Highly variable pharmacokinetics of dexmedetomidine during intensive care: a case report

<p>Abstract</p> <p>Introduction</p> <p>Dexmedetomidine is a selective and potent alpha2-adrenoceptor agonist licensed for use in the sedation of patients initially ventilated in intensive care units at a maximum dose rate of 0.7 μg/kg/h administered for up to 24 hours. Higher dose rates and longer infusion periods are sometimes required to achieve sufficient sedation. There are some previous reports on the use of long-term moderate to high-dose infusions of dexmedetomidine in patients in intensive care units, but none of these accounts have cited dexmedetomidine plasma concentrations.</p> <p>Case presentation</p> <p>We describe the case of a 42-year-old Caucasian woman with severe hemorrhagic pancreatitis following laparoscopic cholecystectomy who received dexmedetomidine for 24 consecutive days at a maximum dose rate of 1.9 μg/kg/h. Samples for the measurement of dexmedetomidine concentrations in her plasma were drawn at intervals of eight hours. On average, the observed plasma concentrations were well in accordance with previous knowledge on the pharmacokinetics of dexmedetomidine. There was, however, marked variability in the concentration of dexmedetomidine in her plasma despite a stable infusion rate.</p> <p>Conclusion</p> <p>The pharmacokinetics of dexmedetomidine appears to be highly variable during intensive care.</p

Effects of dexmedetomidine, propofol, sevoflurane and S-ketamine on the human metabolome A randomised trial using nuclear magnetic resonance spectroscopy

BACKGROUND Pharmacometabolomics uses large-scale data capturing methods to uncover drug-induced shifts in the metabolic profile. The specific effects of anaesthetics on the human metabolome are largely unknown. OBJECTIVE We aimed to discover whether exposure to routinely used anaesthetics have an acute effect on the human metabolic profile. DESIGN Randomised, open-label, controlled, parallel group, phase IV clinical drug trial. SETTING The study was conducted at Turku PET Centre, University of Turku, Finland, 2016 to 2017. PARTICIPANTS One hundred and sixty healthy male volunteers were recruited. The metabolomic data of 159 were evaluable. INTERVENTIONS Volunteers were randomised to receive a 1-h exposure to equipotent doses (EC50 for verbal command) of dexmedetomidine (1.5 ng ml(-1); n = 40), propofol (1.7 mu g ml(-1); n = 40), sevoflurane (0.9% end-tidal; n = 39), S-ketamine (0.75 mu g ml(-1); n = 20) or placebo (n = 20). MAIN OUTCOME MEASURES Metabolite subgroups of apolipoproteins and lipoproteins, cholesterol, glycerides and phospholipids, fatty acids, glycolysis, amino acids, ketone bodies, creatinine and albumin and the inflammatory marker GlycA, were analysed with nuclear magnetic resonance spectroscopy from arterial blood samples collected at baseline, after anaesthetic administration and 70 min post-anaesthesia. RESULTS All metabolite subgroups were affected. Statistically significant changes vs. placebo were observed in 11.0, 41.3, 0.65 and 3.9% of the 155 analytes in the dexmedetomidine, propofol, sevoflurane and S-ketamine groups, respectively. Dexmedetomidine increased glucose, decreased ketone bodies and affected lipoproteins and apolipoproteins. Propofol altered lipoproteins, fatty acids, glycerides and phospholipids and slightly increased inflammatory marker glycoprotein acetylation. Sevoflurane was relatively inert. S-ketamine increased glucose and lactate, whereasbranched chain amino acids and tyrosine decreased. CONCLUSION A 1-h exposure to moderate doses of routinely used anaesthetics led to significant and characteristic alterations in the metabolic profile. Dexmedetomidine-induced alterations mirror a2-adrenoceptor agonism. Propofol emulsion altered the lipid profile. The inertness of sevoflurane might prove useful in vulnerable patients. S-ketamine induced amino acid alterations might be linked to its suggested antidepressive properties.Peer reviewe

Alterations in heart rate variability in patients with peripheral arterial disease requiring surgical revascularization have limited association with postoperative major adverse cardiovascular and cerebrovascular events.

OBJECTIVE:Obstructive sleep apnea (OSA) is common in peripheral arterial disease (PAD) and associates with high mortality after surgery. Since abnormal heart rate variability (HRV) is predictive of postoperative complications, we investigated the relations of HRV with PAD, OSA and major adverse cardiovascular and cerebrovascular events (MACCE). MATERIALS AND METHODS:Seventy-five patients (67±9 years) scheduled for sub-inguinal revascularization and 15 controls (63±6 years) underwent polysomnography and HRV analyses. OSA with an apnea-hypopnea index (AHI) ≥20/hour was considered significant. HRV was measured during wakefulness, S2, S3-4 and rapid eye movement (REM) sleep with time and frequency domain methods including beat-to-beat variability, low frequency (LF) and high frequency (HF) power, and detrended fluctuation analysis (DFA). MACCE was defined as cardiac death, myocardial infarction, coronary revascularization, hospitalized angina pectoris and stroke. RESULTS:Thirty-six patients (48%) had AHI≥20/hour. During follow-up (median 52 months), 22 patients (29%) suffered a MACCE. Compared to controls, fractal correlation of HRV (scaling exponent alpha 1 measured with DFA) was weaker during S2 and evening wakefulness in all subgroups (+/-AHI≥20/hour, +/-MACCE) but only in patients with AHI≥20/hour during morning wakefulness. The LF/HF ratio was lower in all subgroups during S2 but only in patients with AHI ≥20/hour during evening or morning wake. In the covariance analysis adjusted for age, body mass index, coronary artery disease and PAD duration, the alpha 1 during morning wakefulness remained significantly lower in patients with AHI≥20/hour than in those without (1.12 vs. 1.45; p = 0.03). Decreased HF during REM (p = 0.04) and S3-4 sleep (p = 0.03) were predictive of MACCE. In analyses with all sleep stages combined, mean heart rate as well as very low frequency, LF, HF and total power were associated with OSA of mild-to-moderate severity (AHI 10-20/hour). CONCLUSIONS:HRV is altered in patients with PAD. These alterations have a limited association with OSA and MACCE

Comparison of the prognostic value of early-phase proton magnetic resonance spectroscopy and diffusion tensor imaging with serum neuron-specific enolase at 72 h in comatose survivors of out-of-hospital cardiac arrest—a substudy of the XeHypotheca trial

PurposeWe compared the predictive accuracy of early-phase brain diffusion tensor imaging (DTI), proton magnetic resonance spectroscopy (1H-MRS), and serum neuron-specific enolase (NSE) against the motor score and epileptic seizures (ES) for poor neurological outcome after out-of-hospital cardiac arrest (OHCA).MethodsThe predictive accuracy of DTI, 1H-MRS, and NSE along with motor score at 72&nbsp;h and ES for the poor neurological outcome (modified Rankin Scale, mRS, 3 - 6) in 92 comatose OHCA patients at 6&nbsp;months was assessed by area under the receiver operating characteristic curve (AUROC). Combined models of the variables were included as exploratory.ResultsThe predictive accuracy of fractional anisotropy (FA) of DTI (AUROC 0.73, 95% CI 0.62-0.84), total N-acetyl aspartate/total creatine (tNAA/tCr) of 1H-MRS (0.78 (0.68 - 0.88)), or NSE at 72&nbsp;h (0.85 (0.76 - 0.93)) was not significantly better than motor score at 72&nbsp;h (0.88 (95% CI 0.80-0.96)). The addition of FA and tNAA/tCr to a combination of NSE, motor score, and ES provided a small but statistically significant improvement in predictive accuracy (AUROC 0.92 (0.85-0.98) vs 0.98 (0.96-1.00), p = 0.037).ConclusionNone of the variables (FA, tNAA/tCr, ES, NSE at 72&nbsp;h, and motor score at 72&nbsp;h) differed significantly in predicting poor outcomes in this patient group. Early-phase quantitative neuroimaging provided a statistically significant improvement for the predictive value when combined with ES and motor score with or without NSE. However, in clinical practice, the additional value is small, and considering the costs and challenges of imaging in this patient group, early-phase DTI/MRS cannot be recommended for routine use.Trial registrationClinicalTrials.gov NCT00879892, April 13, 2009

Comparison of the prognostic value of early-phase proton magnetic resonance spectroscopy and diffusion tensor imaging with serum neuron-specific enolase at 72 h in comatose survivors of out-of-hospital cardiac arrest-a substudy of the XeHypotheca trial

Purpose We compared the predictive accuracy of early-phase brain diffusion tensor imaging (DTI), proton magnetic resonance spectroscopy (1H-MRS), and serum neuron-specific enolase (NSE) against the motor score and epileptic seizures (ES) for poor neurological outcome after out-of-hospital cardiac arrest (OHCA). Methods The predictive accuracy of DTI, 1H-MRS, and NSE along with motor score at 72 h and ES for the poor neurological outcome (modified Rankin Scale, mRS, 3 - 6) in 92 comatose OHCA patients at 6 months was assessed by area under the receiver operating characteristic curve (AUROC). Combined models of the variables were included as exploratory. Results The predictive accuracy of fractional anisotropy (FA) of DTI (AUROC 0.73, 95% CI 0.62-0.84), total N-acetyl aspartate/total creatine (tNAA/tCr) of 1H-MRS (0.78 (0.68 - 0.88)), or NSE at 72 h (0.85 (0.76 - 0.93)) was not significantly better than motor score at 72 h (0.88 (95% CI 0.80-0.96)). The addition of FA and tNAA/tCr to a combination of NSE, motor score, and ES provided a small but statistically significant improvement in predictive accuracy (AUROC 0.92 (0.85-0.98) vs 0.98 (0.96-1.00), p = 0.037). Conclusion None of the variables (FA, tNAA/tCr, ES, NSE at 72 h, and motor score at 72 h) differed significantly in predicting poor outcomes in this patient group. Early-phase quantitative neuroimaging provided a statistically significant improvement for the predictive value when combined with ES and motor score with or without NSE. However, in clinical practice, the additional value is small, and considering the costs and challenges of imaging in this patient group, early-phase DTI/MRS cannot be recommended for routine use.Peer reviewe