Step-down Infusion Research Articles

Prophylactic barbiturate step-down infusion therapy has similar and favorable effects in elderly and non-elderly patients with severe traumatic brain injuries

With the aging population, the number of elderly patients with severe traumatic brain injury (sTBI) inevitably increases. The high mortality rate for sTBI in the elderly necessitates effective solutions. While we have previously reported the beneficial effects of a novel barbiturate therapy, a prophylactic step-down infusion of barbiturates (sdB), using thiamylal with normothermia (NOR) in patients with sTBI, its effects on elderly patients remain unclear. Therefore, we compared the efficacy and safety of sdB between elderly and non-elderly patients with sTBI.This study included 25 patients with sTBI who underwent sdB between January 2013 and March 2020. Patient characteristics were similar between elderly (≥75 years, n = 8) and non-elderly patients (<75 years, n = 17), except for the sex ratio. The hospitalization period tended to be longer for elderly patients. There were no differences in side effects or complications of sdB between the groups. The primary (favorable outcome at discharge and at 6–12 months) and secondary (composite death at discharge and at 6–12 months) endpoints were similar between the groups. Intracranial pressure and cerebral perfusion pressure were well controlled in the elderly patients.Our results suggest that sdB + NOR is as effective in elderly patients with sTBI as it is in non-elderly patients.

Step-down infusion of barbiturate improves neurofunction in a new rat model of rebleeding subarachnoid hemorrhage

Rebleeding from a ruptured aneurysm is a risk factor for fatal prognosis in subarachnoid hemorrhage (SAH). A novel barbiturate treatment, step-down infusion of barbiturate (sd-B), was previously developed; it showed beneficial effects on patients with severe traumatic brain injuries. The present study established a rebleeding SAH model in rats and evaluated the effect of sd-B. Fifty male Sprague-Dawley rats were divided into sham-operation with distilled water, sham-operation with barbiturate, SAH-rebleeding with distilled water, and SAH-rebleeding with barbiturate groups. For posttreatment with sd-B, thiamylal was intraperitoneally administered at 3 mg/kg/h on days 0–1, 2 mg/kg/h on days 1–2, and 1 mg/kg/h on days 2–3 after SAH using osmotic minipumps. We monitored neurofunction and case fatality as the primary endpoints and evaluated brain injuries, including brain edema and cortical neuronal cell death, as the secondary endpoints. Posttreatment with sd-B improved the modified Garcia test, reduced the brain water content, and inhibited the loss of neuronal cells and microglial expressions in the rat model. Our results revealed that sd-B ameliorated neurofunction and brain injuries on the rebleeding SAH model, suggesting that the novel treatment is a good candidate drug for patients with SAH with rebleeding.

Efficacy of a Novel Prophylactic Barbiturate Therapy for Severe Traumatic Brain Injuries: Step-down Infusion of a Barbiturate with Normothermia.

This study aimed to examine the beneficial effects of a novel prophylactic barbiturate therapy, step-down infusion of barbiturates, using thiamylal with normothermia (NOR+sdB), on the poor outcome in the patients with severe traumatic brain injuries (sTBI), in comparison with mild hypothermia (MD-HYPO). From January 2000 to March 2019, 4133 patients with TBI were admitted to our hospital. The inclusion criteria were: a Glasgow coma scale (GCS) score of ≤8 on admission, age between 20 and 80 years, intracranial hematoma requiring surgical evacuation of the hematoma with craniotomy and/or external decompression, and patients who underwent management of body temperature and assessed their outcome at 6–12 months. Finally, 43 patients were included in the MD-HYPO (n = 29) and NOR+sdB (n = 14) groups. sdB was initiated intraoperatively or immediately after the surgical treatment. There were no significant differences in patient characteristics, including age, sex, past medical history, GCS on admission, type of intracranial hematoma, and length of hospitalization between the two groups. Although NOR+sdB could not improve the patient’s poor outcome either at discharge from the intensive care unit (ICU) or at 6–12 months after admission, the treatment inhibited composite death at discharge from the ICU. The mean value of the maximum intracranial pressure (ICP) in the NOR+sdB group was <20 mmHg throughout the first 120 h. NOR+sdB prevented composite death in the ICU in patients with sTBI, and we may obtain novel insights into the beneficial role of prophylactic barbiturate therapy from suppression of the elevated ICP during the first 120 h.

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).

Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats I: Magnetic resonance imaging.

The mammalian target of rapamycin (mTOR) pathway has received increasing attention as a potential antiepileptogenic target. Treatment with the mTOR inhibitor rapamycin after status epilepticus reduces the development of epilepsy in a rat model. To study whether rapamycin mediates this effect via restoration of blood-brain barrier (BBB) dysfunction, contrast-enhanced magnetic resonance imaging (CE-MRI) was used to determine BBB permeability throughout epileptogenesis. Imaging was repeatedly performed until 6 weeks after kainic acid-induced status epilepticus in rapamycin (6 mg/kg for 6 weeks starting 4 h after SE) and vehicle-treated rats, using gadobutrol as contrast agent. Seizures were detected using video monitoring in the week following the last imaging session. Gadobutrol leakage was widespread and extensive in both rapamycin and vehicle-treated epileptic rats during the acute phase, with the piriform cortex and amygdala as the most affected regions. Gadobutrol leakage was higher in rapamycin-treated rats 4 and 8 days after status epilepticus compared to vehicle-treated rats. However, during the chronic epileptic phase, gadobutrol leakage was lower in rapamycin-treated epileptic rats along with a decreased seizure frequency. This was confirmed by local fluorescein staining in the brains of the same rats. Total brain volume was reduced by this rapamycin treatment regimen. The initial slow recovery of BBB function in rapamycin-treated epileptic rats indicates that rapamycin does not reduce seizure activity by a gradual recovery of BBB integrity. The reduced BBB leakage during the chronic phase, however, could contribute to the decreased seizure frequency in post-status epilepticus rats treated with rapamycin. Furthermore, the data show that CE-MRI (using step-down infusion with gadobutrol) can be used as biomarker for monitoring the effect of drug therapy in rats.

Extravasation into brain and subsequent spread beyond the ischemic core of a magnetic resonance contrast agent following a step-down infusion protocol in acute cerebral ischemia.

BackgroundLimiting expansion of the ischemic core lesion by reinstating blood flow and protecting the penumbral cells is a priority in acute stroke treatment. However, at present, methods are not available for effective drug delivery to the ischemic penumbra. To address these issues this study compared the extravasation and subsequent interstitial spread of a magnetic resonance contrast agent (MRCA) beyond the ischemic core into the surrounding brain in a rat model of ischemia-reperfusion for bolus injection and step-down infusion (SDI) protocols.MethodsMale Wistar rats underwent middle cerebral artery (MCA) occlusion for 3 h followed by reperfusion. Perfusion-diffusion mismatched regions indicating the extent of spread were identified by measuring cerebral blood flow (CBF) deficits by arterial spin-labeled magnetic resonance imaging and the extent of the ischemic core by mapping the apparent diffusion coefficient (ADC) of water with diffusion-weighted imaging. Vascular injury was assessed via MRCA, gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) penetration, by Look-Locker T1-weighted MR imaging after either a bolus injection (n = 8) or SDI (n = 6). Spatial and temporal expansion of the MRCA front during a 25 min imaging period was measured from images obtained at 2.5 min intervals.ResultsThe mean ADC lesion was 20 ± 7% of the hemispheric area whereas the CBF deficit area was 60 ± 16%, with the difference between the areas suggesting the possible presence of a penumbra. The bolus injection led to MRCA enhancement with an area that initially spread into the ischemic core and then diminished over time. The SDI produced a gradual increase in the area of MRCA enhancement that slowly enlarged to occupy the core, eventually expanded beyond it into the surrounding tissue and then plateaued. The integrated area from SDI extravasation was significantly larger than that for the bolus (p = 0.03). The total number of pixels covered by the SDI at its maximum was significantly larger than the pixels covered by bolus maximum (p = 0.05).ConclusionsThese results demonstrate that the SDI protocol resulted in a spread of the MRCA beyond the ischemic core. Whether plasma-borne acute stroke therapeutics can be delivered to the ischemic penumbra in a similar way needs to be investigated.

Longitudinal assessment of blood–brain barrier leakage during epileptogenesis in rats. A quantitative MRI study

The blood–brain barrier (BBB) plays an important role in the homeostasis of the brain. BBB dysfunction has been implicated in the pathophysiology of various neurological disorders, including epilepsy in which it may contribute to disease progression. Precise understanding of BBB dynamics during epileptogenesis may be of importance for the assessment of future therapies, including BBB leakage blocking-agents. Longitudinal changes in BBB integrity can be studied with in vivo magnetic resonance imaging (MRI) in combination with paramagnetic contrast agents. Although this approach has shown to be suitable to detect major BBB leakage during the acute phase in experimental epilepsy models, so far no studies have provided information on dynamics of the extent of BBB leakage towards later phases. Therefore a sensitive and quantitative approach was used in the present study, involving fast T1 mapping (dynamic approach) during a steady-state infusion of gadobutrol, as well as pre- and post-contrast T1-weighted MRI (post–pre approach). This was applied in an experimental epilepsy model in which previous MRI studies failed to detect BBB leakage during epileptogenesis.Adult male Sprague–Dawley rats were injected with kainic acid to induce status epilepticus (SE). MRI experiments were performed before SE (control) and during the acute (1day) and chronic epileptic phases (6weeks after SE). BBB leakage was quantified by fast T1 mapping (Look–Locker gradient echo MRI) with a time resolution of 48s from 5min before up to 45min after 20min step-down infusion of 0.2M gadobutrol. In addition, T1-weighted MRI was acquired before and 45min after infusion. MRI data were compared to post-mortem microscopic analysis using the BBB tracer fluorescein.Our MRI data showed BBB leakage, which was evident at 1day and 6weeks after SE in the hippocampus, entorhinal cortex, amygdala and piriform cortex. These findings were confirmed by microscopic analysis of fluorescein leakage. Furthermore, our MRI data revealed non-uniform BBB leakage throughout epileptogenesis. This study demonstrates BBB leakage in specific brain regions during epileptogenesis, which can be quantified using MRI. Therefore, MRI may be a valuable tool for experimental or clinical studies to elucidate the role of the BBB in epileptogenesis.

Evaluation of the predictive performance of a pharmacokinetic model for propofol in Japanese macaques (Macaca fuscata fuscata)

Propofol is a short-acting intravenous anesthetic used for induction/maintenance anesthesia. The objective of this study was to assess a population pharmacokinetic (PPK) model for Japanese macaques during a step-down infusion of propofol. Five male Japanese macaques were immobilized with ketamine (10 mg/kg) and atropine (0.02 mg/kg). A bolus dose of propofol (5 mg/kg) was administrated intravenously (360 mg/kg/h) followed by step-down infusion at 40 mg/kg/h for 10 min, 20 mg/kg/h for 10 min, and then 15 mg/kg/h for 100 min. Venous blood samples were repeatedly collected following the administration. The plasma concentration of propofol (Cp) was measured by high-speed LC-FL. PPK analyses were performed using NONMEM VII. Median absolute prediction error and median prediction error (MDPE), the indices of prediction inaccuracy and bias, respectively, were calculated, and PE - individual MDPE vs. time was depicted to show the variability of prediction errors. In addition, we developed another population pharmacokinetic model using previous and current datasets. The previous PK model achieved stable prediction of propofol Cp throughout the study period, although it underestimates Cp. The step-down infusion regimen described in this study would be feasible in macaques during noninvasive procedures.

Estimating Blood and Brain Concentrations and Blood-to-Brain Influx by Magnetic Resonance Imaging with Step-Down Infusion of Gd-DTPA in Focal Transient Cerebral Ischemia and Confirmation by Quantitative Autoradiography with Gd-[14C]DTPA

An intravenous step-down infusion procedure that maintained a constant gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) blood concentration and magnetic resonance imaging (MRI) were used to localize and quantify the blood-brain barrier (BBB) opening in a rat model of transient cerebral ischemia (n=7). Blood-to-brain influx rate constant (K(i)) values of Gd-DTPA from such regions were estimated using MRI-Patlak plots and compared with the K(i) values of Gd-[(14)C]DTPA, determined minutes later in the same rats with an identical step-down infusion, quantitative autoradiography (QAR), and single-time equation. The normalized plasma concentration-time integrals were identical for Gd-DTPA and Gd-[(14)C]DTPA, indicating that the MRI protocol yielded reliable estimates of plasma Gd-DTPA levels. In six rats with a BBB opening, 14 spatially similar regions of extravascular Gd-DTPA enhancement and Gd-[(14)C]DTPA leakage, including one very small area, were observed. The terminal tissue-plasma ratios of Gd-[(14)C]DTPA tended to be slightly higher than those of Gd-DTPA in these regions, but the differences were not significant. The MRI-derived K(i) values for Gd-DTPA closely agreed and correlated well with those obtained for Gd-[(14)C]DTPA. In summary, MRI estimates of Gd-DTPA concentration in the plasma and brain and the influx rate are quantitatively and spatially accurate with step-down infusions.

Step-down infusions of Gd–DTPA yield greater contrast-enhanced magnetic resonance images of BBB damage in acute stroke than bolus injections

A rat model of transient suture occlusion of one middle cerebral artery (MCA) was used to create a unilateral reperfused cerebral ischemic infarct with blood-brain barrier (BBB) opening. Opening of the BBB was visualized and quantitated by magnetic resonance (MR) contrast enhancement with a Look-Locker T(1)-weighted sequence either following an intravenous bolus injection (n=7) or during a step-down infusion (n=7) of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA). Blood levels of Gd-DTPA after either input were monitored via changes in sagittal sinus relaxation rate. Blood-to-brain influx constants (K(i)) were calculated by Patlak plots. On the basis of the MRI parameters and lesion size, the ischemic injury was determined to be similar in the two groups. The bolus injection input produced a sharp rise in blood levels of Gd-DTPA that declined quickly, whereas the step-down infusion led to a sharp rise that was maintained relatively constant for the period of imaging. Visual contrast enhancement and signal-to-noise (S/N) ratios were better with the step-down method (S/N=1.8) than with bolus injection (S/N=1.3). The K(i) values were not significantly different between the two groups (P>.05) and were around 0.005 ml/(g min). The major reason for the better imaging of BBB opening by the step-down infusion was the higher amounts of Gd-DTPA in plasma and tissue during most of the experimental period. These results suggest that step-down MR contrast agent (MRCA) administration schedule may be more advantageous for detection and delineation of acute BBB injury than the usually used bolus injections.

Titration of propofol infusion using processed electroencephalogram during combined general and spinal anesthesia.

To determine the necessary mean infusion rate of propofol during combined nitrous oxide (N2O) and propofol spinal anesthesia by using the processed electroencephalogram (pEEG). Twelve elective gynecological patients were monitored by a Dräger pEEG monitor under N2O and propofol spinal anesthesia. To make it easier to detect an inadequate depth of anesthesia, muscle relaxants were not given and the patients breathed spontaneously through a laryngeal mask airway. Manual step-down infusion of propofol was employed to provide intraoperative hypnosis. Propofol infusion was titrated to maintain cardiorespiratory parameters within 20% of baseline and the 90th percentile of the spectral edge frequency (SEF 90) of the pEEG between 10 and 13.5 Hz. The mean (SD) induction dose of propofol was 2.9 (0.4) mg·kg-1. The mean (SD) maintenance infusion rate was 4.2 (0.5) mg·kg-1·h-1. The mean (SD) time from the end of propofol infusion to the opening of the patient's eyes was 5.4 (2.0) min. No gross movements or intraoperative awareness was recognized. The mean (SD) SEF 90 during the maintenance of anesthesia was 12.2 (1.5) Hz, which increased significantly to 16.2 (1.9) Hz at 1 min before the patients opened their eyes in reponse to verbal commands. Titration of propofol infusion using SEF during combined general and spinal anesthesia provided a rapid recovery without any clinical signs of inadequate anesthesia.