Biomedical Engineering Reference
In-Depth Information
served that the patients were dying despite the treatments), its phenotype has
changed somewhat as physicians have tried to preempt its occurrence and pro-
gression. 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 se-
quence precisely mirrored the sequence in which organs matured in fetal life—
kidneys first, then the liver/gut, and last, the lungs. For this reason, multiple or-
gan failure began to be recast as organ systems "falling off line," each function-
ally 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.
2.2. Physiologic Stability
How do organisms maintain function in the face of external stress? There
appear to be two general ways (9). One relies on purpose-specific mechanisms
that have arisen and been refined in the course of evolution. At the resolution of
the individual cell, the "stress response"—originally called the "heat shock re-
sponse" because it was observed in polytene chromosomes of
Drosophila
cells
exposed to high temperatures—activates specific transcription factors, modu-
lates RNA splicing, and applies selection filters to translation. The phenotype of
this stress response is marked alteration in protein synthesis while the cell be-
comes (temporarily) refractory to additional external stimuli. At the resolution
of the intact organism, circulating blood sugar levels are maintained by the se-
cretion 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 twentieth 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 medi-
cal 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—a common predecessor of MODS—is often ac-
