Multiple organ dysfunction syndrome, Inflammatory cytokines and
intraabdominal hypertension
Intraabdominal hypertension contributes to MODS in two ways:
Intra-abdominal hypertension leads to organ
dysfunction via two distinct and separate pathways. First, early on
in the disease process there is a purely mechanical effects that
cause significant and measurable organ dysfunction largely related
to the effect of the elevated pressure on organ function and organ
perfusion (see
figure below, please also see individual organ system discussions
for further detail).
Click here for high resolution PDF of this process
As time
progresses, untreated IAH also causes immune and inflammatory
effects that can result in progressive organ failure –known as
multiple organ dysfunction syndrome or MODS.
Multiple organ dysfunction syndrome (MODS) is well recognized
as a potentially fatal final complication in patients who suffer
from hypovolemic or septic shock. MODS is felt to be due to
excessive systemic inflammation (SIRS) that causes massive cytokine
production.[1, 2] This systemic response, when overly active leads
activation of multiple pathways resulting in acute capillary
permeability syndrome, cellular metabolic alterations, cellular
apoptosis and necrosis.[2, 3] An important factor in the development of MODS is exposure of
the patient to a second insult or “hit” and that there is an
underlying driving force or “motor” that leads to the development of
MODS.[1, 3]
Two Hit model of MODS and how IAH is related
An
emerging body of experimental and clinical evidence suggests that
untreated intra-abdominal hypertension (IAH) acts as this second
insult in the two-event model of multiple organ failure (MOF).
[3-12] The two-event model of multiple organ failure postulates that
an initial insult causing cellular ischemia primes the patients
immune system for an exaggerated response to any secondary
insult.[1, 13, 14] This "priming" occurs for a limited time - about
3-16 hours following the initial insult - at which point the
hyperresponsiveness of the immune system begins to taper.[15, 16]
Interestingly, the most common time for IAH to develop is within an
8-16 hour time range following an initial tissue insult - the exact
period of maximal immune responsiveness. [4, 15, 16] Rezende-Neto el
al found that IAH causes elevated levels of pro-inflammatory
cytokines (tumor necrosis factor, and interleukins IL-6 and IL-1) as
well a lung myeloperoxidase (MPO) in an animal model.[6] They also
found that the presence of IAH during the 8-16 hour "critical" time
period resulted in a 3-fold increase in inflammatory neutrophil
expression.[5] However, animals subjected to IAH insults < 2 hours
or > 18 hours after initial insult fared much better. These authors
conclude that a vulnerable period exists following ischemic injury
and a second insult such as IAH causes a hyper-inflammatory immune
response leading to a high incidence of MOF and death.[5] Other
investigators have also found increases in inflammatory mediators as
well as bacterial translocation across the bowel wall during the
ischemic insult that occurs during from intra-abdominal pressure.[8,
17-20] These data suggest that abdominal compartment syndrome is not
the terminal event caused by refractory shock/multiple organ
failure. Instead, elevated intra-abdominal pressure acts as a
"secondary insult" in the two-event model of multiple organ failure,
leading to an overly aggressive immune response with inflammatory
cytokine release.[4-9] The end result of this undetected and
untreated "secondary insult" is multiple organ failure.
From an etiologic perspective it is likely that the gut is
the initial motor of MODS and that ischemic injury to the gut due to
intra-abdominal hypertension is the “second-hit” that drives the
production of the inflammatory cascade leading to MODS.[3]
Microcirculation of the gut is disrupted during shock.[21, 22] This
can lead to tissue hypoxia and inflammation and loss of endothelial
and epithelial function. This loss of barrier function leads to
capillary permeability, intestinal edema and ascites formation.
Intraabdominal hypertension then develops leading to increases in
intestinal ischemia and a self perpetuating cycle of ischemia and
inflammation.[10] The damaged gut then acts as a continual source of
inflammatory mediators propagating SIRS and eventually MODS. [10,
23]
Interventions that can attenuate the cytokine induced organ
injury:
Kubiak and others provide some very interesting data to suggest that
a therapeutic intervention exists that may attenuate this cascade of
events – the removal of inflammatory cytokines from the gut and
peritoneal cavity.[22-24] By implementing such therapy they were
able to markedly reduce circulating cytokine resulting in a dramatic
improvement in organ function and tissue histopathology (see figures
below). They used negative pressure suction on an open abdomen as
their method of cytokine removal, however there is little reason to
believe that the same therapy instituted at an earlier phase –
before the onset of ACS - could not also remove cytokines via a
percutaneous method as has been demonstrated in multiple case series
and is being investigated right now.[25-30]
Figures: These Figures from Kubiak et al note the dramatic
decrease in both peritoneal and circulating cytokines once negative
pressure therapy is applied to the gut and excess fluid is removed.
The tissue slides show the dramatic effect this therapy has on organ
tissue histopathology.
Summary:
Intra-abdominal hypertension leads to organ dysfunction via two
distinct and separate pathways. Early on IAH causes mechanical
obstruction of blood flow and tissue perfusion, which directly
impact organ function. Later IAH induced ischemia and edema
contribute significantly to gut inflammation and the production of
inflammatory cytokines that act locally and remotely - leading to
multiple organ dysfunction. The inflammation that occurs in the gut
leads to massive increases in gut cytokines – both in the bowel wall
as well as in any surround ascites. This insight may result in a new
way of attenuating MODS in the critically ill patient – by local
removal of gut cytokine via either percutaneous drainage or suction,
or perhaps peritoneal dialysis. It is already being employed in the
clinical setting during open abdominal interventions with negative
pressure therapy.
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