Therapeutic
interventions aimed at preventing organ failure
The widespread use of blood and plasma for the first time during World
War II resulted in the recognition of a new phenomenon — ‘irreversible
shock’. It became apparent that numerous hypovolaemic casualties could have
their vital signs restored with the administration of intravenous blood and
plasma only to develop ‘secondary shock’, often days after the original
insult, which rapidly became resistant to any form of treatment. Fifty years
later the main thing that seems to have changed is the terminology used to
identify the same condition. The terms multiple organ failure syndrome (MOFS),
multiple systems organ failure (MSOF) and, most recently, multiple organ
dysfunction syndrome (MODS) have all been used to describe ‘irreversible
shock’ and organ failure. Rather like the elephant, it seems that we have
difficulty describing it but we all know one when we see one.
In
1943 Blalock summarised the causes of irreversible shock seen in the Armed
Forces as:
(1)
haemorrhage uncomplicated by gross trauma; (2) burns; (3) trauma to large masses
of muscle; and (4) the re-establishment of circulation in a damaged ischaemic
area.
In
the same dissertation he suggests that:
the
initial phases (of shock) are certainly associated with and probably dependent
upon a reduction in the volume of effective circulating blood ... Investigations
have indicated that at some time in the development of irreversible shock there
appear effects that may be ascribed either to toxic substances elaborated in
areas of tissue damage or to a derangement of metabolism produced by a
circulation which, either locally or generally, has been compromised over a
long time.
It is postulated that, as a result of an insult, uncontrolled activation of inflammatory pathways may result in tissue destruction and subsequent organ failure. Inflammation is an essential component of the healing process. From a wide variety of stimuli (e.g. trauma, burns, infection) the final common pathway results in vasodilation, increased endothelial permeability, thrombosis, and leucocyte migration and activation. The systemic inflammatory response syndrome is the latest term proposed to describe a failure of localisation. MODS, due to tissue damage in organs distant to the site of the original injury, is the clinical manifestation of SIRS. Irrespective of the initiating stimulus (e.g. surgery, bacterial infection, pancreatitis), the morphology of necropsy specimens in both animal models and patients is remarkably constant. There is microvascular occlusion, endothelial destruction, interstitial oedema, leucostasis and thrombosis. Therefore, there would seem to be a dichotomy. Inflammation is essential for successful recovery from infection or injury, yet an excessive and uncontrolled inflammatory response can result in organ dysfunction or failure. One hypothesis is that there is a level of stimulation that, once exceeded, leads to uncontrolled activation of inflammatory pathways. There would appear to be a critical balance between activation and modulation (Fig. 4.1).
Fully
established multiple organ failure is almost always fatal. A greater
understanding of the pathogenesis of MODS has provided the basis for treatment
regimens currently being used clinically or tested experimentally for the
prevention of organ damage. (Fig 4.2 See above) summarises the various stages that are
thought to lead to the development of MODS and therefore are targets for
intervention. The rationale behind the apparent success, or failure, of a
cross-section of these regimens is discussed below.
The
primary insult
As always, the earliest treatment is most effective and prevention is
better than cure. If we assume that the primary insult is unavoidable, has been
correctly diagnosed and treated, then all subsequent forms of treatment are
aimed at limiting the degree of tissue damage.
Compounding
insults
Avoiding
tissue hypoxia — simple
resuscitation with intravenous fluids
The commonest compounding insult is probably tissue hypoxia as a result
of inadequate basic resuscitation. Treating the primary insult is almost a waste
of time without restoration of an adequate circulating blood volume. The
majority of patients will respond to the administration of intravenous fluids
and supplementary oxygen via a face mask. There is little doubt that if the aim
is to restore the intravascular volume then this can be done most efficiently
using a colloid. As one of the central abnormalities in SIRS is thought to be
endothelial leak, one might hope that a colloid with a larger molecular
weight than albumin might be more effectively retained within the vascular
compartment and therefore more likely to maintain microvascular flow and organ
perfusion. However, there are no human data that demonstrate that any
particular solution (colloid or crystalloid) is better than another in terms of
outcome, even though there is approximately a 100-fold price difference between
the cheapest and most expensive alternatives. There are, however, good data to
suggest that to avoid tissue hypoperfusion you need to give enough of whatever
you choose and you need to give it promptly with the appropriate level of
monitoring. For rapid restoration of haemodynamic function a colloid does the
job more efficiently than a crystalloid. Albumin has no demonstrable advantages
over cheaper alternatives such as the modified gelatins.
Treating
tissue hypoxia — the global
approach
The rationale here is that patients with SIRS are thought to have an
occult tissue oxygen debt in spite of apparently normal global cardiovascular
variables such as blood pressure and urine output, and that by increasing total
body oxygen delivery, commonly by the administration of ionotropes, this debt
will be repaid and hypoxic tissue damage will be avoided. In patients undergoing
high-risk major surgery and critically ill patients on the intensive therapy
unit (ITU) there appears to be a positive correlation between a high oxygen
delivery and survival. In patients undergoing high-risk major surgery
prophylactically increasing cardiac output and oxygen delivery to predetermined supranormal
levels has been associated with a decrease in subsequent organ dysfunction
and mortality. However, the same principles when applied to established
critically ill patients on the ITU has met with very limited success. Once a
critical degree of tissue hypoperfusion is established then the situation is
apparently irreversible.
There
is an ever increasing list of designer vasoactive drugs (e.g.
dobutamine, dopexamine, enoximone, piroximone, milrinone, amrinone) that can be
used to manipulate global haemodynamics in sepsis. They have attractive
hypothetical advantages in terms of their effects on global oxygen flow
variables that can be confirmed in animal models and humans. However, there is
no evidence to suggest that they are any more effective than the cheaper
alternatives such as adrenaline and noradrenaline in terms of outcome.
Treating
tissue hypoxia — the regional
approach
As a result of the enormous amounts of research that have focused on
global oxygen delivery in SIRS and MODS, it has become evident that regional
perfusion may be compromised in patients who have apparently adequate global
oxygen delivery and consumption. Probably the most commonly monitored end organ
in the ITU has been the kidney, as urine output is easy to measure and relates
crudely to function. The production of 0.5 ml/kg/hour of urine is accepted as an
indicator of adequate regional perfusion. Unfortunately, although anuria
carries a very poor prognosis the converse is not true. Many reno protective
agents have failed to modify outcome in humans. In animal models the use of
mannitol, frusemide and low-dose renal dopamine infusions has been shown to
protect the kidney, but this has not been demonstrated in the clinical
environment. This may be because the infusion of a renal dose of
dopamine, for example, may well produce a diuresis but cannot be expected to
protect the kidney from coexisting hypoxia and hypovolaemia unless it is used as
just a part of a total patient management regimen. Many believe that such agents
used in isolation do more harm than good as they maintain an adequate urine
output in the face of tissue hypoperfusion and also increase myocardial work.
More
recently much attention has focused on the splanchnic region. In particular,
the measurement of gastrointestinal luminal PCO2, using a gastric or
sigmoid tonometer, and calculation of gastrointestinal mucosal pH have become
fashionable as indices of splanchnic perfusion. Splanchnic perfusion and, in
particular, that to the gut mucosa is compromised early and preferentially in
shocked states. There is also a hypothesis that gut mucosal hypoperfusion may
result in leakage of gut luminal contents into the bloodstream and that this may
be a proinflammatory factor tipping the balance in favour of SIRS and MODS. In
support of this hypothesis gut mucosal hypoperfusion, as determined by the
presence of a mural acidosis measured with a tonometer, has been shown to be the
most sensitive predictor of MODS and death in patients undergoing major surgery
and on the ITU. Certain therapeutic manoeuvres have been demonstrated to improve
gut mucosal perfusion both in animal models and in humans. These include the
administration of intravenous fluids, dobutamine, dopexamine and donor blood.
Avoiding
nosocomial infections.
Once a patient has some degree of organ dysfunction on an ITU they are
thought to be at greater risk from nosocomial infection. In the prevention of
secondary infection good hand washing and the avoidance of cross-infection
carried by staff probably have the greatest impact. Assuming that such
cross-infection is avoided then the patient is his or her own enemy and bacteria
carried in the gastrointestinal tract provide the commonest source of secondary
infection. Nosocomial pneumonia is thought to occur commonly as a result of
spillage from the upper gastrointestinal tract into the lungs. It has been
demonstrated that the administration of H2-receptor antagonists with
the intention of reducing gastric acidity and avoiding stress ulceration also
encouraged the growth of bacteria in the stomach and an increased incidence of
nosocomial pneumonias. The use of sucralfate as stress ulcer prophylaxis has the
advantage of also being bacteriostatic and has been associated with a decreased
incidence of nosocomial pneumonia. Another approach to the problem of secondary
infection from the gastrointestinal tract is selective decontamination of the
digestive tract (SDD)
with the aim of reducing the incidence of secondary infection, from both
overspill and translocation. SDD involves the use of a variety of topical and
intravenous antimicrobial agents with the aim of removing the pathogenic gut
flora but maintaining the commensal anaerobes. Numerous studies have
demonstrated that SDD and/or modifying the gastric intraluminal pH reduces the
incidence of nosocomial pneumonia. However, reducing the incidence of nosocomial
pneumonias has had a far lesser effect on outcome than one might anticipate for
a true cause and effect relationship.
Treating
endotoxaemia
Endotoxin is a recognised potent activator of various cellular and
humoral pathways involved in the generalised inflammatory response. Endotoxins
are mostly comprised of lipopolysaccharide, and most of their biological
activity resides in the lipopolysaccharide section. The core region of lipopolysaccharide
is nearly identical for most strains of Gram-negative bacterial endotoxins.
Supranormal levels of naturally occuring endotoxin core antibodies have been
associated with a reduction in organ failure in patients following high-risk
surgery and on the ITU. However, in two large multicentre trials of patients
with presumed Gram-negative infection, the results of giving donor antibodies
against the core region of endotoxin have been inconclusive. Active immunisation
would be an attractive alternative for patients scheduled for major surgery, and
evidence from animal experiments has been encouraging. However, there is no
currently available anti endotoxin vaccine. Other potential anti endotoxin
strategies undergoing human testing include bactericidal/permeability-increasing
protein (BPI), endotoxin-neutralising protein and dextran—polymixin B
conjugate, all of which have the ability to protect animals from endotoxin-mediated
toxicity.
Systemic
inflammatory response syndrome
The organo-protective therapeutic regimens cited above seem to work if
used prophylactically, as is the case in major surgery. However, the results of
adopting similar regimens in established MODS are rather disappointing. This
would suggest that once a systemic inflammatory response is unresponsive to
cardiovascular manipulations and antimicrobials then if the progression to MODS
is to be avoided organ protection must come from a different line of attack. An
increased understanding of the host-derived mediators of the tissue destruction
seen in MODS has opened up a whole new field of therapeutic agents directed
against them. It is hoped that specific manipulation of key mediators will at
least halt the tissue damage in its tracks and hopefully be curative.
Cytokines
Protein cytokines play an important part in the mobilisation,
localisation and subsequent activity of leucocytes in the inflammatory reaction.
Tumour necrosis factor alpha (TNF
Decreasing
cytokine synthesis and secretion
Corticosteroids reduce TNF-alpha mRNA translation in response to a stimulus
and thus reduce secretion. Numerous studies have demonstrated the protective
effects of corticosteroids in animal models of septic and haemorrhagic shock.
The use of low-dose dexamethasone has been shown to improve outcome in
paediatric patients with meningitis. From a purely hypothetical viewpoint,
steroids should be the answer to the treatment of SIRS. However, two large
multicentre, randomised trials of high dose dexamethasone used in the
treatment of septic shock failed to demonstrate any improvement in survival.
Nitric
oxide
In 1987 it was reported that the endothelium-derived relaxant factor
was identical to the free radical nitric oxide (NO). NO is synthesised from r-arginine
by a constitutive enzyme present in the endothelium, which has a physiological
role in the control of blood pressure, and by an inducible nitric oxide synthase,
which is expressed in vessel walls and phagocytic cells in response to
endotoxin or cytokines. NO has a myriad of actions but is predominantly a
vasodilator and can modify the neutrophil—platelet interactions that may
result in the microvascular occlusion seen in MODS. These effects create a
therapeutic dilemma. Should you give NO in an attempt to restore microvascular
flow or block its effects to restore the blood pressure in septic shock? In
patients with severe acute respiratory distress syndrome inhaled NO has been
demonstrated to reduce pulmonary artery pressure and improve pulmonary
oxygenation without affecting systemic vascular resistance. However, it has also
been demonstrated that blocking the production of NO from its precursor Larginine
is possible by the administration of arginine analogues such as
NG-monomethyl-r.-arginine (L-NMMA). In animal studies the administration of NO
antagonists has been shown to restore the vascular response to catecholamines
and improve survival.
Arachidonic
acid metabolites
There is a multitude of animal and human evidence to suggest that
metabolites of arachidonic acid play key roles in the pathogenesis of MODS, both
protective (e.g. prostaglandin E2) and deleterious ones (e.g.
leukotrienes and thromboxane). Cyclo oxygenase inhibitors such as ibuprofen or
indomethacin, which are nonsteroidal anti-inflammatory drugs, have been shown to
reduce tissue damage and improve survival in animal models of sepsis.
Neutrophils
Degranulating neutrophils as part of a systemic inflammatory response
are said to cause microvascular injury and promote organ dysfunction by the
release of destructive enzymes and the generation of oxygen free radicals. Free
radical scavengers such as superoxide dismutase, allopurinol and even vitamin
C are universally successful in reducing the tissue damage seen in septic and
haemorrhagic shock models. Provisional reports from at least two human studies
claim success from free radical scavenging.
Contact,
coagulation and complement activation
A common clinical feature of SIRS is a coagulopathy. Histologically
the microvascular abnormality seen in MODS is not unlike clot. This has led to
the assumption that there is a disturbance of the balance between procoagulant
and anticoagulant pathways in SIRS that can manifest itself most vividly in
the disseminated intravascular coagulation seen in meningococcal meningitis.
There are preliminary results suggesting that the administration of clinical
concentrates of inhibitors of the contact system such as antithrombin III and C1
-esterase inhibitor may modify the outcome in established SIRS.
Endogenous
anti-inflammatory agents
It is now recognised that most proinflammatory acute-phase reactants are
balanced by the production of endogenous anti-inflammatory acute-phase
reactants. For example, antagonists to soluble IL-1 and TNF-alpha are produced by
hepatocytes and released into the circulation, thereby reducing the inflammatory
response. The anti-inflammatory cytokine IL-10 is a potent
macrophage-deactivating factor, and injection of recombinant IL-10 has been shown
to protect mice from endotoxic shock. IL-10 is thought to regulate the effects of
other cytokines (e.g. TNF-alpha), rather than block them completely, and therefore
has the potential for maintaining optimal balance in the inflammatory system.
Multiple
organ dysfunction syndrome
There are no animal or human data to suggest that fully established MODS
is treatable. This does not mean that all patients who have MODS die. However,
the small percentage who survive have probably done so because supportive care
has given them a chance to get better.
Conclusion
Prevention of MODS by the prompt diagnosis and treatment of the primary
insult coupled with cardiovascular resuscitation and supportive care has an
extremely high success rate in patients who have some hope of long-term
survival. However, once the same group of patients has established organ failure
the outlook is extremely gloomy.