Kiyoshi Okabayashi

Mild hypothermia promotes pro-inflammatory cytokine production in monocytes.

Hypothermia is often associated with compromised host defenses and infection. Deteriorations of immune functions related to hypothermia have been investigated, but the involvement of cytokines in host defense mechanisms and in infection remains unclear. We have previously shown that mild hypothermia modifies cytokine production by peripheral blood mononuclear cells. In this study, the effects of hypothermia on the monocytic production of several cytokines and nitric oxide (NO) were determined. Monocytes obtained from 10 healthy humans were cultured with lipopolysaccharide (LPS) under hypothermic (33°C) or normothermic (37°C) conditions for 48 hours. We performed flow cytometric analysis for simultaneous measurement of interleukin (IL)-8, IL-1β, IL-6, IL-10, IL-12p70, and tumor necrosis factor (TNF)-α in culture supernatants. NO production was quantified as accumulation of nitrite in the medium by a colorimetric assay. Compared with normothermia, mild hypothermia raised the levels of IL-1β, IL-6, IL-12p70, and TNF-α produced by monocytes stimulated with LPS. On calculating the ratios of these elevated cytokines to IL-10, however, only IL-12p70/IL-10 and TNF-α/IL-10 ratios were significantly elevated under hypothermic conditions. In contrast, hypothermia did not affect NO production. This study demonstrates that mild hypothermia affects the balance of cytokines produced by monocytes, leading to a pro-inflammatory state. Specifically, monocytic IL-12 and TNF-α appear to be involved in the immune alterations observed in mild hypothermia. However, the clinical significance of these phenomena remains to be clarified.

Hemodynamic Efficacy of Neuroleptanesthesia for Therapeutic Hypothermia in Acute Brain Injury

We have performed a retrospective review of 18 patients with acute brain injury who had therapeutic mild hypothermia. The patients were divided into two groups by anesthesia: droperidol & fentanyl (NLA group), and midazolam & butorphanol (MB group). To induce and maintain mild hypothermia, patients were cooled by a blanket and a mat with circulating cool water. The target core temperature was 32 to 34C. To maintain microcirculation, colloid solution and/or dobutamine were used. We inserted a pulmonary artery catheter in all the patients and measured the hemodynamic parameters (Table 1) at induction phase and maintenance phase of therapeutic mild hypothermia. The doses of anesthetic agents in each group are shown in Table 2.

Hypothermia Prolongs Survival Time of Severely Septic Rats: A Study Using a Computer-Supported Multichannel Thermoregulatory System

We investigated the relationship between core body temperature (BT) and survival time in septic rats. A cecum ligation and needle double-puncture model was made and a telemetry probe for measuring BT was implanted into the abdominal cavity. After surgery, rats were randomized into three groups of six rats each, i.e., hypothermia (32°C), hyperthermia (38°C), and no regulation (control) groups. A thermoregulatory system developed by Colbourne et al. was used to record and to regulate BT in a temperature-controlled room at 20°C. The body temperature of the control rats began to decrease after surgery, and they died when their BT reached approximately 30°C. The mean survival times from the surgery to death were 351 ± 200,274 ± 90, and 612 ± 36 min in the control, hyperthermia (38°C), and hypothermia (32°C) groups, respectively. The hypothermic rats survived significantly longer than the hyperthermic rats and the control rats. In nature the rat might protect itself by reducing its BT against sepsis. In conclusion, sustaining hypothermia prolongs the survival time of severely septic rats.

A Randomized Controlled Trial of Therapeutic Hypothermia in Severe Head-Injured Patients in Japan: Overview of the Protocol

Protection against brain insults is one of the most difficult aspects of clinical practice. Recently, mild hypothermia has been applied to cardiopulmonary resuscitated victims and brain-protective effects were proved by two randomized, controlled trials (RCT). Clifton’s group applied mild hypothermia therapy in severe head-injured cases (Glasgow Coma Scale; GCS < 8), but failed to prove any effectiveness. Our aim is to apply mild hypothermia therapy as a RCT in 300 traumatic brain injury cases in 40 medical centers in Japan. Inclusion criteria are: (1) GCS 4–8, except best motor response of 6; (2) core body temperature must be reduced to less than 35.5°C at 6 h after head injury in the mild hypothermia group; (3) age ≤ 15 to <70 years old. Patients are randomized into either a control group (35.5°–37.0°C, 100 patients) or a mild hypothermia group (32.0°–34.0°C, 200 patients). Core body temperature must be controlled for at least 72 h in the two groups and may be prolonged, if necessary. Brain-oriented intensive care is required; physiologic parameters are qualified by cardiac index, as well as internal jugular venous oxygen saturation and temperature, which are recorded and stored in a computer in every 1 min. Evaluations of the effect of mild hypothermia therapy are carried out using the Glasgow Outcome Scale at 3 and 6 months, and by biochemical parameters such as cytokines, free radical products, and neurotoxic excitatory amino acids between the two groups. At this point in time, 74 patients have been enrolled.