Akihide Kurita

Dose- and time-related effects of dexmedetomidine on mortality and inflammatory responses to endotoxin-induced shock in rats.

PurposeOur previous study demonstrated that dexmedetomidine drastically reduced mortality and inhibited the inflammatory response during endotoxemia in rats. The aim of this study was to clarify the dose- and time-related effects of dexmedetomidine on mortality and inflammatory responses to endotoxemia in rats.MethodsMale Wistar rats (n = 96) were anesthetized intraperitoneally with pentobarbital sodium and assigned to one of two protocols: one representing the dose-related effects of dexmedetomidine, and the other, the time-related effects of dexmedetomidine. To evaluate the dose-related effects, the animals were randomly assigned to one of four groups (n = 15 each): endotoxemic group (group E), receiving intravenous Escherichia coli endotoxin (15 mg·kg−1 over 2 min); small-dose group (group S), treated with a small dose of dexmedetomidine (2.5 μg·kg−1·h−1, IV); medium-dose group (group M), treated with a medium dose (5 μg·kg−1·h−1, IV); and large-dose group (group L), treated with a large dose (10 μg·kg−1·h−1, IV). To evaluate the time-related effects, the animals were randomly assigned to one of three groups (n = 12 per group): endotoxemic group; early posttreatment group, treated with 10 μg·kg−1·h−1 dexmedetomidine at 1 h after endotoxin injection; and late posttreatment group, treated with 10 μg·kg−1·h−1 at 2 h after endotoxin injection. Hemodynamics and arterial blood gases were recorded and plasma cytokine concentrations were measured throughout the observation period. The mortality rate was assessed up to 8 h after endotoxin injection.ResultsIn the dose-related study, the mortality rates at 8 h after endotoxin injection were 81%, 26%, 32%, and 20% for groups E, S, M, and L, respectively. Plasma tumor necrosis factor-alpha (TNF) concentrations were lower in groups M and L than in group E at 2 h after endotoxin injection. Plasma interleukin-6 (IL-6) concentrations were lower in groups M and L than in group E at 4 and 5 h after endotoxin injection. In the time-related study, the mortality rates at 8 h after the endotoxin injection were 83%, 33%, and 58% for the endotoxemic, early posttreatment, and late posttreatment groups, respectively. The TNF concentration was lower in the early posttreatment group than in the endotoxemic group at 2 h after endotoxin injection, and the IL-6 concentration was lower in the early posttreatment group than in the endotoxemic group at 5 h after endotoxin injection.ConclusionDexmedetomidine dose-dependently attenuated extremely high mortality rates and increases in plasma cytokine concentrations after endotoxin injection. Moreover, the early administration of dexmedetomidine drastically reduced the high mortality rate and inhibited cytokine responses in endotoxin-exposed rats. These findings suggest that dexmedetomidine administration may be effective during sepsis.

Comparison of a cytokine adsorbing column and an endotoxin absorbing column for the treatment of experimental endotoxemia

The present study compared the effects of direct hemoperfusion (DHP) using a cytokine absorbing (CTR) column with those using an endotoxin absorbing (PMX) column with endotoxin-induced shock in rats. Thirty-six rats were injected intravenously with endotoxin (15 mg/kg), and then allocated into one of the following three groups: control group, treated without CTR; PMX group, treated with a PMX column for 120 min; CTR group, treated with a CTR column for 120 min. The present study showed that CTR treatment decreased the mortality rate 8h after endotoxin injection and inhibited inflammatory responses (cytokine, hemodynamics and acidosis) similar to PMX treatment.

Effects Of Carvedilol On Mortality And Inflammatory Responses To Severe Hemorrhagic Shock In Rats

The nonselective &bgr;-adrenoceptor and the selective &agr;1-adrenoceptor blocker carvedilol are widely used in hypertensive and/or cardiac failure patients because of its efficacy. However, there have been few studies regarding the effects of carvedilol on severe hemorrhagic shock. The present study was performed to evaluate the effects of carvedilol on severe hemorrhagic shock in rats. Twenty-four male Sprague-Dawley rats were randomly assigned to 1 of the following 2 groups (n = 12 per group): control group, no medication; and treatment group, oral administration of carvedilol (10 mg/kg per day) for 5 days. All animals were anesthetized with i.p. pentobarbital. Severe hemorrhagic shock was induced by partial exsanguination. Eight minutes after shock, all removed blood was returned to the animal. No other treatments were administered before, during, or after shock. Hemodynamics and arterial blood gases were recorded, mortality was calculated for the 5-h observation period, and plasma cytokine concentrations were measured at 5 h after shock. The mortality rates at 5 h after cardiac arrest were 8% and 50% for control and treatment groups, respectively. The increases in base deficit and lactate concentrations were less in the control group than that in the treatment group. Moreover, the increases in TNF-&agr; concentrations were less in the control group than in the treatment group. The present study indicated that oral administration of carvedilol had adverse effects on mortality and inflammatory responses to severe hemorrhagic shock in rats. These findings suggest that carvedilol may adversely affect recovery from severe hemorrhagic shock.

505 DEXMEDETOMIDINE, ALPHA-2 ADRENERGIC RECEPTOR AGONIST, IS A SUITABLE DRUG FOR THE MANAGEMENT OF BLOOD PRESSURE IN PATIENTS WITH ACUTE AORTIC DISSECTION

Background: In patients with acute aortic dissection, the reduction of blood pressure and sympathetic nervous activity is crucial. Dexmedetomidine, alpha-2 adrenergic receptor agonist, has a vasodilatory effect and decreases in sympathetic activity. On the other hand, other antihypertensive agents such as nicardipine often increase sympathetic activity. Therefore dexmedetomidine can be more ideal drug than other antihypertensive agents for the management of blood pressure in patients with acute aortic dissection. Objective: To investigate if dexmedetomidine improves mortality in intensive care unit and decreases blood pressure without heart rate elevation in patients with acute aortic dissection. Methods: We reviewed all patients with acute aortic dissection who admitted to our intensive care unit. Blood pressure, heart rate and mortality in intensive care unit were compared between patients treated with and without dexmedetomidine. The primary endpoint was mortality in intensive care unit. The secondary endpoint was the decrease in blood pressure and heart rate. Results: Among 109 patients with acute aortic dissection, dexmedetomidine was used for 59 patients (Dex group) and other antihypertensive drugs for 50 patients (non-Dex group). Mortality in intensive care unit was lower in patients treated with dexmedetomidine (1.7% in Dex group vs. 10% in non-Dex group). Dexmedetomidine reduced blood pressure without increase in heart rate. Conclusion: Dexmedetomidine is suitable as an antihypertensive drug in patient with acute aortic dissection.

Effects of Direct Hemoperfusion Using a Cytokine-Adsorbing Column on Endotoxin-Induced Experimental Acute Lung Injury in Rats

Background: Effects of direct hemoperfusion with a cytokine-adsorbing column, CTR, on endotoxin-induced experimental acute lung injury in rats were evaluated. Methods: 36 Sprague-Dawley rats were ventilated mechanically and allocated to one of the following three groups (n = 12 per group): saline control, saline instilled into trachea; endotoxin control, endotoxin (40 mg/kg) instilled into trachea, and treatment group, CTR treated for 90 min after endotoxin (40 mg/kg) instillation. Blood gases, cytokine concentrations and lung histopathology were evaluated. Results: The decreased PaO2 in the treatment group had recovered at 120 min after instillation and was significantly higher than that in the endotoxin control. The increased PaCO2 in the endotoxin control was significantly higher than that in the treatment group. The elevated cytokine concentrations and the neutrophil infiltration into the lungs were less in the treatment group than in the endotoxin control. Conclusion: The present study showed that CTR treatment inhibited hypoxia, hypercapnia, and inflammatory responses in an acute lung injury model.