksuniversiteit Groningen. Tijdens zijn studie was hij actief in de
jaarvertegenwoordiging en was student-lid van de Stuurgroep Klinische Fase. In 1999
begon hij met een onderzoeksproject bij de vakgroep Chirurgisch Oncologie o.l.v. prof. dr.
J.Th. Plukker naar gedifferentieerd schildkliercarcinoom. Zijn wetenschappelijke stage
deed hij bij de vakgroep Klinische Immunologie bij dr. A.P. van den Berg en prof. dr. T.H.
The. In november 2000 werd hij bevorderd tot arts. Hierna werkte hij als ANIOS bij de
afdeling heelkunde in het Universitair Medisch Centrum Groningen en vanaf april 2001 op
de Chirurgische Intensive Care. Naast zijn werkzaamheden op de Intensive Care, pakte hij
zijn onderzoek bij de afdeling Klinische Immunologie weer op, wat uiteindelijk leidde tot
dit proefschrift.
Vanaf september 2004 begon hij met de opleiding heelkunde in de Isala klinieken in
Zwolle; opleider dr. J.E. de Vries en later dr. E.G.J.M. Pierik. Vanaf september 2008
vervolgde hij zijn opleiding in het Universitair Medisch Centrum Groningen; opleider prof.
dr. H.J. ten Duis.
Jan Willem is getrouwd met Helen Lutgers.