Ketamine as an Anesthetic for Patients with Acute Brain Injury: A Systematic Review.

For years, the use of ketamine as an anesthetic to patients suffering from acute brain injury has been debated because of its possible deleterious effects on the cerebral circulation and thus on the cerebral perfusion. Early studies suggested that ketamine could increase the intracranial pressure thus lowering the cerebral perfusion and hence reduce the oxygen supply to the injured brain. However, more recent studies are less conclusive and might even indicate that patients with acute brain injury could benefit from ketamine sedation. This systematic review summarizes the evidence regarding the use of ketamine in patients suffering from traumatic brain injury. Databases were searched for studies using ketamine in acute brain injury. Outcomes of interest were mortality, intracranial pressure, cerebral perfusion pressure, blood pressure, heart rate, spreading depolarizations, and neurological function. In total 11 studies were included. The overall level of evidence concerning the use of ketamine in brain injury is low. Only two studies found a small increase in intracranial pressure, while two small studies found decreased levels of intracranial pressure following ketamine administration. We found no evidence of harm during ketamine use in patients suffering from acute brain injury.

Pre-hospital emergent intubation in trauma patients: the influence of etomidate on mortality, morbidity and healthcare resource utilization.

BACKGROUND: Due to its favorable hemodynamic characteristics and by providing good intubation conditions etomidate is often used for induction of general anesthesia in trauma patients. It has been linked to temporary adrenal cortical dysfunction. The clinical relevance of this finding after a single-dose is still lacking appropriate evidence. METHODS: This retrospective multi-centre study is based on merged data from a German Helicopter Emergency Medical Service (HEMS) database and a large trauma patient registry. All trauma patients who were intubated prior to hospital admission with a documented Injury Severity Score ≥ 9 between 2008 and 2012 were eligible for analysis. The primary endpoint was hospital mortality. Other outcome measures were organ failures, sepsis, length of ventilation, as well as length of stay in hospital and ICU. RESULTS: One thousand six hundred ninety seven patients were enrolled into the study. Seven hundred sixty two patients received etomidate and 935 patients received other induction agents. The in-hospital mortality was similar in both groups (18.9% versus 18.2%; p = 0.71). Incidences of organ failures and sepsis were not increased in the etomidate group. However, health care resource utilization parameters were prolonged (after adjusting: + 1.3 days for ICU length of stay, p = 0.062; + 0.8 days for length of ventilation, p = 0.15; + 2,7 days for hospital length of stay, p = 0.034). A multivariable logistic regression analysis did not identify etomidate as an independent predictor of hospital mortality (OR: 1.10, 95% CI: 0.77-1.57; p = 0.60). CONCLUSIONS: This is the largest trial investigating outcome data for trauma patients who had received a single-dose of etomidate for induction of anesthesia. The use of etomidate did not affect mortality. The influence on morbidity and health care resource utilization remains unclear.

The protective effect of propofol against TNF-α-induced apoptosis was mediated via inhibiting iNOS/NO production and maintaining intracellular Ca2+ homeostasis in mouse hippocampal HT22 cells.

AIM: Inflammation cytokine tumor necrosis factor-α (TNF-α) induces apoptosis in neuronal cells. We hypothesized that propofol may attenuate TNF-α-induced apoptosis in mouse hippocampal HT22 cells and aimed to explore the underlying mechanisms. METHODS: Mouse hippocampal HT22 cells were pretreated with propofol, and then stimulated with TNF-α. Cell viability was measured by cell counting kit 8 (CCK8). Cell apoptosis was examined by flow cytometry analysis. The effect of propofol on TNF-α-modulated nitric oxide production was measured by a nitrate reductase assay kit, intracellular calcium release and mitochondrial membrane potential (MMP) depolarization were measured by flow cytometry analysis, and the expression of inducible nitric oxide synthase (iNOS), C/EBP homologous protein (CHOP), B-cell lymphoma 2 (Bcl2) family and caspases were detected by Western blot. RESULTS: Compared with control, TNF-α concentration- and time-dependently increased HT22 cell apoptosis, which was attenuated by 25µmol/l propofol. TNF-α (40ng/ml, 24h) induced the overexpression of iNOS and the release of nitric oxide, caused the accumulation of intracellular Ca2+ and endoplasmic reticulum (ER) stress, and therefore leading to mitochondrial dysfunction. Importantly, these effects were alleviated by 25µmol/l propofol. CONCLUSIONS: We demonstrated that propofol could attenuate TNF-α-induced HT22 apoptosis. More importantly, we indicated that the underlying mechanism may involve iNOS/NO, Ca2+ and mitochondrial dysfunction.

Population pharmacokinetic-pharmacodynamic modeling and dosing simulation of propofol maintenance anesthesia in severely obese adolescents.

BACKGROUND: Optimal dosing of propofol to maintain appropriate anesthetic depth is challenging in severely obese (SO) adolescents. We previously reported that total body weight (TBW) is predictive of propofol clearance. This study was aimed at characterizing pharmacokinetics (PK) and pharmacodynamics (PD) of propofol in SO adolescents, using bispectral index (BIS), and toward developing PK/PD model-based dosing guidelines. METHODS: A prospective PK/PD study was conducted in 26 SO children and adolescents aged 9-18 years (body mass index 31-69 kg·m(-2)), undergoing surgery with intravenous propofol anesthesia clinically titrated by providers blinded to BIS. BIS data and propofol infusion schemes were recorded. Venous blood samples collected during and after propofol infusion were assayed for propofol concentrations. A propofol PK/PD model was developed using NONMEM and model-based simulations were performed to determine propofol dosing regimens targeting BIS of 50 ± 10. RESULTS: A three-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant, adequately described the propofol concentration (n = 375) and BIS (n = 3334) data. TBW was the most predictive covariate for propofol clearance [CL (l·min(-1) ) = 1.65 × (TBW/70)(0.75)]. An effect-site propofol concentration of 3.19 µg·ml(-1) was estimated for half-maximal effect, with no identifiable predictive covariates. The proposed maintenance dosing regimen targeted to a BIS of 50 ± 10, based on our PK/PD model, was able to predict desired propofol concentrations and BIS in a representative obese teen when used in conjunction with accepted PK/PD models for children/obese adults (PK:Eleveld/PD: Cortinez), further supporting evidence for the dosing based on TBW. CONCLUSION: This is the first study to describe the PK/PD of propofol in SO adolescents. The proposed maintenance dosing regimen for propofol uses TBW in an allometric function as a dosing scalar, with an exponent of 0.75. Our results suggest no relevant effect of obesity on the propofol concentration-BIS relationship.