Alpha2 sympathoadrenergic drugs in combination with benzodiazepines and opioids are frequently used in anaesthesia and pain therapy. The aim of our study was to assess the safety and effects of a new alpha-2 sympathoadrenergic drug dexmedetomidine combined with midazolam and fentanyl. Material and methods: A prospective randomised double blinded clinical study in patients scheduled for laparoscopic cholecystectomy was performed. After ethic committee approval and patients consent, a premedication with atropine 0.5 mg and 5 other combinations: dexmedetomidine 1 µg.kg-1 + midazolam 50 µg.kg-1 (group DexMid), dexmedetomidine 1 µg.kg-1 + midazolam 50 µg.kg-1 + fentanyl 1.0 µg.kg-1 (group DexMidFN), midazolam 50 µg.kg-1 + fentanyl 1.0 µg.kg-1 (group PlaMidFN), dexmedetomidine 1 µg.kg-1 + midazolam 25 µg.kg-1 + fentanyl 1.0 µg.kg-1 (group DexMid2F) and midazolam 25 µg.kg-1 + fentanyl 1.0 µg.kg-1 (group Mid2FNT) was administered to a deltoid muscle 15 min before anaesthesia. Induction and maintenance of anaesthesia were standard. Parameters of vital functions, side effects and time to the request for analgesics after surgery were examined. The groups DexMidFN and PlaMidFN were randomised first, but after several cases of serious respiratory depression occurred, the study was deblinded after 15 patients and results were processed. After discovery that the depression was in group DexMidFN only, other 3 groups were added. Statistical analysis: The basic statistical characteristics, i.e. means and standard deviations were calculated for continuous variables. Group comparison was assessed by Kruskal-Wallis test with multiple comparisons method. Relative frequencies in different groups were tested using chi-square test. Adjusted standardized deviates between observed and expected values for each cell were approximated by Z-scores to identify large differences. P – value less than 0.05 was considered significant. Statistical analysis was performed using BMDP (version PC90) statistical software. Results: There were 7 patients in group PlaMidFN, 8 in DexMidFN, 15 in DexMid2F, 9 in Mid2FNT and 7 in DexMid. The main differences between PlaMidFN vs. DexMidFN were in perioperative fentanyl consumption (SD): 207 (110) µg vs. 25 (40) µg, p = 0.0014, time to the first request for analgesic (SD): 0.21(0.39) h. vs. 1.25 (0.88) h., p= 0.0094, occurance of respiratory rate < 6/min after administration 0% vs. 75%, p = 0.0070 and SpO2 ?90% in 0% vs. 87.5% of patients, p = 0.0014. A trend to lower incidence of hypertension during capnoperitoneum was observed in DexMidFN, 42.9% vs. 0%, p = 0.0769. In comparison of all groups with dexmedetomidine (DexMidFN, DexMid2F, DexMid) vs. control groups without dexmedetomidine (PlaMidFN, Mid2FN), there was suppressed reaction to capnoperitoneum, 16.7% vs. 58.3%, p<0.05, less fentanyl consumption (SD): 48.3 (56.8) µg vs. 162.5 (97.32) µg, p<0.001 and more frequent respiratory depression: 40.0% vs. 0%, p<0.01. Dexmedetomidine potentiated sedation level (p<0.001), but without practical importance. Conclusions: Dexmedetomidine potentiates the sedative effect of midazolam and significantly potentiates the effect of midazolam and fentanyl on respiratory depression. Dexmedetomidine in combination with fentanyl and midazolam suppresses adverse hemodynamic effects of capnoperitoneum, decreases perioperative fentanyl consumption and produces mild to moderate sedation, but can result in serious respiratory depression. The patient after administration of the combination of dexmedetomidine and midazolam with fentanyl needs close observation because of risk of vital functions disturbances and this combination cannot be used in standard praxis. Because of this reason, we have abandoned further research of this combination.

Klinika anesteziologie a resuscitace 3 LF UK a FNKV

Pracoviště experimentální medicíny IKEM

UK 3 lékařská fakulta a Fakultní nemocnice Královské Vinohrady Klinika anesteziologie a resuscitace Praha

Ústav farmakologie 3 LF UK

Dexmedetomidine in combination with fentanyl and midazolam can induce serious respiratory depression

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