FIRST-PHASE AND 2ND-PHASE OF BIPHASIC FEVER - 2 SEQUENTIAL STAGES OF THE SICKNESS SYNDROME

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 .