New Insights in the Occurrence of Venous Thromboembolism in Critically Ill Patients with COVID-19-A Large Postmortem and Clinical Analysis.

Critically ill COVID-19 patients are at high risk for venous thromboembolism (VTE), namely deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and death. The optimal anticoagulation strategy in critically ill patients with COVID-19 remains unknown. This study investigated the ante mortem incidence as well as postmortem prevalence of VTE, the factors predictive of VTE, and the impact of changed anticoagulation practice on patient survival. We conducted a consecutive retrospective analysis of postmortem COVID-19 (n = 64) and non-COVID-19 (n = 67) patients, as well as ante mortem COVID-19 (n = 170) patients admitted to the University Medical Center Hamburg-Eppendorf (Hamburg, Germany). Baseline patient characteristics, parameters related to the intensive care unit (ICU) stay, and the clinical and autoptic presence of VTE were evaluated and statistically compared between groups. The occurrence of VTE in critically ill COVID-19 patients is confirmed in both ante mortem (17%) and postmortem (38%) cohorts. Accordingly, comparing the postmortem prevalence of VTE between age- and sex-matched COVID-19 (43%) and non-COVID-19 (0%) cohorts, we found the statistically significant increased prevalence of VTE in critically ill COVID-19 cohorts (p = 0.001). A change in anticoagulation practice was associated with the statistically significant prolongation of survival time (HR: 2.55, [95% CI 1.41-4.61], p = 0.01) and a reduction in VTE occurrence (54% vs. 25%; p = 0.02). In summary, in the autopsy as well as clinical cohort of critically ill patients with COVID-19, we found that VTE was a frequent finding. A change in anticoagulation practice was associated with a statistically significantly prolonged survival time.

Propofol sedation is reduced by delta9-tetrahydrocannabinol in mice.

BACKGROUND: Delta9-tetrahydrocannabinol (Delta9-THC) induces analgesic effects and alterations of alertness. It has been reported that propofol increases endocannabinoid levels in the brain, but the effects of Delta9-THC on propofol sedation remain unclear. Our aim was to characterize the interaction between Delta9-THC and propofol in terms of sedation and analgesia. METHODS: Sedation was monitored by a rota-rod and analgesia by tail-flick latencies. Twenty mice received intraperitoneal injections of 50 mg/kg Delta9-THC with 50, 75 and 100 mg/kg propofol after baseline values were established for each drug. Control experiments were performed with Delta9-THC and thiopental or Intralipid. RESULTS: Injection of 50 mg/kg propofol caused a rapid onset of sedation with a minimum of 24 s on the rota-rod. Fifty mg/kg Delta9-THC alone had no sedative effects. Administration of Delta9-THC significantly reduced the sedative effect of propofol to at least 60 s on the rota-rod (P < 0.001). After increasing the propofol dose to 100 mg/kg in the presence of Delta9-THC, sedation was re-established with 27 s on the rota-rod. Thiopental sedation was significantly reduced (P < 0.01) in the presence of Delta9-THC. CONCLUSION: The results indicate a dose-dependent antagonistic interaction between Delta9-THC and propofol, and also between Delta9-THC and thiopental.

Additive interaction of the cannabinoid receptor I agonist arachidonyl-2-chloroethylamide with etomidate in a sedation model in mice.

BACKGROUND: Both propofol and volatile anesthetics have been reported to interact with the endocannabinoid system. The purpose of this study was to evaluate the effect of selective agonists for cannabinoid receptor types 1 and 2 on etomidate-induced sedation. METHODS: A controlled, blinded, experimental study was performed in 20 mice that received intraperitoneal injections of etomidate, the cannabinoid1 receptor agonist arachidonyl-2-chloroethylamide (ACEA), the cannabinoid2 receptor agonist JWH 133 alone, and both ACEA and JWH 133 combined with etomidate. The cannabinoid1 receptor antagonist AM 251 and the cannabinoid2 receptor antagonist AM 630 were administered 10 min before the delivery of ACEA and JWH 133, respectively. Each drug combination was applied to 6-8 mice of these 20 study animals. Sedation was monitored by a Rota-Rod (Ugo Basile, Comerio, Italy). Isobolographic analysis was used for evaluation of pharmacologic interaction. RESULTS: Single drug administration of etomidate and ACEA produced dose- and time-dependent decreased time on the Rota-Rod (P < 0.05). No sedative effect was seen after JWH 133. Etomidate-induced sedation was significantly increased and prolonged with ACEA (P < 0.05), but not with JWH 133. Isobolographic analysis revealed an additive interaction between ACEA and etomidate that was antagonized by the cannabinoid1 receptor antagonist AM 251. The cannabinoid1 receptor antagonist had no effect on etomidate alone. CONCLUSIONS: Etomidate-induced sedation was increased and prolonged by activation of the cannabinoid1 receptor, but not of the cannabinoid2 receptor, in mice. However, this interaction was only additive.

Meperidine, remifentanil and tramadol but not sufentanil interact with alpha(2)-adrenoceptors in alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptor knock out mice brain.

alpha(2)-adrenoceptor agonists like clonidine or dexmedetomidine increase the sedative and analgesic actions of opioids. Furthermore opioids like meperidine show potent anti-shivering effects like alpha(2)-adrenoceptor agonists. The underlying molecular mechanisms of these effects are still poorly defined. The authors therefore studied the ability of four different opioids (meperidine, remifentanil, sufentanil and tramadol) to interact with different alpha(2)-adrenoceptor subtypes in mice lacking individual alpha(2A)-, alpha(2B)- or alpha(2C)-adrenoceptors (alpha(2)-adrenoceptor knock out (alpha(2)-AR KO) mice)). The interaction of opioids with alpha(2)-adrenoceptors was investigated by quantitative receptor autoradiography in brain slices of alpha(2A)-, alpha(2B)- or alpha(2C)-adrenoceptor deficient mice. Displacement of the radiolabelled alpha(2)-adrenoceptor agonist [(125)I]-paraiodoclonidine ([(125)I]-PIC) from alpha(2)-adrenoceptors in different brain regions by increasing opioid concentrations was measured, and binding affinity of the analysed opioids to alpha(2)-adrenoceptor subtypes in different brain regions was quantified. Meperidine, remifentanil and tramadol but not sufentanil provoked dose dependent displacement of specifically bound [(125)I]-PIC from all alpha(2)-adrenoceptor subtypes in cortex, cerebellum, medulla oblongata, thalamus, hippocampus and pons. Required concentrations of meperidine and remifentanil for [(125)I]-PIC displacement from alpha(2B)- and alpha(2C)-adrenoceptors were lower than from alpha(2A)-adrenoceptors, indicating higher binding affinity for alpha(2B)- and alpha(2C)-adrenoceptors. In contrast, [(125)I]-PIC displacement by tramadol indicated higher binding affinity to alpha(2A)-adrenoceptors than to alpha(2B)- and alpha(2C)-adrenoceptors. Our results indicate that meperidine, remifentanil and tramadol interact with alpha(2)-adrenoceptors in mouse brain showing different affinity for alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptors. In contrast, the micro-agonist sufentanil did not show any alpha(2)-adrenoceptor interaction. These effects may have an impact on the pharmacologic actions of these opioids.

The anesthetic effects of etomidate: species-specific interaction with alpha 2-adrenoceptors.

BACKGROUND: The IV anesthetic, etomidate, has structural and clinical similarities to specific alpha2-adrenoceptor agonists such as dexmedetomidine. We investigated whether the sedative effects of etomidate may be mediated by alpha2-adrenoceptors. METHODS: The anesthetic potency of etomidate (1-20 microM) was determined in Xenopus laevis tadpoles in the absence and presence of the specific alpha2-adrenoceptor antagonist atipamezole (10 microM). Anesthesia was defined as loss of righting reflex. Nonlinear logistic regression curves were fitted to the data and half-maximal effective concentrations and the slopes of the curves were calculated. Additionally, sedative/ hypnotic effects of etomidate (8 mg/kg IP) were studied by rotarod test in wild-type (WT) mice and mice carrying targeted deletions of the alpha2A-adrenoceptor gene (alpha2A-KO). Data are presented as mean +/- sem. RESULTS: The fraction of anesthetized tadpoles increased with increasing concentrations of etomidate. Atipamezole significantly increased the half-maximal effective concentration of etomidate (4.5 +/- 0.2 microM; slope: 2.6 +/- 0.3) to 8.4 +/- 0.4 microM (slope: 2.3 +/- 0.3). Etomidate resulted in time-dependent sedative effects in all mice, as assessed by rotarod performance. In WT mice, the sedative effects of etomidate were not decreased by atipamezole (2 mg/kg). Consistently, etomidate-induced sedation was not reduced in alpha2A-KO animals compared with WT mice. CONCLUSIONS: The sedative effects of etomidate exhibit a species-specific interaction with alpha2-adrenoceptors. Although the decrease in potency of etomidate by atipamezole may be caused by an interaction with alpha2-adrenoceptors in X. laevis tadpoles, results in mice indicate that the hypnotic effect of etomidate does not require alpha2-adrenoceptors.

Cerebral metabolism assessed with microdialysis in uncontrolled hemorrhagic shock after penetrating liver trauma.

In a porcine model of uncontrolled hemorrhagic shock, we evaluated the effects of fluid resuscitation versus arginine vasopressin (AVP) combined with hypertonic-hyperoncotic hydroxyethyl starch solution (HHS) on cerebral perfusion pressure (CPP) and on cerebral metabolism using intracerebral microdialysis. Sixteen anesthetized pigs were subjected to uncontrolled liver bleeding until hemodynamic decompensation, followed by resuscitation using either fluid (n = 8) or AVP/HHS (n = 8). Thirty minutes after drug administration, bleeding was controlled by manual compression, and colloid and crystalloid solutions were administered in both groups. All surviving animals were observed for one hour. After hemodynamic decompensation, fluid resuscitation resulted in a smaller increase of CPP than did AVP/HHS (mean +/- sem; 24 +/- 5 vs 45 +/- 7 mm Hg; P < 0.01). Mean (+/- sem) cerebral venous partial pressure of oxygen was significantly decreased (P < 0.01) 5 min after fluid compared with 5 min after AVP/HHS administration (36 +/- 3 vs 64 +/- 4 torr). Cerebral metabolism was comparable in both groups. In conclusion, AVP/HHS proved to be superior to fluid in the initial phase of therapy with respect to CPP and cerebral oxygenation, but was comparable to fluid regarding cerebral metabolism and secondary cell damage in surviving animals.