Aa. Romanovsky et al., FIRST-PHASE AND 2ND-PHASE OF BIPHASIC FEVER - 2 SEQUENTIAL STAGES OF THE SICKNESS SYNDROME, American journal of physiology. Regulatory, integrative and comparative physiology, 40(1), 1996, pp. 244-253
We hypothesized that the systemic inflammatory response undergoes two
consecutive stages, each characterized by different nonspecific sickne
ss patterns. To test this hypothesis, we studied thermal, nociceptive,
and motor responses to lipopolysaccharide (LPS) in 43 unanesthetized,
habituated, and lightly restrained male Wistar rats previously implan
ted with a catheter in the jugular vein. Escherichia coli LPS was inje
cted intravenously in a dose of 0, 0.1, 1, 10, 100, or 1,000 mu g/kg.
Colonic temperature (T-c) was measured with a thermocouple. Changes in
nociception were assessed by tail flick latency (TFL) to a noxious he
at stimulus. Motor activity was evaluated using an observation-based a
ctivity score (AS). The two lowest doses were apyrogenic. The next dos
e induced a monophasic fever with a maximal T-c rise of 0.9 +/- 0.2 de
grees C at 108 +/- 11 min post-LPS. The next two higher doses caused b
iphasic fevers with the first and second peaks of 0.7 +/- 0.1 and 1.4
+/- 0.1 degrees C (10 mu g/kg) and 0.7 +/- 0.1 and 1.4 +/- 0.2 degrees
C (100 mu g/kg) occurring at 60 +/- 6 and 165 +/- 17 min and at 45 +/
- 3 and 141 +/- 6 min, respectively. The highest dose of LPS resulted
in a T-c fall (nadir, -0.6 +/- 0.1 degrees C at 83 +/- 6 min). Two dif
ferent sickness patterns were exhibited. The first (high T-c, low TFL,
and high AS) occurred during the monophasic fever and the first (earl
y) phase of the biphasic fevers, and it was termed the early phase syn
drome. The second pattern (high or low T-c, high TFL, and low AS) deve
loped during the second (late) phase of the biphasic fevers and LPS-hy
pothermia (endotoxin shock), and it was termed the late phase syndrome
. Occurring at different stages of the systemic inflammatory response
and developing through different coping patterns [fight/flight (energy
expenditure) vs. depression/withdrawal (energy conservation)], the tw
o syndromes represent two different types of adaptation to infection a
nd have different biological significance. Viewing sickness as a dynam
ic entity is justified clinically. Such a dynamic approach to the prob
lem resolves several contradictions in the current concept of sickness
.