Sepsis was initially defined as systemic inflammatory response syndrome (SIRS) due to infection (1, 2); the definition was recently changed to life-threatening organ dysfunction caused by a dysregulated host response to infection (3). The brain may be suitable as a novel therapeutic target for sepsis because sepsis-associated encephalopathy is an independent risk factor for mortality in patients with sepsis (4).
Orexin is a neuropeptide produced in the lateral hypothalamus; the secretion of this substance from orexin-producing neurons regulates the sleep/wake cycle through its regulatory roles in the autonomic nervous system, neuroendocrine system, and monoaminergic system (5). In healthy humans, orexin can be detected (range: 250–500 pg/ml) in cerebrospinal fluid (CSF), and its concentration shows a circadian rhythm. Orexin deficiency causes narcolepsy, a sleep disorder, and CSF orexin levels are 100 pg/ml or less in patients with type 1 narcolepsy. In patients with certain pathological conditions of the brain (e.g., head trauma and Guillain–Barre syndrome), CSF orexin levels are moderately low (range 100–200 pg/ml). However, orexin is generally not detected (< 40 pg/ml) in blood by a standard orexin radioimmunoassay, which is used for the diagnosis of type 1 narcolepsy (6).
We previously reported that orexin improved survival in mice with endotoxin shock, a well-studied model of sepsis, by acting on the brain (7). Regarding the principle of this therapeutic effect, we hypothesized that reduced CSF orexin under the condition of systemic inflammation is restored by orexin treatment. The results obtained from animal experiments need to be carefully validated in patients with sepsis. We recently reported a case in which CSF orexin levels were reduced in a patient with sepsis. Reduced CSF orexin levels returned to normal after the patient recovered from sepsis. Unexpectedly, orexin was detected in the blood, suggesting that CSF orexin might leak into the blood because of blood–brain barrier dysfunction. As a result, the abnormal detection of blood orexin could predict reduced CSF orexin levels (8). In this study, we first investigated orexin levels in the CSF and blood of rats with lipopolysaccharide-induced systemic inflammation. Next, we attempted to validate orexin levels in the CSF and blood in patients with sepsis. However, it is not ethically acceptable in Japan to perform lumbar puncture in patients with sepsis. Instead, we retrospectively selected patients who were diagnosed with SIRS among the patients who were admitted to the Department of Neurology, where lumbar puncture is routinely performed during hospitalization. This patient study was a single-center, retrospective observational study. To the best of our knowledge, no previous studies have measured CSF orexin levels in patients with sepsis and compared the orexin levels in CSF with those in blood under the condition of systemic inflammation.