[Brain death diagnosis after sedation with propofol or sufentanil. Recommendations for the usage of toxicological analytics]. / Hirntoddiagnostik nach Gabe von Propofol oder Sufentanil. Empfehlungen zum Umgang mit toxikologischer Analytik.

BACKGROUND: Before the clinical diagnosis of brain death is made, toxicological analyses are often performed for the exclusion of effective serum levels of previously applied sedating drugs. For propofol and sufentanil there are no uniform recommendations for the usage of toxicology test results. OBJECTIVES: To develop a standard practice in the diagnosis of brain death after therapeutic application of one of these drugs. MATERIAL AND METHODS: Based on the current literature and the available analytical assays, an ad hoc working group consisting of specialists in toxicology and intensive care medicine compiled recommendations for the usage of toxicological analytics in the diagnosis of brain death at the Rostock University Hospital. RESULTS: For propofol, current analytical assays allow the quantification of serum concentrations of 0.2 µg/ml and lower; the execution of clinical brain death diagnostics is recommended by the ad hoc group only at propofol serum levels lower than 0.4 µg/ml. For sufentanil, the currently prevalent assays set lower determination limits of about 0.2 ng/ml in serum and 0.1 ng/ml in urine, which is above the cautiously adopted lower therapeutic serum concentration of 0.02 ng/ml. Therefore after negative determination of sufentanil (< 0.2 ng/ml) in blood serum, the following alternative procedures are recommended: (1) the execution of clinical brain death diagnostics under administration of naloxone; or (2) at intact renal function the additional negative determination of sufentanil in urine (< 0.1 ng/ml). If an assay allowing the detection of sufentanil at ≤ 0.01 ng/ml is available, brain death diagnostics should be carried out only at a serum level lower than 0.02 ng/ml. CONCLUSION: These recommendations may serve as a proposal for similar standards in other hospitals.

Determination of fentanyl, metabolite and analogs in urine by GC/MS.

A rapid and sensitive method for the simultaneous determination of alfentanyl, sufentanyl and fentanyl (and its major metabolite norfentanyl) in urine was developed and validated. The method involved a liquid-liquid extraction in alkaline conditions, derivatization with pentafluoropropionic anhydride to improve the sensitivity for norfentanyl and subsequent analysis in GC/MS. The LODs are 0.08 ng ml(-1) for all substances (0.04 ng ml(-1) for alfentanyl). Intra- and inter-day precision coefficient of variation was always below 15%; mean relative error (accuracy) was always below 15%. The method was linear for all analytes, with quadratic regression of calibration curves always higher than 0.99. The method was applied to real samples of subjects who had received therapeutic doses of fentanyl, showing its suitability for the determination of low levels of these substances. The method was also applied to a subject whose death was attributed to fentanyl overdose.

No hyperalgesia following opioid withdrawal after the oripavine derivative etorphine compared to remifentanil and sufentanil.

BACKGROUND AND OBJECTIVE: The concept of opioid-induced hyperalgesia has recently gained prominence as a contributing factor for long-term treatment failure. METHODS: To evaluate possible differences of opioids used in anaesthesia, cumulative doses of sufentanil and remifentanil were compared with escalating doses of the oripavine derivative etorphine, in awake and trained canines. This was followed by naloxone unmasking a possible hyperalgesic state, which had developed during opioid administration. Heart rate, blood pressure and propagation of nociceptive volleys in somatosensory-evoked potentials as well as the skin-twitch reflex were evaluated. RESULTS: Opioid-related hypotension and bradycardia were reversed by naloxone with a late (30 min) overshoot of R43 and R17% after remifentanil and sufentanil, respectively. Following etorphine, overshoot in mean blood pressure was R9%, whereas heart rate still remained below S9% when compared with control. Peak hyperalgesia, as detected in the somatosensory-evoked potential and skin-twitch, increased by R70% after remifentanil and by R43% after sufentanil. This reflected a significant (P<0.005) increase in propagation of nociceptive afferents as late as 30 min after naloxone reversal. Such potentiation was not observed in the etorphine group, as peak somatosensory-evoked potential deflection and skin-twitch remained below S80% when compared with control. CONCLUSION: The pure mu-agonists sufentanil or remifentanil seem to induce a 'bimodal' inhibitory followed by an excitatory effect. The latter is unmasked by naloxone in the postadministration period. In contrast, this is not seen with etorphine, a close congener of buprenorphine. The proposed mode of action of such hyperexcitatory effects may involve second-messenger-mediated G-protein activation, originally proposed by others. Ligands of the oripavine series may present an alternative for prevention of opioid-induced hyperalgesia in patients.

Interaction between sufentanil and U-50488H with respect to antinociception and respiratory depression in rats.

BACKGROUND: Opiate receptors have been argued to differentially regulate analgesia and respiratory depression. In order to validate possible interactions between the opiate mu- and kappa-receptors, interactions between sufentanil and U-50488H were studied in rats. METHODS: Rats equipped with an arterial catheter were tested in the tail flick latency (TFL) test after intravenous treatment with sulentanil (a mu-agonist), U-50488H (a kappa-agonist) or fixed ratio combinations of both drugs. Simultaneously, respiratory changes were monitored by blood gas analysis. RESULTS: The ED50s of sufentanil for a TFL > 6.0 and > or = 10.0 s were 0.0002 and 0.00059 mg/kg. For U-50488H the corresponding values were 1.53 and 8.11 mg/kg. Using a fixed dose ratio of 1/10,000, an additivity was demonstrated between sufentanil and U-50488H in terms of antinociception. With regard to respiratory parameters, PaCO2 significantly increased after all doses of sufentanil early after treatment. At the higher doses tested, there was also a decrease in PaO2 and O2 saturation. For U-50488H only the highest doses resulted in an early and small shift in PaCO2. The combination of sufentanil/U-50488H resulted in only a small increase in PaCO2 at the highest dose regimen tested. CONCLUSION: The results presented here demonstrate that drug mixtures of sufentanil and U-50488H can be additive with respect to antinociception with additionally less risk for respiratory side-effects, as compared with sufentanil alone. Therefore, a combination of mu- and kappa-opiate-receptor agonists might be more beneficial than each agent alone.

Effect of chronic administration of dihydropyridine Ca2+ channel ligands on sufentanil-induced tolerance to mu- and kappa-opioid agonists in the guinea pig ileum myenteric plexus.

The present investigation was aimed at elucidating if the entry of Ca2+ plays a role in the development of tolerance to mu- and kappa-opioid agonists in the guinea pig ileum myenteric plexus. For this purpose, the influence of the L-type Ca2+ channel modulators nimodipine (Ca2+ blocker) and Bay K 8644 (Ca2+ activator) on the expression of tolerance to the inhibitory effects of mu- and kappa-opioid agonists in the ileum of guinea pigs rendered tolerant to sufentanil was investigated. Chronic perfusion of guinea pigs with nimodipine (2 micrograms/microliter/h for 7 days) or Bay K 8644 (0.5 microgram/microliter/h for 7 days) did not cause any modification of the height of contractions induced by electrical stimulation of the myenteric plexus-longitudinal muscle (MPLM) strip from naive animals. Tolerance to sufentanil (a selective mu-agonist) was induced by s.c. implantation of osmotic minipumps for 7 days, which deliver at 2 micrograms/microliter/h. Control groups received saline. Tolerance to sufentanil as well as to U-50,488H (selective kappa-agonist) was observed following chronic treatment with sufentanil and was revealed as a rightward shift of the concentration-response curves. Chronic perfusion of guinea pigs with the Ca2+ antagonist nimodipine concurrently with chronic sufentanil, markedly blocked the expression of tolerance to sufentanil, as well as the cross-tolerance between sufentanil and U-50,488H. On the contrary, when guinea pigs were perfused with the Ca2+ agonist Bay K 8644 concurrently with sufentanil, it enhanced the magnitude of tolerance to both sufentanil and U-50,488H. These results suggest that, in guinea pig ileum, chronic exposure to opioids may involve the activation of L-type Ca2+ channel, which would indicate that intracellular Ca2+ may be one of the final pathways through which myenteric neurons adapt to the chronic opioid exposure.