Sepsis and Modes

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SEPSIS AND MODS 
Clinical problems 
Module Authors 
John C. Marshall 
Departments of Surgery 
and Critical Care Medicine 
St. Michael’s Hospital 
University of Toronto 
Toronto, Canada 
Satish Bhagwanjee 
Department of Anaesthesiology 
University of the Witwatersrand 
and Johannesburg Hospital 
Johannesburg, South Africa 
Bert Thijs † 
Department of Intensive 
Care 
Free University Hospital 
Amsterdam 
The Netherlands 
With 
input/comments 
from 
Herwig Gerlach, Berlin, Germany 
Barbara McLean, Texas, USA (N&AHP committee) 
Francesca Rubulotta, Catania, Italy 
Susanne Toussaint, Berlin, Germany 
and the following members of the EDIC Committee: Kurt Espersen, Hans Flaatten, Armand 
Girbes, Charles Hinds, Paulo Maia and Jan Zwaveling 
Editor-in-Chief 
Graham RAMSAY 
Chairman of the PACT Steering Committee 
Medical Director, West Hertfordshire Hospitals NHS Trust, 
UK 
Past President, European Society of Intensive Care Medicine 
 
Sub-editor 
Dermot Phelan, Dublin, Ireland 
Module Editor 
AB Johan Groeneveld, Free University Hospital, Amsterdam, 
the Netherlands 
 
Educational Editor 
Lia Fluit, Medical Education Training and Consultancy 
(METC), Nijmegen, the Netherlands 
 
Editorial Manager 
Kathleen A Brown, Triwords Limited, Tayport, UK 
Editorial Secretary 
Laurence Van den Bossche, ESICM, Brussels, Belgium 
Sepsis and MODS 
Clinical problems 
LEARNING OBJECTIVES 
After studying this module on Sepsis and MODS, you should be able to: 
1. Recognise sepsis in the critically ill patient 
2. Resuscitate and haemodynamically support the septic patient 
3. Identify and control the source of infection 
4. Discuss adjunctive therapies for sepsis 
5. Minimise organ dysfunction in ICU patients. 
 
FACULTY DISCLOSURES 
The authors of this module have not reported any disclosures. 
 
DURATION 
7 hours 
Copyright©2008. European Society of Intensive Care Medicine. All rights reserved. 
ISBN 978-92-9505-197-3 - Legal deposit D/2005/10.772/44 
FOREWORD 
One of the authors, Professor Bert Thijs, died during the production of this 
module. Bert was a valued colleague and friend of many of the officers of the 
Society. He was a past president of the Society, a respected researcher and an 
outstanding teacher – and as such he would have been proud of his 
contribution to this module. 
Bert, we miss you! 
Graham Ramsay, Editor-in-Chief, PACT programme. 
INTRODUCTION 
Intensive care units were established to provide support of vital organ function during 
a time of life-threatening physiologic dysfunction. Their success is reflected in the fact 
that the vast majority of patients admitted to an ICU survive an illness that half a 
century ago would have been rapidly lethal. However, in the successes of intensive 
care lie the roots of its greatest unsolved challenges. 
Sepsis is a lethal disease process, with mortality rates of 25% to 60% or higher, 
depending on the severity of the illness, but also varying substantially from one 
country to the next. By convention, the word sepsisis used to describe the syndrome 
of systemic inflammation when infection is the cause, while the systemic 
inflammatory response syndrome or SIRS denotes that process without reference to 
its causative trigger. However, it may be difficult to determine whether infection is 
truly present, and if it is, whether it is the cause, or the consequence of the 
deterioration that is evolving. The word is used in this module in a looser clinical 
sense, to denote a syndrome that is commonly, but not always caused by infection, 
but that heralds significant risk to the patient, and tremendous challenges to the 
clinician. Nevertheless, when sepsis is suspected it is crucial to look for infection, as 
the rapid and effective treatment of infection improves outcome. 
Multiple organ dysfunction syndrome or MODS is responsible for 80% of all ICU 
deaths, and evolves in the wake of a syndrome of systemic inflammation. Sometimes 
inflammation is a consequence of a sterile insult such as pancreatitis, but more often, 
it is the result of infection and sepsis, acquired in the community or complicating the 
course of a complex illness. 
A general overview of the problems of sepsis and MODS, and the evolution of ideas 
in their description and management, can be found in the following references. 
 
 
1/ RECOGNISING SEPSIS IN THE CRITICALLY ILL PATIENT 
What is sepsis? 
Death for patients admitted to an intensive care unit is rarely a direct effect of the 
disorder that led to ICU admission. Rather, critically ill patients die as a consequence 
of a syndrome of secondary organ system disorders known as the multiple organ 
dysfunction syndrome (MODS). For the patient admitted with pneumonia, the 
infection is treated, but after a course characterised by renal failure, persistent 
hypotension, failure to wean from the ventilator, and recurrent bouts of nosocomial 
infection often with relatively low virulence organisms, the patient may succumb 
weeks later. A similar course follows admission for very divergent illnesses — acute 
pancreatitis, ruptured abdominal aortic aneurysm, refractory congestive heart failure, 
or decompensated liver cirrhosis. 
The terminology conventionally used to describe the septic patient is confusing, and 
attempts to simplify or clarify these concepts really have not accomplished their 
objectives. This confusion arises from both the complexity of the disease, and our 
intellectual sloppiness in trying to describe it. 
The word 'sepsis' is attributed to Hippocrates (460 – 370 BC). In Hippocrates´ view, 
living things died and were transformed through one of two basic, but opposite 
processes. Pepsis denoted tissue breakdown that was restorative and life-giving, 
and was exemplified by the digestion of food, or the fermentation of grapes to 
produce wine. Sepsis, on the other hand, was tissue breakdown associated with 
disease, decay, a foul smell, and death – for example, putrefaction, infection of 
wounds, and the vapours arising from stagnant swamps. The advent of the 
microscope and the work of Louis Pasteur demonstrated that the processes of sepsis 
arose through the actions of micro-organisms; intriguingly, those of pepsis – whether 
fermentation or peptic ulceration – are also a product of microbial activity. 
Sepsis to the clinician has a somewhat different connotation. It describes an acute 
clinical syndrome that is quite variable and often non-specific in its clinical 
presentation, but that suggests the presence of uncontrolled infection, and the threat 
of imminent clinical deterioration. 
THINK How would you define sepsis? Must a patient have a culture-proven infection to be called septic, or 
is the essence of the syndrome the clinical response of the host? Do all patients with infection have 
sepsis? Do all patients with sepsis have infection? 
 
Write down five physiological or laboratory abnormalities that you believe to be most 
characteristic of sepsis. Now ask a colleague to do the same, and compare your lists? Are they 
the same? Is there a single clinical syndrome that we might call sepsis? 
The definition of sepsis is frustratingly elusive, because sepsis is not so much a 
syndrome or a disease, as it is a state of profoundly deranged host-microbial 
homeostasis. In health, humans, like all multicellular creatures, live in a state of 
symbiosis with the microbial world. We consume micro-organisms when we eat, they 
colonise our mucosal surfaces in health, and as mitochondria, they even power the 
fundamental processes of cellular metabolism that allow us to live. Bacteria in the gut 
aid in the digestion of food, stimulate intestinal epithelial development, and inhibit the 
growth of exogenous and potentially more virulent organisms. In turn, we provide 
nutrients and a favourable environment for growth, and a state of mutually beneficial 
tolerance ensues. In sepsis, however, this state is disrupted: micro-organisms 
become athreat to the host, and the host activates a series of processes to kill the 
micro-organism. Normal patterns of microbial colonisation are altered, as are normal 
patterns of the host antimicrobial response. Infection becomes both the cause of 
sepsis and a manifestation of the disorder; the host response, heralded by 
inflammation, becomes both evidence of the disorder, and a cause of the tissue 
destruction that results. 
However, concepts such as this are perhaps too esoteric to guide clinical decision-
making, and instead, we have, over time, developed a series of generally agreed 
upon, though imperfect, definitions for the clinical syndrome of sepsis. 
Infection is a microbial phenomenon: the invasion of normally sterile host tissues by 
viable micro-organisms. Infection both triggers and exacerbates the host response, 
and should always be sought and treated. For example, patients with sterile 
pancreatic necrosis may have MODS but infected necrosis greatly increases the risk 
of death. Similarly, burn patients exhibit SIRS but most deaths are due to infection of 
the burn wound. 
Microbial invasion typically evokes a response in the host that may be local, in which 
case the local signs of inflammation – rubor, calor, dolor, tumor, and functio laesa – 
are present, or it may be systemic.Sepsis, therefore, is defined as the systemic host 
response to invasive infection. 
However, it will be apparent that just as local signs of inflammation may arise from 
sterile insults – a foreign body, an allergic reaction, or an autoimmune disease such 
as arthritis, for example, so too systemic inflammation may result from a sterile insult 
– multiple trauma, burns, blood transfusion, a drug reaction, pancreatitis, or 
thrombotic thrombocytopenic purpura, to name a few. Thus the term thesystemic 
inflammatory response syndrome (SIRS) was coined to denote clinical 
manifestations of systemic inflammation, independent of cause; in this model, sepsis 
is present when SIRS arises as a consequence of infection from various sources, 
such as lung, abdomen, urinary tract, (solid blue circles in figure, below). 
 
Overlap between infection, 
SIRS and sepsis 
 
A moment´s thought will disclose a further nuance that must be considered. A 
systemic inflammatory response may be desirable and beneficial to the host when 
infection is present. Yet, clinicians generally use the word sepsis to denote a state 
that is perceived as a threat. Thus the severity of sepsis can be graded. Severe 
sepsis is sepsis in association with hypoperfusion and mediator-induced organ 
dysfunction, an intuitively undesirable state, while septic shock is severe sepsis of 
sufficient severity that perfusion is even more profoundly jeopardised, vaso-
regulatory mechanisms being overcome and tissues becoming ischaemic. Some 
authors have proposed terms such as severe SIRS and distributive or 
vasodilatory shock to describe the equivalent gradations in the patient without 
infection. Regardless of terminology, it is clear that each represents increasingly 
more profound derangements in systemic homeostasis, reflected in an increasing 
rate of mortality. 
NOTE 
The terminology of sepsis is inherently controversial and imprecise, but the underlying 
concepts are not.The acute clinical syndrome – however defined or characterised – identifies a 
patient at risk of clinical deterioration or death, and must prompt the clinician to institute 
adequate resuscitative measures rapidly. The syndrome reflects the response of the host, not 
the cause: it is critical that a diagnosis be established, appropriate therapy be instituted, and 
unnecessary interventions be minimised. 
The immediate threat faced by the septic patient is not only the uncontrolled growth 
of bacteria, but also the consequences of the systemic inflammatory response on 
oxygen delivery to the tissues. In the most advanced stages, septic shock is said to 
be present – a state in which oxygen availability is compromised, normal oxidative 
metabolism at the cellular level is jeopardised, and anaerobic metabolism occurs. 
This state is characterised biochemically by the release of lactate from the cells; 
although elevated serum lactate levels are neither sensitive nor specific for shock. 
Altered cellular metabolism results in altered cellular function, and even in cell death 
as a consequence of necrosis or apoptosis. Apoptosis is a more physiologic and 
controlled process of programmed cell death, however, those programmes may be 
heightened due to inflammatory stimulation. 
The biochemical processes of sepsis are enormously complex – the consequence of 
the coordinated interaction of literally hundreds of host-derived mediator molecules 
including cytokines, the complement and coagulation cascades, vasoactive 
mediators such as kinins, prostaglandins, acute phase reactants, and short-lived 
intermediates of oxygen and nitrogen. However, the resultant effects on blood flow 
and oxygen delivery to the tissue can be readily understood as the consequence of 
four key acute changes, described below. 
Vasodilation 
Vasodilation involving small arterioles and nutrient vessels reflects the presence of 
mediators and the dysfunction of compensatory mechanisms. A number of cytokines 
can induce the expression of an enzyme known as inducible nitric oxide synthase 
(iNOS) in vascular endothelial cells. iNOS catalyses the conversion of the amino acid 
arginine to citrulline, in the process generating a molecule of nitric oxide. Nitric oxide 
is a potent smooth muscle relaxing agent, and causes local vasodilatation – indeed 
this property accounts for the pharmacologic effects of such classical vasodilatory 
agents as nitroglycerin and nitroprusside. This may be a local process that directly 
opposes sympathetic stimulation. Vasodilatation drastically increases the diameter of 
the vascular tree, reducing resistance, inducing relative hypovolaemia (as the volume 
required to fill the tree is significantly increased) and therefore lowers the effective 
blood pressure. Moreover, the loss of normal microvasculature resistance results in 
accelerating the passage of blood through the capillary beds, and therefore reduces 
the time available for passive unloading of oxygen from the saturated red. 
Loss of endothelial barrier function 
Loss of integrity of the endothelial barrier – a consequence of disruption of the 
endothelial tight junctions and loss of endothelial cells – results in loss of proteins 
and fluid into the interstitium. This further decreases the effective intravascular 
volume. Moreover, the resulting oedema aggravates cellular hypoxia by increasing 
the distance between the erythrocyte in the capillary, and the adjacent cells, and so 
increasing the distance that oxygen must diffuse to reach the cell. 
Occlusion of capillaries 
Occlusion of capillaries by thrombi, activated leukocytes, and aggregates of 
erythrocytes, whose capacity for deforming during passage through the 
microvasculature has been reduced, significantly impairs perfusion. Oxygenated 
blood bypasses these occluded capillaries (shunt), failing to unload the oxygen and 
therefore increasing the local tissue oxygen deficit. 
 
 
 
Intravital sidestream dark 
field images of the 
sublingual 
microcirculation: 
capillaries with red cells 
flowing (normal, upper image) 
and obstructed with minimal 
flow (sepsis, lower image). 
 
Images courtesy of C Ince, 
Amsterdam, the Netherlands 
For further information, see the following references. 
 
 
Impaired myocardial contractility 
Impaired myocardial contractility as a consequence of poorly characterised 
myocardial depressant factors further affects compensation. Reduced myocardial 
contractility is readily demonstrable in animal models and in septic humans; its 
biologic basis is poorly understood and probably multifactorial. Moreover its 
significance is uncertain, since the cardiac output in sepsis is characteristically 
increased,and clinical evidence of impaired cardiac output commonly reflects 
inadequate fluid resuscitation. 
The net consequence of these abnormalities is the classical haemodynamic profile of 
resuscitated sepsis: tachycardia, peripheral oedema, a hyperdynamic circulation 
(assuming adequate fluid resuscitation), warm extremities, and hypoperfusion 
characterised by elevated mixed venous oxygen saturation. 
 
What is the pathologic basis for each of the following clinical features of severe sepsis or septic shock? 
 Tachycardia 
 Tachypnoea 
 Pyrexia 
 Leukocytosis 
 A reduced systemic vascular resistance 
 An increased mixed venous oxygen saturation 
THINK The classical signs of local inflammation – rubor, tumor, calor, dolor, and functio laesa – have their 
systemic counterparts in patients with systemic inflammation. What are they? Why is each of these 
beneficial to the host in the setting of local inflammation? Why is each detrimental in systemic 
inflammation? 
Recognising sepsis in the critically ill patient 
Earlier consensus statements suggested that sepsis could be recognised by 
relatively non-specific physiologic alterations thought to be characteristic for SIRS 
and including tachycardia (a heart rate >90 beats per minute), tachypnoea (a 
respiratory rate >20 per minute or the need for mechanical ventilation), hypo- or 
hyperthermia (a core temperature <36.0 °C or >38.0 °C), and leukopenia or 
leukocytosis (a white blood cell count <4000/mm
3 
or >11 000/mm
3
). While each of 
these reflects the physiologic abnormalities that accompany the onset of systemic 
inflammation, they are neither specific for the process, nor comprehensive in 
encompassing the acute derangements that signal sepsis. What is more important 
from a clinical perspective is sensitivity to an acute change in clinical status that 
denotes the systemic derangements of sepsis. In fact a large number of acute 
changes in systemic physiologic homeostasis may be the early signs of the clinical 
syndrome of sepsis (see reference below). 
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Sepsis is not a disease, but a syndrome whose evolution should prompt the clinician 
to look for a treatable cause. The list of possible causes of SIRS is extensive (See 
Task 3 ). Infection is common, important, and generally readily treatable. For this 
reason it should always be considered first. However, the clinician must also consider 
such causes as tissue ischaemia, injury, non-infective inflammatory disorders such 
as pancreatitis or systemic lupus erythematosus, drug or transfusion reactions, and 
other immunologically-mediated processes such as thrombotic thrombocytopenic 
purpura. An educated team triage utilising simple tools or reminders of SIRS and 
possible infections will facilitate the constant vigilance required. If clinical monitoring 
systems are employed, simple alerts remind clinicians of potential inflammatory 
processes. 
NOTE 
The diagnosis of infection in a patient admitted from the community is usually 
straightforward, whereas establishing a definitive diagnosis of nosocomial infection may be 
much more challenging. As a general rule, early and appropriate treatment of community-
acquired infection has a greater impact on outcome. For more information see the PACT 
module on Severe infection 
The early recognition of sepsis is not primarily the diagnosis of a specific disease, but 
the recognition that a patient is ill and in danger of acute deterioration, and that 
immediate intervention is needed to: 
 Restore haemodynamic stability and tissue perfusion 
 Determine the cause, and reverse or correct it 
 Institute appropriate physiologic support to prevent further tissue injury. 
Let's now consider how these goals are accomplished. 
2/ RESUSCITATION AND HAEMODYNAMIC SUPPORT OF THE SEPTIC 
PATIENT 
The most immediate threat facing the septic patient is tissue hypoxia resulting from 
inadequate oxygen delivery (DO2) in the development and course of septic shock, 
defined by sepsis plus hypotension. At the cellular level, a lack of oxygen causes the 
cell to switch from aerobic to anaerobic metabolism. This shift is accompanied by 
increased production of lactate – the metabolic by-product of anaerobic metabolism – 
but also by altered cellular metabolism, or even cell death, because of inadequate 
energy generation. 
Multiple factors contribute to tissue hypoxia in sepsis: 
 Peripheral vasodilatation resulting in an increased intravascular diameter 
requiring a higher vascular volume 
 Increased capillary permeability with leakage of protein-rich intravascular 
fluid into the interstitium 
 Maldistribution of blood flow at the capillary level – secondary to 
microvascular thrombosis, to capillary plugging by platelet thrombi or 
aggregates of red cells and leukocytes, or to altered vasomotor tone – 
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resulting in shunting of oxygenated blood to the venous side of the 
circulation 
 Myocardial depression secondary to poorly characterised circulating 
factors. 
How is oxygen carried in the blood transferred to cells adjacent to capillaries? List three factors that 
might impede cellular uptake of oxygen in sepsis. 
Recognising the perfusion defect of sepsis 
Impaired tissue perfusion in sepsis in the development and course of septic shock is 
recognised through its physiologic consequences; the manifestations are many, 
though variable from one patient to the next. 
 
Any acute change in normal haemodynamic homeostasis that is not readily explained by 
another obvious diagnosis (for example, haemorrhage, myocardial infarction, intoxications or 
poisoning) should prompt you to consider the possibility of septic shock, particularly when 
there is suspicion for infection. 
Tachycardia, a common finding in sepsis, is in part, a reflexive response to a relative 
intravascular volume deficit. Physical examination of the patient with unresuscitated 
septic shock reveals signs of peripheral hypoperfusion, a rapid, weak pulse, cool 
extremities, and tissue pallor and cyanosis. 
Reduced intravascular volume is also reflected in reduced pressure in the venous 
side of the circulation. Under normal circumstances, the right atrial or central venous 
pressure (CVP) is 0 to 5 mmHg, and the pulmonary capillary occlusion (or wedge) 
pressure (PAOP or PCWP) is 5 to 12 mmHg when the plateau of the cardiac function 
curve relating cardiac output to filling pressure is approached; lower levels are highly 
suggestive of an intravascular volume deficit and of fluid responsiveness, i.e. a rise in 
cardiac output upon a fluid challenge. For more information see the PACT module on 
Haemodynamic monitoring . 
In the absence of factors that modify the distribution of blood in the microvasculature 
or the normal relationship between the capillaries and cells in the immediately 
adjacent tissues, reduced oxygen delivery results in increased oxygen extraction 
(VO2/DO2). This is a compensatory mechanism that maintains oxygen consumption, 
as blood moves more slowly through the microvasculature, and the gradient down 
which oxygen diffuses becomes steeper. When oxygen extraction has reached a 
maximum, further lowering of DO2 reduces VO2 below tissue needs. See the PACT 
module on Hypotension for more information . 
When oxygen extraction increases, the oxygen saturation of the haemoglobin of 
venous blood returning to the heart is lower than its normal 70% thus directly 
reflecting an increased release of oxygen and providing us with a measurement that 
indicates poor oxygen delivery. While the most representative sample of venous 
blood from the entire body is the mixed venous bloodin the pulmonary artery (as it 
evaluates the mixing of total body including coronary sinus and cerebral blood), a 
sample drawn from the superior vena cava or right atrium through a central venous 
catheter provides a reasonably reliable estimate of the extent to which haemoglobin 
has become deoxygenated in the peripheral tissues. Low central venous saturations 
indicative of inadequate resuscitation were well demonstrated in early sepsis in the 
following study. 
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Following resuscitation, the central venous saturation rises for reasons discussed 
above. Decreased tissue perfusion can be detected indirectly as metabolic acidosis, 
or more directly, as an increased serum lactate level. 
Reduced tissue perfusion results in acute alterations in organ function (see Task 
5 ). This altered function is apparent in the kidney, where reduced blood flow 
results in reduced urine production (oliguria) and increasing serum creatinine (see 
the PACT module on Oliguria and anuria ). It is also seen in the cardiovascular 
system as persistent tachycardia and hypotension (shock), and in the central nervous 
system, as confusion. Hepatic hypoperfusion can result in hepatocellular injury, 
reflected in elevated levels of hepatic transaminases. Pulmonary dysfunction is 
manifest as hypoxaemia due to ventilation–perfusion mismatching, despite increased 
oxygen support. 
The clinical and biochemical manifestations of tissue hypoperfusion are, as a rule, 
readily apparent, and often multiple. A serialised measure of serum lactate in 
conjunction with central or mixed venous monitoring facilitates evaluation of benefits 
of treatment. Their rapid correction is critical. 
Cardiovascular support in sepsis 
The mainstay of cardiovascular support of the septic shock patient is the rapid 
administration of intravenous fluids with the goal of restoring haemodynamic stability. 
The choice of fluid is much less important than the amount. Large randomised trials, 
or systematic syntheses of smaller studies, have failed to provide convincing 
evidence for the superiority of crystalloids or colloids during fluid resuscitation. 
 
 
Adequate intravenous access is established, and normal saline, Ringer´s lactate, or 
another balanced electrolyte solution is rapidly administered, with the goal of giving a 
litre or more of fluid within the first 30 minutes. Initial assessment of the response to 
resuscitation entails monitoring of vital signs and urine output, and so a urinary 
catheter provides the clinician with a tool to evaluate the dynamic response to 
intravenous fluids. Restoration of a normal blood pressure and heart rate, and 
maintenance of a urinary output greater than 0.5 ml/kg/hr (adults) suggest that initial 
resuscitative measures have been successful. But what if they aren't? More invasive 
strategies must be used to optimise tissue perfusion. The best validated of these, 
and the approach adopted by the Surviving Sepsis Campaign, is the algorithmic 
approach popularised by Rivers (below). 
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Treatment algorithm of 
septic shock 
 
 
 
First, continue to provide intravenous fluids, but insert a central venous catheter to 
monitor the central venous pressure and the oxygen saturation of the central venous 
blood. Fluids are given rapidly until the CVP is at least 6-8 mmHg, but continued 
improvement may occur as the CVP is pushed to even higher levels, and so it is 
advisable to continue fluid resuscitation as long as the blood pressure, urine output 
and, more specific measures of fluid responsiveness respond, and pulmonary gas 
exchange is not significantly jeopardised. 
THINK Optimising fluid resuscitation requires maximising the benefits of further fluids, while minimising 
the risk –titrating therapy to the response of the individual patient. 
List three physiologic responses that suggest your patient is responding adequately. 
List three physiologic responses that suggest your patient is not responding appropriately, but may 
in fact be experiencing harm. 
 
For the next six patients with central venous catheters in place, and to whom you are 
administering fluid, record the total amount of fluid you have given, the CVP level at which 
you decided to stop administering fluids, and the time it took to reach this goal from the time 
that resuscitation began. Are the responses similar in all patients? How do your actions 
compare with the recommendations of the Surviving Sepsis Campaign? 
If the blood pressure remains low despite adequate volume resuscitation, then 
vasopressors should be administered, and dosed so that the mean arterial pressure 
is raised to about 65 mmHg. This target seeks to maximise vital organ perfusion, 
while minimising the adverse consequences of the resulting vasoconstriction. Either 
norepinephrine or dopamine are the vasopressor agents recommended by the 
Surviving Sepsis Campaign but there is no compelling evidence that one is superior 
to the other. Other vasoactive agents such as epinephrine (or perhaps vasopressin) 
might be equally effective. Practically speaking, it is best to use the agent whose 
dosing and side-effect profile you and your team are most comfortable with. 
An increase in blood pressure does not necessarily result in increased tissue 
perfusion, and perfusion, not pressure, is our therapeutic objective. The adequacy of 
global tissue perfusion can be inferred by measuring the ScvO2, either with a 
specially designed catheter, or simply by blood gas analysis of a sample of blood 
withdrawn through the CVP catheter. The objective is to increase the ScvO2 to at 
least 70%, and this objective is achieved by one or both of two strategies. First, an 
inotropic agent such as dobutamine is administered at a dose of 5 µg/kg/min, and the 
dose titrated upwards based on the response of the central venous oxygen 
saturation. High doses of dobutamine have been associated with increased mortality, 
and so the total dose should probably not exceed 20 µg/kg/min. Second, if the 
haemoglobin level is low (less than 4.96 mmol/l; 8.0 g/dl), packed red cells can be 
transfused to raise the level to 6.2 mmol/l (10 g/dl). 
Most patients will respond to these measures; those who do not pose a 
formidable challenge for the intensivist and the critical care team, and one for 
which approaches must be systematically clinical and empirical. Moreover their 
risk of death is high. A reasoned approach to this situation would consider 
diagnostic or iatrogenic error. First, re-evaluate the clinical situation. Is the 
failure to respond a function of refractory septic shock, or has another 
unrecognised complication occurred; for example, tension pneumothorax 
following insertion of a central catheter, severe pulmonary oedema resulting 
from aggressive resuscitation, inappropriate/inadequate antimicrobial therapy or 
acute myocardial infarction with cardiogenic shock. 
If the patient does not 
respond as expected, 
reconsider the possibility of 
another diagnosis 
Once these are ruled out, consider the clinical context is aggressive therapy likely to 
result in an acceptable quality of life for the patient,or are you simply engaging in a 
battle of wills with what is clearly an irreversible process? Is the therapeutic objective 
reasonable? Set your sights lower, and consider accepting a mean arterial pressure 
of 55, or even 50 mmHg, if trying to increase the pressure proves unsuccessful; 
consider a further fluid challenge if the CVP is high but oxygenation acceptable. 
Before you initiate a further intervention, define a therapeutic target, and decide what 
you must measure in order to evaluate whether you are achieving your objectives. 
A 67-year-old man is admitted with septic shock following an extensive small bowel resection for 
intestinal infarction secondary to a superior mesenteric artery embolism. Following your initial 
resuscitation, he is tachycardic with a heart rate of 136/min, and hypotensive with a blood pressure of 
76/40 mmHg; the central venous pressure is 12 mmHg, and the ScvO2 is 72%. He has produced 20 ml 
urine in the last two hours. His haemoglobin is 6.5 mmol/l (10.6 g/dl), and he is receiving norepinephrine 
at a dose of 20 µg/min. He is mechanically ventilated, and his SaO2 is 96% with an FiO2 of 0.6, and 
PEEP of 12 cmH2O. 
Describe three potential interventions you might employ to manage this man, and the specific 
parameters you will use to evaluate whether you have been successful. 
3/ IDENTIFICATION AND CONTROL OF THE SOURCE OF INFECTION 
Once resuscitation has been started, the next priority in the management of the 
septic patient is to establish a diagnosis and to institute appropriate measures to treat 
the inciting infection – specifically, performing appropriate cultures, thereafter 
starting empiric antibiotics directed against the probable infecting pathogen(s) and 
undertaking source control to eradicate a discrete infective focus. 
Diagnosing infection in the acutely ill patient 
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Establishing an infective diagnosis in the acutely ill patient may be quite 
straightforward, but is often enormously challenging. Our objective is to answer, as 
reliably and rapidly as possible, three questions: 
 Is my patient infected? 
 What is the site from which the infection is arising? 
 What is/are the infecting pathogen(s)? 
Is the patient infected? 
The initial history and physical examination may establish a diagnosis of infection. In 
the patient presenting to the emergency department with an acute illness, fever, 
malaise, and a new cough productive of purulent sputum, this suggests the diagnosis 
of community-acquired pneumonia, while acute abdominal pain with findings of 
peritoneal irritation suggests intra-abdominal infection. Physical examination may 
provide other evidence of a localised infective process – a necrotising soft tissue 
infection, infected joint or head and neck infection, for example. Recent hospital 
admission and indwelling catheters, among other examples should alert the clinician 
to other possible infections. 
Laboratory investigations can support the presumptive diagnosis of infection. An 
increased white blood cell count is often present, however life-threatening infection 
can present with leukopenia. Although an increased percentage of immature forms 
should be present in either instance, the discriminatory ability of leukocyte changes 
to differentiate infective and non-infective causes of fever is poor. Some studies have 
shown increased levels of C-reactive protein to have a better discriminatory capacity, 
with an odds ratio of 5.4 for the diagnosis of infection in patients with clinical signs of 
systemic inflammation. Increased procalcitonin (PCT) levels provide even greater 
diagnostic accuracy, with an odds ratio of 15.7; procalcitonin has shown particular 
efficacy in discriminating infective from non-infective aetiologies in patients 
presenting to the emergency department with acute respiratory symptoms. Other 
biomarkers of infection – for example soluble TREM-1 for the diagnosis of 
pneumonia and endotoxin activity levels for the diagnosis of Gram-negative infection 
– show diagnostic promise but experience is limited. 
 
 
Culture evidence of tissue invasion currently represents the gold standard for the 
diagnosis of infection. Specimens should be obtained prior to initiating antibiotics to 
maximise the diagnostic yield. Positive blood cultures provide objective evidence of 
systemic dissemination of a micro-organism; however the yield of blood culture 
positivity is variable, depending on the nature of the infection as well as the methods 
of sampling. Following adequate skin preparation, at least two samples should be 
taken from a peripheral site, inoculating at least 10 ml blood into each specimen 
bottle. Positive cultures, taken using sterile technique, of normally sterile tissue fluid – 
pleural or peritoneal fluid, for example – also provide conclusive evidence of 
infection. Cultures obtained from a surface are less reliable, for the differentiation of 
normal or pathologic colonisation from invasive infection is difficult. Positive sputum 
or urine cultures in intubated or catheterised patients may reflect colonisation of the 
tracheobronchial tree or lower urinary tract respectively; the use of quantitative 
culture techniques, and invasive interventions such as bronchoscopy to obtain 
specimens from a distal source, can improve the reliability of culture data. 
Which of the following has not been shown to reduce the rate of contamination (false positivity) during 
the performance of blood cultures? 
a/ Skin preparation with chlorhexidine rather than povidone-iodine 
b/ Aspiration of blood through a central catheter using full sterile technique 
c/ Changing the needle prior to inoculating the specimen into a culture bottle 
d/ Disinfecting the stopper on the culture bottle prior to inoculation 
Definitive identification of the isolated microbial species, and evaluation of its 
sensitivity profile to common antibiotics, typically involves a delay of at least two 
days. An earlier presumptive microbial diagnosis can be made using a Gram stain 
(particularly of CSF or urine samples), which can provide information on the class of 
organism within an hour. 
When the suspected infection is a nosocomial infection arising in a hospitalised 
patient, the diagnosis is particularly challenging. For this reason, it is probably 
clinically more accurate to think of the probability that infection is present, rather than 
to try to definitively establish or rule out infection. In other words, a decision to treat 
with antibiotics is made not on the basis of a diagnosis of infection, but rather on the 
probability that infection is the cause of the presenting clinical syndrome. Therefore, 
after cultures have been collected, a broad-spectrum antibiotic should be considered, 
primarily based on the likely source of the infection and knowledge of local 
pathogens. 
 
For the next ten patients you are called on to evaluate for suspected sepsis, write down your 
initial clinical impression of the probability of infection (very unlikely, unlikely, neutral, 
likely, very likely) and the presumptive infective focus. Repeat this evaluation three days 
later, using the results of laboratory, radiographic, and microbiological investigations to guide 
your reassessment. How accurate was your initial assessment? And don't be discouraged if it 
is imperfect. Diagnostic inaccuracy is one of the intrinsic challenges of managing the septic 
patient. 
If the initial clinical assessment, augmented by the results of rapidly available 
investigations, suggests that infection is likely to be present, then empiric antibiotic 
therapy should be started expeditiously, guided by knowledge of local resistance 
patterns and the probable infective focus. Delays in initiating therapy when severe 
sepsis or septic shock is present have been associated with a time-dependent 
increase in the risk of death (figure below). Equally, escalation of antibiotic therapy 
should be considered if thepatient fails to respond or if microbiological studies 
suggest this is necessary. Lastly, de-escalation must be appropriately invoked when 
culture results indicate that treatment with a narrower spectrum antibiotic is possible. 
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Delay between onset of 
hypotension and the 
initiation of antimicrobials 
versus mortality 
 
From Kumar A, Roberts D, 
Wood KE, Light B, Parrillo JE, 
Shrama S et al. Duration of 
hypotension before initiation 
of effective antimicrobial 
therapy is the critical 
determinant of survival in 
human septic shock. Crit 
Care Med 2006; 34(6): 1589-
1596. PMID 16625125 
 
What is the site of the infection? 
Determining the site from which the infection is arising enables the clinician to refine 
the prediction of the likely infecting organism(s), and to determine whether (surgical 
or interventional) source control measures are indicated for definitive management of 
the infective episode. 
Physical examination may aid in establishing the origin of the infection, but radiologic 
imaging studies are typically needed to document the precise site of origin and extent 
of spread. A chest X-ray may support the diagnosis of pneumonia by showing lobar 
consolidation or other acute alterations. If an effusion is also present, particularly in 
the patient with pneumonia who has failed to respond to systemic antibiotics, the 
diagnosis of empyema should be entertained, and investigated by aspirating a 
sample of the pleural fluid. 
Ultrasonography is inexpensive, and rapidly as well as widely available. Its greatest 
utility lies in detecting infections arising from an obstructed abdominal hollow 
viscus – for example, the gall bladder and biliary tree producing acute cholecystitis 
or cholangitis, respectively, or from the urinary tract in the case of pyelonephritis. 
Ultrasonography is operator-dependent, and its use may be limited by external 
dressings, or by significant quantities of air in the gastrointestinal tract. 
Computerised tomography (CT) scanning is the most useful diagnostic modality for 
patients with deep space infections in the abdomen or thorax; it is also useful in 
evaluating the extent of complex soft tissue infections. Oral or rectal contrast aids in 
CT interpretation by delineating the lumen of the gastrointestinal tract, and by 
demonstrating leaks from the GI tract when these are present. Intravenous contrast 
permits the identification of major vascular structures, and can demonstrate areas of 
tissue non-perfusion, suggestive of ischaemia or infarction. For more information see 
the PACT module on Clinical imaging 
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=DetailsSearch&Term=16625125%5Buid%5D
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Accurate delineation of the anatomic site of infection provides a diagnosis of the 
infection responsible for the septic state, and may facilitate image-guided 
management using percutaneously placed drains, and therefore obviating the need 
for surgical intervention. 
 
Fluid collections 
suggestive of abcesses, 
with drain in situ 
Less common foci of infection should also be considered. In the patient with multiple 
positive blood cultures, a diagnosis of endocarditis should be considered, particularly 
in the patient with pre-existing risk factors – for example, valvular heart disease or a 
prosthetic heart valve, intravenous drug abuse, a long-standing central venous 
catheter. The diagnosis is supported by clinical features and established by 
transoesophageal echocardiography and blood culture. Altered neurological status or 
focal findings suggests the possibility of a cerebral or spinal focus, and should be 
assessed further by CT scan or MRI. Invasive tests like bone marrow aspiration must 
be considered for systemic infections such as tuberculosis especially in the 
immunocompromised host. 
What is the infecting pathogen? 
Accurate identification of the nature and antibiotic sensitivity profile of the infecting 
pathogen enables the clinician to tailor antibiotic therapy, using a regimen that is 
effective, but narrow spectrum, and so minimally disruptive to the patient's 
endogenous flora. 
An initial prediction of the likely infecting pathogen is made on the basis of the 
presumptive site of the infection (pneumonia, intra-abdominal infection, prosthetic 
device-related infection, etc), and on the mode of acquisition – community-acquired 
or nosocomial. Presumptive empiric therapy can then be initiated with reasonable 
confidence that the actual infecting organism will be susceptible (see the PACT 
module on Severe infection ). 
Accurate identification of the infecting organism requires the results of microbiological 
culture and sensitivity testing, which typically are not available for two or three days 
after the initial specimens were taken. Once these data are available, the antibiotic 
spectrum should be narrowed to target the particular pathogen specifically; if cultures 
are negative after 72 hours, strong consideration should be given to stopping all 
antibiotics. Alternately, other causative organisms should be considered if the patient 
has persistent clinical signs of sepsis. 
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Managing infection in the septic patient 
Once a presumptive diagnosis of infection as the cause of sepsis is made, treatment 
should be initiated expeditiously. 
Systemic antibiotics appropriate to the working diagnosis and based on knowledge of 
local resistance patterns, should be given as soon as cultures have been drawn and, 
ideally, within an hour of presentation. Antibiotic selection is discussed further in the 
following reference and in the PACT module on Severe infection . 
 
 
When a discrete focus of infection is identified, source control measures should be 
considered, and implemented once the patient has been stabilised. Some general 
principles underlie their use. 
A 74-year-old man is admitted to the ICU following repair of a ruptured abdominal aortic aneurysm; 
significant co-morbidities include hypertension, insulin-dependent diabetes mellitus, and chronic 
obstructive pulmonary disease. He is intubated, and has a Foley catheter, pulmonary artery catheter, 
peripheral intravenous, and nasogastric tube placed in the operating room (OR). What specific sites of 
nosocomial infection is he at risk for? Why? 
What organisms are most likely to be cultured from each of these sites? 
Source control is a term that encompasses all those physical measures undertaken 
to control a source of infection, to stop ongoing microbial contamination, and to 
restore optimal anatomy and function. Source control measures are applicable to 
most infections causing severe sepsis, and fall into two broad categories. 
Drainage is the creation of a controlled sinus (a connection between a closed cavity 
and an epithelial surface) or fistula (an abnormal communication between two 
epithelially-lined surfaces). By draining an abscess (a localised focus of infection and 
host inflammatory cells, walled off by a fibrin capsule), a deep-seated infection is 
converted to a controlled sinus or a fistula (figure below). 
 
Drainage creates a controlled sinus or fistula Draining abcesses, 
percutaneously or 
surgically 
The drain is a foreign body 
that keeps the tract open 
Based on this principle, the optimal approach to achieving source control is that 
which accomplishes the objective with the least degree of upset to the patient, and 
with full consideration to minimising the risk associated with subsequent 
reconstructive efforts. For example, perforated diverticulitis causing severe sepsiscan be managed operatively by resection of the involved segment of colon, followed 
by the creation of an end-colostomy, or by primary anastomosis. Resection removes 
the site of ongoing contamination, while the colostomy or anastomosis is the 
controlled fistula (because it is an abnormal communication between two epithelially-
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lined surfaces). However, if the CT scan shows a localised process, percutaneous 
image-guided drainage can accomplish the same objectives with a lesser degree of 
physiologic insult to the patient. Drainage procedures are most effective if the 
infected material is liquid; if it includes solid tissue, then debridement must be 
employed. 
Debridement is the mechanical removal of infected non-viable tissue, typically by 
surgical resection, but in the case of superficial infection, by the use of dressing 
changes, or in the case of an infected foreign body, by its removal. As a general rule, 
debridement of infected necrotic tissue should be performed as rapidly as feasible: 
for patients with necrotising soft tissue infection, for example, prognosis is directly 
related to the interval between onset and definitive surgery. However, the benefits of 
debridement must be weighed against the risks of intervention: for patients with 
infected peripancreatic necrosis, it has become evident that delayed debridement is 
preferable, because of the substantial risk of uncontrollable haemorrhage that may 
occur when adequate demarcation of viable and non-viable tissues has not occurred. 
The ultimate objective in managing the patient with severe sepsis or septic shock is 
to achieve survival with a good quality of life. Careful consideration of the definitive 
measures needed to manage a focus of infection can shorten the period of time the 
patient is hospitalised, and improve the ultimate quality of life. For example, avoiding 
a stoma will obviate the need for subsequent surgical reconstruction and its attendant 
risks. When a stoma is deemed necessary, creating it in such a manner that it can be 
closed through a single small incision will reduce the morbidity associated with 
subsequent reconstruction. 
THINK For each of the following clinical scenarios resulting in severe sepsis or septic shock, consider: 
 What are the options for achieving source control? 
 How can the problem be managed using the principles outlined above? 
 What is your preferred approach and why? 
A 66-year-old woman presents to the emergency department with fever, chills, 
jaundice, and right upper quadrant pain, 14 years after a cholecystectomy. Her 
blood pressure is 70/40, and her heart rate 130/minute. An ultrasound exam 
shows the common bile duct to be dilated to 1.8 mm. 
A 47-year-old man presents with diffuse abdominal pain; he is hypotensive and 
tachypnoeic, with a temperature of 38.7 °C. Following resuscitation, he 
undergoes CT scanning which shows sigmoid diverticulitis with an associated 
abscess. 
An 86-year-old woman develops confusion, a supraventricular dysrhythmia, 
and oliguria, three days following a right hemicolectomy for cancer. She is 
afebrile. Her CT scan is shown below. 
 
CT scan with free air in the 
abdomen suggestive of 
leaking anastomosis 
A 59-year-old man, intubated five days after a right lower lobectomy for lung 
cancer, develops a fever, and a new right-sided infiltrate. There is an 
associated pleural effusion; diagnostic thoracentesis yields Gram-positive 
cocci. 
THINK Invasive devices are a common nidus of infection in critically ill patients. What factors contribute to 
device colonisation? 
What steps can be taken to reduce the risk of colonisation? 
For which of the following nosocomial infections should device removal be an integral part of 
infection management, and under what circumstances? 
 Bacteraemia 
 Urinary tract infection 
 Ventilator-associated pneumonia 
 Septic thrombophlebitis 
 Peritonitis during chronic ambulatory peritoneal dialysis 
 A-V or V-V shunts for chronic renal replacement therapy 
 Indwelling central catheters (short or long-term) 
Non-infective causes of severe SIRS 
A diagnosis of severe sepsis or septic shock implies an infective aetiology. However 
an identical clinical syndrome may evolve in the absence of infection, and 
management principles do not differ, with the important exception that anti-infective 
measures are unnecessary, and potentially even harmful. 
To establish that infection is not the cause of the acute illness requires primarily the 
exclusion of infection as a cause, and secondarily making a reasonable alternative 
diagnosis (table below). Appropriate empiric antibiotics and a systematic attempt to 
establish an anatomic and microbiologic diagnosis are indicated if there is a 
moderate or high probability of an infective cause. However, it is equally important, if 
these investigations fail to confirm a diagnosis of infection, that empiric antibiotics be 
stopped as soon as the diagnosis has been ruled out, and certainly by 72 hours after 
initial presentation. 
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Non-microbial causes of 
SIRS 
4/ ADJUNCTIVE THERAPY FOR SEPSIS 
Despite advances in our understanding of sepsis, the mortality after treatment is over 
50% in the presence of shock. Earlier in this module, the importance of diagnosis, 
early resuscitation and directed therapy for sepsis were emphasised. It is, however, 
crucial to appreciate that several other aspects of the disease and its treatment also 
impact on the outcome from sepsis. This discussion will highlight the adjunctive 
interventions, based on available evidence, which may be considered part of a 
comprehensive approach to treatment. Such interventions must equally be with 
minimal risk of adverse events. The considerations for paediatric patients are 
uniquely different and will not be addressed. 
 
Several therapeutic interventions have been investigated for sepsis in an attempt to reduce 
morbidity and mortality. Where the benefits of such therapy are unproven, their introduction 
cannot be justified. 
 
Adjunctive 
therapy for 
sepsis 
 
 
*rhAPC: 
recombinant 
human activated 
protein C, 
DVT: deep vein 
thrombosis, 
LOS: length of 
stay, 
NOS: Nitric oxide 
synthase 
Recombinant human activated protein C 
Many novel therapeutic agents have been investigated over the last three decades. 
None have shown incontrovertible evidence of benefit in patients with sepsis. 
Recently, recombinant human activated protein C (rhAPC) has been shown to 
reduce mortality (absolute mortality reduction of 6.1%) in adult patients with severe 
sepsis when administered to patients within 24 hours of diagnosis of severe sepsis 
and sepsis induced organ dysfunction. There are many postulated mechanisms of 
action including reduction of thrombin formation, an anti-inflammatory effect and 
reduction of rolling of monocytes and neutrophils. The dose required is 24 µg/kg/hour 
for 96 hours. Bleeding is the commonest complication associated with therapy. 
Treatment with rhAPC should be avoided in patients with active bleeding or at high 
risk for bleeding and the drug has not yet been shown to be effective in less severe 
septic patients. 
 
Treatment must be curtailed where significant risks are associated with drug administration. 
The Surviving Sepsis Campaign guidelines (2008) recommend that the drug be 
considered in septic patients with an APACHE 2 score ≥25 but not in those with a 
score <20. 
NOTE 
The European Medicines Agency (EMeA) and other regulatory bodies have individualised the 
indications for rhAPC use in severe sepsis and it is advised that you know the licensedindication in your own jurisdiction. 
http://www.emea.europa.eu/htms/human/epar/a.htm 
 
In patients who require surgery, the drug should be discontinued for at least one hour prior to 
surgery. It may be recommenced one hour after minor procedures and 12 hours after major 
surgery – once concern re bleeding complications has subsided. 
Absolute contraindications for rhAPC 
 Active internal bleeding 
 Recent (within 3 months) haemorrhagic stroke 
 Recent (within 2 months) intracranial or intraspinal surgery, or severe 
head trauma 
 Trauma with an increased risk of life-threatening bleeding 
 Presence of an epidural catheter 
 Intracranial neoplasm or mass lesion or evidence of cerebral herniation 
 Thrombocytopenia <30 x 10
9
/l. 
 
 
http://www.emea.europa.eu/htms/human/epar/a.htm
Steroids 
Earlier studies using high dose steroid therapy for sepsis demonstrated no mortality 
benefit and were associated with an increased prevalence of nosocomial sepsis. Low 
dose hydrocortisone (200-300 mg per day) was shown in the Annane (single-centre) 
study to reduce mortality in corticotropin unresponsive patients with septic shock who 
require fluids and vasopressor support. However, the larger, multi-centre CORTICUS 
study showed only that hydrocortisone hastened the reversal of shock in those in 
whom shock was reversed. Hydrocortisone did not improve survival or reversal of 
shock in patients with septic shock, either overall or in patients who did not have a 
response to corticotropin. 
 
 
When using hydrocortisone, treatment should not be delayed for confirmation of the 
presence of hypoadrenalism (by corticotropin stimulation testing). 
The mechanism of action is thought to be via improving catecholamine receptor 
responsiveness to exogenous catecholamines. Modulating immune responsiveness 
in patients who have relative adrenal insufficiency is also thought to occur. Treatment 
with steroids should be weaned once shock has resolved. It is common practice to 
administer steroids for 5-7 days as abrupt withdrawal of therapy may result in 
adverse haemodynamic and immunological effects. There are no data supporting the 
use of steroids for protracted periods and a higher rate of steroid-related septic 
complications have been confirmed, even in the 11 day duration of therapy utilised in 
the CORTICUS study (above). 
NOTE 
Therapeutic interventions must only be introduced when there is clear evidence of benefit 
AND where the risks of treatment are out-weighed by the benefits. 
THINK A known asthmatic is being ventilated for severe bronchospasm. He develops septic shock from a 
nosocomial pneumonia. What are the considerations for steroid therapy in this patient? The 
following scenarios illustrate the multiple reasons to start steroids in this, and many other cases. 
Three scenarios are possible in this case: 
 Steroids prior to admission: If the patient is a known asthmatic, it is 
possible that he would have been receiving steroids prior to ICU 
admission. In this instance, he would be on steroids at the time of 
development of nosocomial sepsis, in which case steroid therapy must 
be continued to treat acute on chronic bronchospasm and must be 
continued after the episode of septic shock has resolved. 
 Steroids for bronchospasm: The patient may not have been on steroids 
prior to admission in which case steroids may have been administered 
for the management of refractory bronchospasm. In this instance, steroid 
therapy must be withdrawn after resolution of bronchospasm or seven 
days after treatment for septic shock, whichever is later. 
 Steroids for septic shock: The standard approach to steroid therapy for 
fluid resuscitated and vasopressor-dependent septic shock should be 
considered. 
A patient has been treated for an episode of septic shock with steroids. Two days later, he develops 
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another episode of septic shock. Would you administer steroids again? Justify your answer. 
Glucose control 
Glucose control was demonstrated to reduce morbidity and mortality in surgical 
patients when the serum glucose was kept between 4.4-5.5 mmol/l (80-100 mg/dl). In 
medical patients there is a significant reduction in morbidity, however, the benefits 
were more significantly realised in medical patients with an ICU stay >3 days. 
Glucose control should be initiated as soon as initial stabilisation of the patient has 
been completed. It is recommended that the glucose level to be targeted is <8.3 
mmol/l (<150 mg/dl), with a goal of 4.4-5.5 mmol/l (80 to 100 mg/dl). This higher level 
is suggested because of the significant risk of hypoglycaemia. Glycogen depletion 
during sepsis increases the risk of hypoglycaemia. Hypoglycaemia has been 
reported even during the conduct of rigorous clinical trials. This is a serious life-
threatening complication in the sedated patient and must be assiduously avoided. 
Clear adherence to a well thought through protocol, well-trained nursing/medical 
involvement and supervision, regular blood testing and routine administration of 
glucose containing solutions (to avoid inadvertent hypoglycaemia) must be 
considered mandatory when patients are receiving insulin. Hourly glucose testing 
should be performed until the levels have stabilised and thereafter four hourly testing 
is acceptable. Point-of-care testing has been shown to overestimate glucose levels 
and must be used with caution. 
 
 
THINK What are the clinical signs of hypoglycaemia? How would you suspect and diagnose 
hypoglycaemia in a sedated, ventilated patient? 
Blood products 
Red blood cells 
Current data suggest that a haemoglobin level between 7-9 g/dl is as effective as a 
level between 10-12 g/dl in resuscitated patients. The Rivers trial mentioned above 
indicates this may not be true in sepsis patients with shock and persistent lactic 
acidosis or low ScvO2 on initial presentation. Red blood cells (RBCs) increase the 
oxygen carrying capacity of blood but do not immediately release bound oxygen and 
therefore may not result in increases in oxygen consumption. In addition, increasing 
the RBC concentration may adversely affect blood rheology thereby reducing oxygen 
delivery. Since the ideal haemoglobin concentration is unknown, RBC transfusion 
should likely be directed to achieving a level of 7-9 g/dl. In certain groups of patients 
where oxygen delivery and consumption is critical e.g. post-cardiac surgery or 
persistent ischaemic lactic acidosis, higher levels of haemoglobin (10-12 g/dl) may be 
preferable. 
Platelets and fresh frozen plasma 
Platelets should be administered when the count is <5 x 10
9
/l since these patients 
are at risk for spontaneous bleeding. A platelet count >50 x 10
9
/l is recommended 
prior to surgery. Abnormal laboratory tests of coagulation alone should not be used 
as an indication for coagulation factors. Fresh frozen plasma and/or platelets should 
be used in the presence of documented bleeding or prior to surgery and abnormal 
laboratory tests suggest their use. For more information see the PACT module on 
Bleeding and thrombosis 
Erythropoietin and antithrombin 
There are no data to support the use of either therapy in patients with sepsis. 
Erythropoietin may be indicated for other conditions e.g. pre-existing chronic renal 
failure and impaired erythropoietin production. High dose antithrombin increases 
bleeding when co-administered with heparin. 
THINK A patient with intra-abdominal sepsis receiving rhAPC requires major surgery. The drug infusion is 
stopped one hour prior to surgery. Excessive blood loss with anaemia occurs in ICU after surgery. 
What causes of bleeding should be considered and what should be done? 
Analgesia, sedation and muscle relaxation 
Patients with sepsis frequently require mechanical ventilation. Details on airway care, 
intubation and extubation, ventilation, analgesia, sedation and the use of muscle 
relaxants are covered in the PACT moduleson Airway management , Mechanical 
ventilation and Sedation . 
THINK The ICU nurse reports that a patient with sepsis requires increasing doses of sedative drugs without 
achieving adequate sedation. What are the likely causes for this behaviour? 
Thromboembolism prophylaxis 
ICU patients are at risk for the development of deep vein thrombosis (DVT) and 
pulmonary embolus (PE). Prophylaxis has been shown to reduce the prevalence of 
these complications, which should therefore be considered to be standard care for 
patients with sepsis. Unfractionated heparin (UFH) (eight hourly) is as efficacious as 
low molecular weight heparin (LMWH) (once daily) when administered 
subcutaneously. UFH should be used instead of LMWH when cost constraints are a 
factor. LMWH is renally excreted and may accumulate in patients with severe renal 
dysfunction. A dosage reduction/monitoring of anti-xa has been recommended in 
patients with creatinine clearance of <30 ml/minute. 
In patients with active bleeding, coagulation disturbances and proven heparin-
induced thrombocytopenia (HIT), both agents should be avoided and anticoagulation 
with non-heparin agents may be considered. Mechanical devices should be used in 
such patients. Patients at high risk for DVT and PE should receive both drug 
prophylaxis (UFH or LMWH) and mechanical devices (compression stockings or 
intermittent compression devices). 
THINK What factors constitute high risk for DVT/PE? What are the clinical signs of PE? 
For more information see the PACT module on Bleeding and thrombosis . 
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Stress ulcer prophylaxis 
Upper gastrointestinal bleeds occur less frequently in ICU patients who receive 
prophylaxis for stress ulcers but there is no evidence of a reduction in mortality from 
this therapy. Given that mechanical ventilation, coagulopathy and hypotension are 
the risk factors and that these occur commonly in patients with sepsis, prophylaxis 
should be administered in all patients with severe sepsis. Histamine-2 (H2) receptor 
antagonists and proton pump inhibitors are equivalent in producing this benefit. The 
choice of agent should be based on cost, availability of drug and side effects 
associated with these agents. Sucralfate has been shown to be less effective than 
H2 receptor antagonists. For more information see the PACT modules on 
Nutrition and Infection control strategies . 
Intravenous immunoglobulin 
Several studies have suggested the use of intravenous immunoglobulin (IVIG) as an 
adjunctive intervention in patients with sepsis. The rationale is based on 
augmentation of the immune response to infection. The Surviving Sepsis Campaign 
Guidelines suggest that immunoglobulin may be considered in children with severe 
sepsis but there is no corresponding suggestion of recommendation in adults. There 
have been three recent meta-analyses but given differences in study methodology, 
issues relating to dose standardisation and safety, not to mention other advances in 
the management of sepsis, a large, prospective randomised trial is indicated before 
this form of treatment should be considered as routine adjunctive therapy. 
Granulocyte colony-stimulating factor 
Granulocyte colony-stimulating factor (G-CSF) has been used in neutropenic patients 
for several years to bolster receptor-mediated neutrophil and macrophage 
responsiveness and has been used clinically in severely septic, neutropenic 
neonates. Serum concentrations of G-CSF are elevated in sepsis but have no 
relationship to outcome. The Surviving Sepsis Campaign Guidelines do not include 
mention of G-CSF and further studies are required to elucidate where this 
intervention may be beneficial. 
In conclusion, adjunctive therapeutic strategies have reduced morbidity and mortality 
associated with sepsis and should be routinely considered in clinical practice. These 
interventions should be carefully evaluated for benefit to ensure that unacceptable 
side effects (e.g. hypoglycaemia, bleeding or superinfection are controlled as far as 
possible. An area that will require careful ongoing consideration is the potential 
negative consequences from the multiple therapies that have been advocated for 
sepsis. 
5/ MINIMISING ORGAN DYSFUNCTION IN ICU 
Acute multiple organ dysfunction is the defining complication of severe sepsis and 
septic shock. Organ dysfunction arises as a consequence of the profound systemic 
homeostatic derangements that accompany an uncontrolled systemic inflammatory 
response. It also develops, however, as a consequence of what the healthcare team 
does to treat these derangements. Organ dysfunction therefore may develop 
because of both the successes and the shortcomings of contemporary ICU care. 
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Whilst all organ systems are affected, the cardiac and respiratory dysfunction 
typically manifest early in the clinical course of severe sepsis. 
What is MODS? 
MODS can be defined as the development of acute physiologic organ system 
dysfunction following an acute life-threatening insult. Its manifestations may involve 
virtually every aspect of normal physiologic function but by convention, the syndrome 
of MODS is usually considered to involve derangements in the function of six organ 
systems – the respiratory, cardiovascular, renal, haematologic, hepatic, and 
neurologic systems. The concept that the syndrome represents dysfunction rather 
than failure is preferred, since the process is reversible, and prognosis correlates not 
only with the number of failing systems, but also with the degree of 
dysfunction within a system. This conceptual model is reflected in the emergence of 
a number of similar systems to quantify the severity of the syndrome using a score 
(Table below). 
 
Measuring 
Organ 
Dysfunction: 
the MOD and 
sequential 
organ failure 
assessment 
(SOFA) scores 
 
The capacity to quantify MODS provides the clinician with a tool to measure changes 
in global severity of illness over time, and the investigator with a means of evaluating 
the epidemiology and natural history of critical illness. The MODS score uses six 
continuous physiologic variables, and so measures organ dysfunction independent of 
a therapeutic decision, since such decisions vary and may not only reflect evolving 
illness, but contribute to its evolution. Function of the cardiovascular system is 
measured using a simple calculated variable, analogous to the PO2/FiO2 ratio – the 
pressure-adjusted rate (PAR), calculated as the product of the heart rate and CVP, 
divided by the mean arterial pressure, and reflecting hypotension that does not 
respond to fluid resuscitation: 
 
A normal value is 10 or less; increasing values reflect worsening cardiovascularfunction. In the absence of an actual measure of right atrial pressure, a normal value 
of 8 is used. The SOFA score incorporates therapy-dependent variables in the 
measurement of respiratory and cardiovascular dysfunction; urine output is also 
included as a measure of renal function. These differences, however, have only a 
minimal effect on the reliability of each. 
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The measuring systems provide different and complementary information on the 
clinical course of the patient. The score on the day of admission is a measure of 
illness severity at the onset of care, and correlates directly with ultimate prognosis: it 
is, in effect, a snapshot of how sick the patient is before critical care begins. Scores 
measured on a daily basis provide a reflection of how the global course of illness is 
evolving. Moreover the domains of improvement or deterioration can be followed 
over time, particularly if the raw data for each variable are used – is respiratory 
function, measured by the PaO2/FiO2ratio, getting better or worse? Is there particular 
deterioration or improvement in one organ system that might point to a correctable 
problem? Change over time can also be measured using the delta score – either by 
taking the worst values in each system over the ICU stay, and subtracting them from 
the admission score, or by looking at the change in scores from one day to the next; 
the former calculation provides a global measure of new organ dysfunction 
developing during the ICU stay, and so is a reflection of potentially preventable ICU 
morbidity. 
Preventing organ dysfunction in the critically ill 
The ultimate objective of critical care practice is to support a patient during a period 
of life-threatening physiologic instability, while treating the process that triggered the 
illness on the one hand and minimising the associated multi-organ dysfunction 
including the adverse consequences of support measures. For convenience, this 
topic can be addressed in terms of one organ at a time. 
Respiratory dysfunction 
The acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) reflect a 
particularly severe form of the respiratory dysfunction that develops in many critically 
ill patients. This respiratory dysfunction results from both the systemic inflammatory 
response to the acute injury that led to ICU admission, and the local response of the 
lung to additional, and preventable insults arising from the technique of ventilatory 
support used, or superimposed lung infection producing ventilator-associated 
pneumonia. A state of generalised vasodilatation and increased capillary permeability 
results in interstitial oedema in the lung, and exudation of protein-rich fluid into the 
alveolar space. Both of these compromise gas exchange, producing alterations that 
can be detected early in the course of the process as tachypnoea, hypoxaemia, and 
hypocarbia, as well as loss of lung compliance. The institution of mechanical 
ventilation introduces a new insult to the vulnerable lung, as positive pressure 
ventilation applies unnatural shear forces to the lung units, and repeated opening and 
closing of these units causes local tissue injury. 
This injury evokes a further inflammatory response, with the influx of neutrophils into 
the lung, further exacerbating the local injury, and compromising gas exchange. 
Thrombosis in small, medium, or large vessels – secondary either to systemic 
activation of the coagulation cascade, or to embolisation from the extremities, further 
compromises gas exchange. Aspiration of bacteria from the stomach, oropharynx, 
and endotracheal tube evokes a further response, and adds to the complex picture of 
ALI. Finally, the process of tissue repair, with local fibrosis, contains the injured 
tissue, but at the cost of its function, and gas exchange is even further impaired. 
While the initial insult has usually already occurred by the time the physician sees the 
patient, the subsequent secondary injury is eminently amenable to preventive 
measures. 
Gas exchange in the lung is compromised by alveolar oedema, and so early 
pulmonary function can be improved by judicious fluid resuscitation, administering a 
volume adequate to support the circulatory system without producing excessive 
alveolar or interstitial oedema. Monitoring resuscitation through the measurement of 
central venous pressure can aid in attaining this objective. It remains controversial 
whether clinically relevant oedema can be further reduced by the use of colloids such 
as albumin or starch solution in preference to crystalloids. 
The development of ventilator-associated pneumonia (VAP) exacerbates acute 
respiratory dysfunction. A variety of strategies have been shown to be effective in 
reducing the risk of VAP, including elevation of the head of the bed, use of closed 
system suction devices, reduced frequency of ventilator tubing changes, and 
subglottic drainage of secretions. 
Selective decontamination of the digestive tract (SDD) – a strategy that reduces 
pathologic colonisation of the oropharynx and GI tract through the use of topical non-
absorbed antibiotics and a short course of a parenteral agent – has been shown to be 
very effective in reducing the risk of VAP. Similarly, avoiding over-sedation, and 
removing the endotracheal tube as early as is feasible are additional effective 
strategies to lower the risk of VAP. 
Protective lung ventilation strategies, accomplished by the use of low tidal volumes 
(6-8 ml/kg) and higher levels of PEEP, have been shown to reduce not only 
pulmonary, but also distant organ injury, and to improve survival. These effects may 
be modulated by the gradual introduction of pressure control ventilation and 
appropriate dosing of sedation. For more information see the PACT modules on 
Mechanical ventilation , Respiratory failure , Respiratory monitoring and 
Haemodynamic monitoring . 
Cardiovascular dysfunction 
The cardiovascular dysfunction of MODS includes peripheral vasodilatation, 
increased capillary permeability, microvascular occlusion with deranged capillary 
flow, and myocardial depression. While these abnormalities are not readily 
manipulated directly, the ultimate consequence – tissue hypoxia – can be attenuated 
by judicious clinical management. 
The adverse effects of tissue oedema can be minimised. The use of a goal-directed 
approach, dosing fluid volumes to physiologic response can aid in refining fluid 
resuscitation. Commonly, once resuscitation has been accomplished, the patient will 
remain in a significantly positive fluid balance for many more days; cautious removal 
of this excess volume using pharmacologically-induced diuresis or renal replacement 
therapies can aid in mobilising this fluid. 
The objective of haemodynamic support is to maximise oxygen delivery to the tissues 
(DO2). Since tissue oxygenation cannot be readily measured directly, it must be 
inferred indirectly. A reduced venous saturation indicates increased O2 extraction, 
and so suggests tissue hypoxia. Similarly an elevated lactate level suggests 
anaerobic metabolism secondary to reduced DO2. Both of these abnormalities have 
multiple causes, and therefore must be interpreted carefully. Hypotension is also 
inferred to reflect impaired DO2 since one must assume either inadequate cardiac 
output or loss of vascular tone, or both. However increasing blood pressure 
pharmacologically may not increase DO2, but actually reduce it, since increased 
pressure is achieved through constriction of, and perhaps reduction of flow in, small 
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