A Novel Step-Down Infusion Therapy: Its Safety and Effectiveness in Intracranial Pressure Control Using Barbiturate Therapy

Background: Barbiturate therapy has been widely used to suppress increased intracranial pressure (ICP); however, classical barbiturate therapy has disadvantages such as cardiac function depression. This is due to lack of detailed pharmacological dynamics of barbiturate and an established safety infusion method. Methods: Two healthy male beagles intubated and anesthetized using thiamylal (4·0 mg/kg/h) and propofol (4·0 mg/kg/h) were maintained for 36 h; one dog was maintained under normothermia and the other, hypothermia. A 1·0 mL blood sample was collected at 0, 12, 24, 36, 42, 48 h and drug concentration measured using liquid chromatography-mass spectrometry. Barbiturate therapy was performed at the earliest convenience using the ‘Step-Down Infusion’ method for severe traumatic brain injury patients or sever cerebrovascular disease patients having a Glasgow coma scale 8, and ICP was measured for at least 7 days. Findings: In the animals, thiamylal concentration increased with time and was influenced by body temperature; the dog with hypothermia had a higher concentration than normothermic dog. Stable values were noted with propofol. In the clinical study, step-down infusion of thiamylal under normothermia resulted in stable concentrations with no abnormal accumulation or threatening changes in serum potassium. Blood pressure was also stable under 25·0 g/mL and no hemodynamic instability was found. ICP increase was inhibited by the increase in thiamylal concentration and cerebral perfusion pressure (CPP) was maintained over 65 mmHg during the time course. Interpretation: Fixed long-term infusion of barbiturate induced marked drug accumulation, which was enhanced by hypothermia. Our novel “Step-down infusion” method under normothermia can maintain stable, safe thiamylal concentration to achieve both ICP reduction and CPP maintenance without serious side effects such as hypotension or hypokalemia. As the safe maximum concentration of barbiturate remains unclear, further clinical investigation is warranted. Funding Statement: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Declaration of Interests: All authors declare that no support, financial or otherwise, has been received from any organization that may have an interest in the submitted work, and there are no other relationships or activities that could appear to have influenced the submitted work. Ethics Approval Statement: All procedures in this study were carried out in strict accordance with the guidelines for animal experimentation at the Animal Research Center of Kurume University. All the animal experiments were reviewed and approved by the Institutional Animal care and use committee (No. P150516). Induction was performed under anesthesia and all efforts made to minimize suffering. The clinical study was reviewed and approved by the Institutional ethical committee of Kurume University (No. 12268).