James Arden

Increased sensitivity to etomidate in the elderly: initial distribution versus altered brain response

To determine the effect of aging on the pharmacokinetics and pharmacodynamics of etomidate, we administered etomidate (5 to 10 mg/min) by intravenous infusion to 21 healthy surgical patients, age 22 to 82 yr. Etomidate produced progressive slowing of the EEG to an easily recognized pattern (stage 3) that determined the dosage endpoint. Subsequent power-spectrum analysis of the EEG gave the median frequency. Median frequency values and simultaneous measurements of blood etomidate concentration were incorporated into a sigmoid Emax pharmacodynamic model that permitted an estimate of IC50, the blood etomidate concentration which produced a 50% reduction in the median frequency. The dose of etomidate required to reach the uniform EEG endpoint decreased significantly with increasing age (r2 = .68) as did the dose needed to produce maximal median frequency depression (r2 = .69). None of the parameters of the pharmacodynamic effect model, including IC50, correlated with age, suggesting that increased brain sensitivity in the elderly does not cause the age-related change in dose requirement. The initial distribution volume for etomidate decreased significantly with increasing age (r = .56), implying that a higher initial blood concentration in the elderly following any given dose of etomidate is part of the cause of the lower dose requirement in the elderly patient. A contracted initial distribution volume in the elderly may result from well described physiologic changes of age. Etomidate clearance also decreased with age. Age-dependent changes in etomidate pharmacokinetics rather than altered brain responsiveness may be the basis for the decreased etomidate dose requirement in the elderly.

Optimised anaesthesia to reduce post operative cognitive decline (POCD) in older patients undergoing elective surgery, a randomised controlled trial.

Background The study determined the one year incidence of post operative cognitive decline (POCD) and evaluated the effectiveness of an intra-operative anaesthetic intervention in reducing post-operative cognitive impairment in older adults (over 60 years of age) undergoing elective orthopaedic or abdominal surgery. Methods and Trial Design The design was a prospective cohort study with a nested randomised, controlled intervention trial, using intra-operative BiSpectral index and cerebral oxygen saturation monitoring to enable optimisation of anaesthesia depth and cerebral oxygen saturation in older adults undergoing surgery. Results In the 52 week prospective cohort study (192 surgical patients and 138 controls), mild (χ2 = 17.9 p<0.0001), moderate (χ2 = 7.8 p = 0.005) and severe (χ2 = 5.1 p = 0.02) POCD were all significantly higher after 52 weeks in the surgical patients than among the age matched controls. In the nested RCT, 81 patients were randomized, 73 contributing to the data analysis (34 intervention, 39 control). In the intervention group mild POCD was significantly reduced at 1, 12 and 52 weeks (Fisher’s Exact Test p = 0.018, χ2 = 5.1 p = 0.02 and χ2 = 5.9 p = 0.015), and moderate POCD was reduced at 1 and 52 weeks (χ2 = 4.4 p = 0·037 and χ2 = 5.4 p = 0.02). In addition there was significant improvement in reaction time at all time-points (Vigilance Reaction Time MWU Z =  −2.1 p = 0.03, MWU Z = −2.7 p = 0.004, MWU Z = −3.0 p = 0.005), in MMSE at one and 52 weeks (MWU Z = −2.9 p = 0.003, MWU Z = −3.3 p = 0.001), and in executive function at 12 and 52 weeks (Trail Making MWU Z = −2.4 p = .0.018, MWU Z = −2.4 p = 0.019). Conclusion POCD is common and persistent in older adults following surgery. The results of the nested RCT indicate the potential benefits of intra-operative monitoring of anaesthetic depth and cerebral oxygenation as a pragmatic intervention to reduce post-operative cognitive impairment. Trial Registration Controlled-Trials.com ISRCTN39503939

The pharmacodynamics and pharmacokinetics of vecuronium in patients anesthetized with isoflurane with normal renal function or with renal failure.

The duration of action and the pharmacokinetics of vecuronium were compared in patients with and without renal function. Twenty patients were studied: 12 with renal failure who were to receive kidney transplants from cadaveric donors, and eight with normal renal function. After oral premedication with diazepam, 10 mg, anesthesia was induced with thiopental, 4 mg/kg iv, and maintained with the inhalation of 60% nitrous oxide and 0.9–1.1% isoflurane, end-tidal concentration, in 40% oxygen. The force of thumb adduction in response to supramaximal ulnar nerve stimulation was monitored and recorded. An intravenous bolus of vecuronium, 0.1 mg/kg, was administered after 15 min of a stable end-tidal isoflurane concentration, as measured by mean spectrometry. Venous blood was then sampled at frequent intervals for 4 h following the bolus. Vecuronium concentrations in plasma were quantified by a sensitive and specific gas chromatographic assay. Data were analyzed by nonlinear least squares regression and described by a two-compartment model. The duration of neuromuscular blockade was longer in patients with renal failure than in those with normal renal function. This increased duration may be related to both a decreased plasma clearance duration may be related to both a decreased plasma clearance and a prolonged elimination half-life of vecuronium in the renal failure group.

Vecuronium in alcoholic liver disease: a pharmacokinetic and pharmacodynamic analysis.

To determine the effect of alcoholic liver disease on the pharmacokinetics and pharmacodynamics of vecuronium, the authors administered vecuronium 0.1 mg ± kg-1 iv to ten surgical patients with alcoholic liver disease and ten healthy surgical patients. All patients were anesthetized with nitrous oxide and isoflurane. We recorded and quantitated the force of thumb adduction in response to supramaximal ulnar nerve stimulation. Plasma concentrations of vecuronium and its 3-desacetyl metabolite were determined by a capillary gas chromatography assay. Only the time to attain 100% twitch ± depression (onset time) was prolonged in liver disease patients (2.8 ± 0.7 min; mean ± SD) as compared to control patients (1.9 ± 0.4 min). The time from vecuronium administration to recovery of twitch tension was unaffected by alcoholic liver disease. The time to the reappearance of twitch response was 32.7 ± 9.7 min in patients with liver disease and 36.8 ± 15.5 min in controls. Plasma concentration-time data were fit to two-compartment model. Vecuronium clearance, steady-state volume of distribution, and elimination half-time were unchanged by alcoholic liver disease. The authors conclude that alcoholic liver disease does not affect the pharmacokinetics or duration of action of vccuronium when an intravenou bolus dose of 0.1 mg ± kg-1 is administered.

Analysis of Neuron-Specific Enolase and S100B as Biomarkers of Cognitive Decline Following Surgery in Older People

Background/Aims: Post-operative cognitive decline is frequent in older individuals following major surgery; however, biomarkers of this decline are less clearly defined. Methods: Sixty-eight participants over the age of 60 provided blood samples at baseline and 24 h post-surgery. Cognitive decline was measured at baseline and 52 weeks post-surgery using the Cambridge Assessment for Mental Disorder in the Elderly, section B (CAMCOG) score. Plasma levels of neuron-specific enolase (NSE) and S100B were measured by ELISA. Results: Baseline NSE and the change in NSE levels between baseline and 24 h were correlated with the change in CAMCOG score between baseline and 52 weeks. Conclusion: NSE concentrations may be a useful predictor of individuals at risk of more severe long-term cognitive decline.

Cognitive Decline in Older Subjects

POCD, one would expect that postevent decline was greatly close to the event. The illness group had a median difference of 1.7 fewer annual postevent measures contributing to their slope estimate. As these preevent and postevent measures are linear and marginal, it is conceivable that having a different number of observations preevent and postevent could mask important differences. Once again, we applaud the investigators’ effort to facilitate our understanding of this information.