The histologic features of the organs involved in MODS are less well

characterized, but generally include evidence of edema, inflammation, tissue

ischemia or necrosis, and variable degrees of fibrosis and repair. These
alterations, in turn, are responsible for the clinical features of MODS in each of its
component systems.

Lung

The characteristic abnormality of the lung in MODS is a failure of normal gas

exchange, reflected predominantly in arterial hypoxemia. Multiple pathologic
factors contribute to impaired gas exchange. Early in the course of lung injury,
atelectasis and intravascular thrombosis or altered regional flow contribute to
ventilation/perfusion mismatch, while increased capillary permeability leads to
alveolar flooding and an increased diffusion distance for oxygen. Regional injury
resulting from infection or trauma contributes to compromised lung function.
With the institution of ventilatory support, lung injury can be aggravated through
what has been termed volutrauma and barotrauma, leading to further atelectasis
in dependent lung zones, and cyst formation in the anti-dependent zones. Finally,
the process of tissue repair, initiated with the influx of inflammatory cells into the
injured lung, results in fibrosis and hyaline membrane formation, the cardinal
pathologic features of late ARDS.

Kidney

Renal dysfunction in MODS is reflected in impairment of normal selective

excretory function, initially in oliguria despite adequate intravascular volume, but
later in a rising creatinine level, and fluid and electrolyte derangements of
sufficient magnitude that dialysis is required. Its causes are both pre-renal and
renal. Reduced renal blood flow secondary to systemic hypotension, altered
regional perfusion, or increased intra-abdominal pressure is an early risk factor;
evolution of the disorder is compounded by pre-existing physiologic deficit and
the effects of nephrotoxic drugs. Obstructive causes must be considered and
ruled out. As is the case for lung injury, ICU interventions contribute to the
evolution of the syndrome: vasopressor agents cause further reductions in renal
blood flow, while potentially nephrotoxic drugs are a key part of the anti-infective
arsenal used in the ICU.

Heart and cardiovascular system

The acute cardiovascular derangements of MODS consist of five features:

1. a generalized reduction in peripheral vascular tone, mediated largely through

the local vasodilatory activity of nitric oxide

2. a generalized increase in capillary permeability producing diffuse capillary leak

and edema, and contributing to further dysfunction in other organ systems

3. alterations in regional blood flow to specific organ beds

4. microvascular plugging and stasis, resulting from occlusion of the

microvasculature by abnormally rigid erythrocytes and leukocytes, and resulting
in arteriovenous shunting that contributes to a high mixed venous saturation

5. myocardial depression, affecting the right side of the heart in particular

It is readily apparent that these abnormalities predispose to impaired oxygen

delivery, and therefore contribute to the injury of other organ systems. Since their
net physiologic consequence is hypotension that is refractory to increased
preload, we have used a measure called the pressure-adjusted heart rate (PAR) to
quantify cardiovascular dysfunction in the MOD score. Calculated as the product
of the heart rate and the ratio of central venous to mean arterial pressure (HR ×
CVP/MAP), it is, like the PO2/FIO2 ratio, a reflection of physiology, corrected for
therapy; increasing values reflect worsening cardiovascular dysfunction.

Gastrointestinal/hepatic

Gastrointestinal dysfunction in critical illness likely results from the interacting

effects of reduced regional blood flow, impaired motility, and alterations in the
normal microbial flora. In the past, upper gastrointestinal bleeding or stress
ulceration was the most common manifestation of gut dysfunction; this
complication has become uncommon with improvements in hemodynamic
support, earlier diagnosis of infection, and the appropriate use of effective
prophylaxis. Intolerance of enteral feeding, reflected in bloating and diarrhea is
another manifestation of gut dysfunction. However, in contrast to other organ
systems, simple clinical measures of gut dysfunction are not readily available.

Hepatic dysfunction in MODS is reflected in hyperbilirubinemia and cholestasis,

rather than in biochemical evidence of hepatocellular injury or synthetic
dysfunction. A stereotypical pattern of altered hepatic protein synthesis - the
acute phase response - typically accompanies MODS as a non-specific
manifestation of systemic inflammation. Serum levels of C reactive protein and
alpha-1 anti-trypsin are elevated as part of the acute phase response, whereas
levels of albumin, a negative acute phase reactant, are depressed.

Neurologic

An altered level of consciousness, reflected in a reduction in the Glasgow Coma

Score, is the most readily recognizable manifestation of the neurologic
dysfunction of MODS. Its causes are multiple, including the iatrogenic effects of
sedatives and analgesics, metabolic alterations, subclinical cerebral edema and
reduced cerebral perfusion pressure, and, perhaps, micro-abscesses in the brain.
A peripheral neuropathy - the so-called ‘critical illness polyneuropathy’ - is
commonly present, though harder to measure.

Hematologic

Leucocytosis is an adaptive response to a variety of acute stresses and therefore

commonly present, although not truly a manifestation of organ dysfunction.
Similarly a mild anemia resulting from both bone marrow suppression and
iatrogenic blood-taking is common. However the most widely cited manifestation
of dysfunction of the hematologic system in MODS is thrombocytopenia, in its
most extreme form resulting in disseminated intravascular coagulation (DIC). Like
other manifestations of

MODS, the causes of thrombocytopenia in critical illness are many - heparin-

induced thrombocytopenia, intravascular consumption, and reduced production
to name a few.
Immunologic

Multiple abnormalities of non-specific and specific immune function are described

in the critically ill patient, including impaired delayed type hypersensitivity
responsiveness, altered production of antibodies, and a complex spectrum of
abnormalities in the regulation of lymphocyte responses. The most readily
evident, and clinically relevant manifestation of altered immunity in MODS is the
development of nosocomial ICU-acquired infection, caused by relatively avirulent
organisms. The characteristic flora of ICU-acquired infection in MODS includes
coagulase-negative Staphylococci, Enterococci, Candida, and Pseudomonas.

Endocrine/metabolic

Multiple metabolic and endocrine abnormalities are evident during MODS,

although they are less well-characterized, Hyperglycemia and relative insulin
resistance is both common and readily detected. Less accessible abnormalities
include the sick euthyroid syndrome, and relative adrenal insufficiency. The latter
has recently gained prominence as a promising therapeutic target for the patient
with prolonged inflammation and organ dysfunction.