Physiologic Failure: Multiple Organ Dysfunction Syndrome
Timothy G. Buchman, Ph.D., M.D. Edison Professor of Surgery Professor of Anesthesiology and of Medicine Washington University School of Medicine St. Louis, Missouri 63110 [email protected]
Acknowledgement: This work was supported, in part, by award GM48095 from the National Institutes of Health
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Humans, like other life forms, can be viewed as thermodynamically open systems that continuously consume energy to maintain stability in the internal milieu in the face of ongoing environmental stress. In contrast to simple unicellular life forms such as bacteria, higher life forms must maintain stability not only in individual cells but also for the organism as a whole. To this end, a collection of physiologic systems evolved to process foodstuffs; to acquire oxygen and dispose of gaseous waste; to eliminate excess fluid and soluble toxins; and to perform other tasks. These systems—labeled respiratory, circulatory, digestive, neurological, and so on—share several features.
• Physiological systems are spatially distributed. Food has to get from
mouth to anus. Urine is made in the kidneys but has to exit the urethra.
Blood may be pumped by the heart but has to reach the great toe.
• Physiologic systems are generally spacefilling and structurally fractal.
Each cell has demand for nutrients; each cell excretes waste. Information
has to travel from the brain throughout the body. While not every
physiologic system is self-similar at all levels of granularity, there is
typically a nested architecture that facilitates function: microvillus to villus
to intestinal mucosa; alveolus to alveolar unit to bronchial segment;
capillary to arteriole to artery.
• Physiologic systems are functionally integrated. After eating, blood is
redistributed to the gut and splanchnic circulation. When alveoli become
atelectatic, blood is shunted away from these hypoxic regions. Ingestion 3 Buchman
and delivery of excess fluid to the circulation is quickly followed by
augmented production of urine.
• Physiologic systems have characteristically variable time signatures that
lose their variability in aging and disease. (1) Instantaneous cardiac and
respiratory rates vary from one event (heart beat or breath) to the next.
Many hormones exhibit not only diurnal variation, but also a superimposed
pattern or irregular pulses. The product of physiologic systems—such as
gait which combines neural, musculoskeletal, cardiac and respiratory
systems into a semivoluntary activity (one usually doesn’t think about
putting one foot in front of the next) –display characteristically variable
time signatures.
The first three features of physiologic systems have medical consequences.
Both aging and illness can compromise one or more physiologic systems.
Management of such compromise was, until about fifty years ago, directed
exclusively towards minimizing the performance demand placed on the
system. For example, in advancing pulmonary insufficiency, patients were
progressively confined to home, to chair and finally to bed. Each organ
system had a critical level of compromise, and once the compromise
exceeded the critical level, the patient simply died.
Two major advances in the last half-century have changed the clinical
trajectory. The first major advance was the development of mechanical 4 Buchman
supports for failing mechanical systems. Ventilators (respirators), ventricular
assist devices and renal replacement therapies (dialysis machines) have
come into widespread clinical use. These supports have evolved to the point
that individual system failures can be managed by outpatient use of these
devices: many patients thus gain years of useful life. The second advance
was the development of organ transplantation. Beginning with blood
components (transfusion is a type of transplantation) and progressing to
kidney, heart, lung, pancreas and intestine, component replacement is
increasingly frequent and relatively safe. Both advances—mechanical support
and tissue transplantation—compromise immune system function, but this
compromise is usually a good trade for survival.
It is hardly surprising that organ dysfunction and failures accumulate. Like the
aging automobile with worn bearings, cracked hoses and leaking engine
valves, many humans eventually acquire an illness to which they cannot
successfully respond even with medical care—a bleed into the brain, a
metastatic cancer or a high speed motor vehicle crash. They die with multiple
organs failing to perform their appropriate function. The subject of this
chapter, however, is a syndrome of widespread, progressive and
disproportionate multiple organ dysfunction (MODS) that rapidly accumulates
following a minor or modest insult. (2) Despite timely and appropriate
reversal of the inciting insult—whether a pneumonia, intraabdominal abscess,
pancreatitis or simply the stress of an anesthetic and elective surgery—many 5 Buchman
patients develop the syndrome. Mortality is proportional to the number and
depth of system dysfunctions (4), and the mortality of MODS after (for
example) repair of ruptured abdominal aortic aneurysm is little changed
despite three decades of medical progress. (2,5) Unfortunately, MODS
remains the leading cause of death in most intensive care units.
MODS: The Phenotype
Autopsy findings in patients who succumbed to MODS are surprisingly bland.
Tissue architecture is preserved, cells do not appear abnormal, there is no
widespread thrombosis. At least anatomically, the body appears to be largely
intact. (The exception is lymphatic tissues, which are often exhausted through
accelerated programmed cell death [apoptosis] (6) ) Nor does organ function
appear to be irretrievably lost: among MODS survivors, many—especially
younger survivors—experience return of multiple organ performance to levels
approaching that which they enjoyed prior to the syndrome. (7) These two
observations –anatomic integrity and the potential for near-complete
recovery—led to replacement of the old descriptor (“multiple organ failure”)
with the current and more apt label of multiple organ dysfunction syndrome.
Using the jargon of information technology, the focus shifted from the
hardware to the software.(8)
Bearing in mind that MODS is only three decades old (multiple organ
supports had to be developed and used in enough patients before it could be 6 Buchman
observed that the patients were dying despite the treatments), its phenotype
has changed somewhat as physicians have tried to preempt its occurrence
and progression. In its original –and perhaps purest-- form, organ
dysfunctions would accumulate in a more or less predictable sequence.(2,3)
The lungs would fail first, and the patient would require intubation and
mechanical ventilation. A few days later, evidence of gut and liver failure
would appear—patients would fail to absorb nutrients and fail to manufacture
critical proteins such as clotting factors. Artificial nutrition and transfusion
medicine were therefore administered. A few days after that. kidney failure
would become apparent and the patient would require dialysis. Not only was
the dysfunction sequential, but this particular sequence precisely mirrored the
sequence in which organs matured in fetal life—kidneys first, then the
liver/gut and lastly, the lungs. For this reason, multiple organ failure began to
be recast as organ systems “falling off line”, each functionally separating from
the whole. For this reason, physicians initiate organ-specific support earlier
and earlier—at the first sign of dysfunction. This strategy of early intervention
has muddied the failure sequence, unfortunately with little effect on outcome:
four-organ failure is still quite lethal.
Physiologic Stability
How do organisms maintain function in the face of external stress? There
appear to be two general ways. (9) One way relies on purpose-specific
mechanisms that have arisen and been refined in the course of evolution. At 7 Buchman
the resolution of the individual cell, the “stress response”—originally called the
“heat shock response” because it was observed in polytene chromosomes of
Drosophila cells exposed to high temperatures—activates specific
transcription factors, modulates RNA splicing and applies selection filters to
translation. The phenotype of this stress response is marked alteration in
protein synthesis while the cell becomes (temporarily) refractory to additional
external stimuli. At the resolution of the intact organism, circulating blood
sugar levels are tightly maintained by the secretion of insulin and of glucagon,
which sequester and mobilize (respectively) carbohydrates. Such engineered
mechanisms have been identified at all levels of granularity, and their product
was termed “homeostasis” by Walter B. Cannon early in the 20th century. A
central dogma of medical care as articulated by Cannon instructs the
physician to render “external aid” when homeostatic mechanisms are
overwhelmed by disease. This has been translated by the medical
community into the “fix-the-number” imperative: if the bicarbonate level is low,
give bicarbonate; if the urine output is low, administer a diuretic; if the
bleeding patient has a sinking blood pressure, make the blood pressure
normal. Unfortunately, such interventions are commonly ineffective and even
harmful. (10, 11) For example, sepsis—which is a common predecessor of
MODS—is often accompanied by hypocalcemia. In controlled experimental
conditions, administering calcium to normalize the laboratory value increases
mortality. (12)
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The other fount of stability is network structure. At the same time that Cannon
described homeostasis, Lawrence J. Henderson—a colleague of Cannon’s at
Harvard—studied the physiology of blood with an emphasis on its capacity to
buffer changes in pH brought about by addition of fixed acids or carbon
dioxide. (13) Henderson recognized and provided a mathematical foundation
for this buffer system, which even today is known eponymously as the
Henderson-Hasselbach equation. He observed that the mere presence of a
system of interacting components conferred stability. Chauvet has provided a
framework for the study of formal biological systems and has reached two
important conclusions. First, such stability is not unique to blood or other
buffers but rather is an expected consequence of interactions among
biological elements. Second, nesting such systems—this may be thought of
as organelles into cells, cells into tissues, tissues into organs and so on—
confers further stability onto formal biological systems. (14)
Biological stability must not be confused with invariance—survival of
organisms from bacteria to man requires adaptive capacity. Purpose-specific
homeostatic mechanisms typically include engineering features such as
negative feedback that provide such adaptive responses. Self-aggregating
networks are another matter: once a fitness maximum (or energy minimum) is
reached, simulations of such networks often assume a trivial and biologically
useless trajectory in state space, such as occupying a single point or
endlessly traversing a few points. How might the characteristic variability and 9 Buchman
long-range correlations of biological signals (for example, heart rate
variability: see chapter ## for detail) arise?
Coupling and Uncoupling
Several years ago, we suggested that the networks of organ systems that
collectively constitute macrophysiology are not only coupled, but also that the
couplings are intrinsically unstable. (15) Subsequently, Schaefer and
colleagues presented data in support of this conjecture: analysis of the
interaction between cardiac and respiratory cycles in healthy athletes at rest
suggested that the coupling between heart and lungs was not fixed but rather
dynamic. (16) These athletes’ organs would couple (for example, 5
heartbeats for 2 respirations) then uncouple, then recouple at the same or at
a different ratio (for example, 6 heartbeats for every two respiratory cycles).
The inference is that health may be associated with a search through the
space of possible interactions to find the one best suited to current
physiologic challenges.
Experimental manipulation of the connections suggests that physiologic
optima do indeed exist. Hayano and colleagues experimentally interrogated
the relationship among cardiac cycles, respiratory cycles and the vagally
mediated respiratory sinus arrhythmia that reflects central respiratory drive
and the lung inflation reflex in dogs. (17) These investigators electrically
paced the diaphragm, applied electrical stimuli to the vagus nerve to simulate 10 Buchman
normal, absent or inverse respiratory sinus arrhythmia, and measured the
matching of lung ventilation with perfusion, which is critical to healthy
physiology. The data showed that normal respiratory sinus arrhythmia (i.e.
physiologic coupling of respiratory and cardiac cycles) minimized wasted
ventilation (dead space) and perfusion (shunt fraction) whereas the inverse
arrhythmia was physiologically much less efficient. These investigators
suggest that respiratory sinus arrhythmia is an intrinsic resting function of the
cardiopulmonary system that provides a continuous fitness maximum for the
coupled heart-lung system. (18)
MODS: Uncoupled Oscillators?
MODS is not a disease but rather a syndrome, a common pathway that is all
too often final. Yet some patients do recover. Two features of recovery are
invariant. First, the time to recover is significantly longer than the time to
become ill. Second, measured physiologic parameters do not retrace their
paths, implying hysteresis in the clinical trajectory. These features led to
speculation that MODS did not follow a specific event, but rather reflected a
more general phenomenon of network failure at multiple levels of granularity.
What kind of networks might fail at the level of organ physiology? We
observed that most organs had characteristic varying time signals, and
further speculated that the network failure might represent failure of the 11 Buchman
uncoupling./recoupling process of these biological oscillators. (19) Several
lines of evidence support such a conjecture.
First, it is possible to directly estimate coupling among select physiologic
systems from common continuous clinical measurements such as heart rate
and blood pressure. Goldstein’s studies of critically ill children as diverse as
those with sepsis (20) and with severe head injury (21) suggest loss of heart
rate/blood pressure coupling as patients deteriorate, and recovery of transfer
function as the patients themselves recover. Second, Pincus’ conjecture—
that loss of variability implies greater system isolation (uncoupling) between
systems that contain stochastic components—allows for additional inferences
based on heart rate information alone. (22) Godin and colleagues
demonstrated precisely such loss of variability in humans experimentally
exposed to bacterial endotoxin, a common predecessor of MODS.(23) Seiver
and colleagues have just reported startling loss of physiologic variability with
the appearance of monotonous sinusoidal variation in cardiac output among
critically ill humans. (24) Winchell and Hoyt have shown that loss of heart rate
variability in critically ill patients is a predictor of death. (25)
Implications for Treatment
If MODS is the clinical expression of network recoupling failure, then therapy
might logically be directed towards facilitating that recoupling. Paradoxically,
severe illness prompts physicians to suppress biologic variation in many organ 12 Buchman
systems. For example, ventilators are set to fire at fixed intervals,
catecholamines are infused at fixed rates, fixed composition nutrition is
administered without interruption, venovenous hemofiltration is conducted at a
fixed rate around the clock and so on. Such rigidity invites perceptions of
therapeutic success: “the patient in bed 21 is now stable as a rock”. Perhaps the
more important question is whether such therapeutic rigidity promotes or
suppresses clinical recovery.
Although no trials have been performed on patients with MODS, reports have
begin to appear in which normal physiologic variability has been synthetically
applied to the function of mechanical ventilators. Gas exchange and respiratory
mechanics are improved by biologically variable ventilation not only in models of
lung injury but also in healthy lungs. (26, 27) More to the point, a group of
patients at risk for MODS—those undergoing surgical repair of abdominal aortic
aneurysm -- also enjoyed better lung function when the ventilation algorithm included simulated biological variation. (28)
During cardiac surgery, the perfusion of the body is supported by the “heart-lung” machine. This perfusion, called cardiopulmonary bypass, can be continuous,
pulsatile at fixed sinusoidal frequency, or aperiodically pulsatile. Mutch and
colleagues have demonstrated improved brain blood flow characteristics with the
aperiodic (biologically variable) algorithm versus the conventional clinical
techniques of constant or periodic flow. (29) Suboptimal brain blood flow is 13 Buchman
clinically associated with cognitive impairment, a manifestation of central nervous
system “organ failure”.
While none of these data directly address MODS, they raise the disquieting
possibility that conventional therapeutic rigidity that applies fixed or strictly
periodic inputs to the network of dysfunctional biological systems may actually
hinder recovery. The need for trials comparing monotonous versus biological
variable algorithms applied to existing therapies is evident.
Summary and Perspective
The list of diseases that are associated with breakdown of network interactions
and appearance of highly periodic dynamics continues to grow: epilepsy, fetal
distress, sudden cardiac death, Parkinson’s disease and obstructive sleep apnea
are among the recent additions. Herein, we have suggested that breakdown of
network interactions may actually cause disease, and when this breakdown is
widespread the clinical manifestation is the multiple organ dysfunction syndrome.
If the hypothesis is correct, then network dysfunction might be expected at
multiple levels of granularity, from organ systems to intracellular signal
molecules. Restoration of network integrity may be a reasonable therapeutic
goal, and a more permissive approach to clinical support (including algorithms that simulate biological variability) might facilitate restoration of network
complexity that now appears essential to health.
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