In a comparison among groups, the mean ANA at t3 in group 1 (50.43 ± 18.35 pmol/mL) also differed significantly from that in group 2 (15.20 ± 2.00 pmol/mL; P < 0.05;Fig. 3). 2-AG at t2 was 130.12 ± 33.22 pmol/mL in group 1 and 42.58 ± 13.59 pmol/mL in group 2 (P = 0.011;Fig. 4). In addition, 2-AG at t3 was 263.57 ± 65.97 pmol/mL and 53.98 ± 12.39 pmol/mL in groups 1 and 2, respectively (P = 0.001); 2-AG at t4 was 179.05 ± 57.39 pmol/mL and 67.67 ± 19.70 pmol/mL, respectively (P < 0.05); and 2-AG at t5 was 231.30 ± 66.45 pmol/mL and 93.10 ± 30.72 pmol/mL, respectively (P < 0.05;Fig. 4).
The purpose of the present study was to investigate potential effects of endogenous cannabinoids in patients undergoing cemented hip arthroplasty. BCIS is characterized by hypotension, hypoxemia, cardiac arrhythmias, cardiac arrest, or a combination of these. Numerous hypotheses have been proposed to explain the pathophysiologic basis of BCIS. Powell et al. (14) first reported BCIS in 1970, 10 years after Charnley introduced the use of bone cement for hip arthroplasty surgery (15). Reaction to heat, direct toxic or vasodilating effects of the monomer, anaphylaxis, embolization of fat, air, or polymer, and apposition thrombi generated by impaction have all been implicated in the development of this syndrome (2,3,16). A number of investigators have stressed the important role of changes in intramedullary pressure in the genesis of intraoperative embolic phenomena (2,17,18). Conventional techniques of implantation with cement (19,20) provide a maximum bone-acrylic interlock by means of a combination of a lower viscosity of cement and pressurization. However, these techniques generate extreme intramedullary pressures within the femoral canal, which often exceed the pressures in the general venous circulation and cause disruption of the thin-walled medullary vessels. This allows intravasation and flow of bone fat, bone marrow, bone debris, and polymethylmethacrylate (PMMA) though the natural drainage system of the diaphysis, located along the linea aspera, and through the metaphyseal veins (21–23). As a new approach to avoid increase in intramedullary pressure and intravasation of fat and bone marrow, the venting hole and bone-vacuum technique was developed (3). A computer-assisted implantation technique is also under examination (24).
However, during percutaneous vertebroplasty, which involves consolidation of a vertebral body with PMMA and is used for the treatment of benign and malignant lesions of the spine, transient hypotension is induced by injection of 3–4 mL PMMA. No data exist concerning increase in intramedullary pressure and the potential release of bone marrow emboli during percutaneous vertebroplasty (25). Furthermore, methylmethacrylate monomer produced hypotension by direct relaxation of vascular smooth muscle of the rabbit in vitro (26). Although we agree that embolism is an important pathogenic factor of BCIS, we believe that the fall in blood pressure observed in this study is not attributable to any single factor, but is caused by combined effects of multiple factors.
PMB is a cationic antibiotic that also stoichiometrically neutralizes the lipid A moiety of endotoxin (30,31). Very recently, we have shown that ANA and 2-AG in saline/ethanol solution and in serum were efficiently absorbed in a PMB-immobilized beads column and eluted with ethanol (12,13). This is a greatly simplified and highly reproducible method for simultaneous measurement of ANA and 2-AG. Macrophages and platelets generate endogenous cannabinoids (8), and our findings of increases in ANA and 2-AG levels up to 50 pmol/mL and 263 pmol/mL, respectively, indicated that these cannabinoids contributed to severe hypotension after cementing. Endogenous cannabinoids are potent vasodilators and elicit hypotension and bradycardia (7,8). Endogenous cannabinoids released from platelets and macrophages during bone cement implantation might act as activators of vascular CB1 receptors.
Effects of anandamide on systemic hemodynamics have been investigated in anesthetized rats (32), and it has been found that a 4 mg/kg injection of anandamide produces a profound, dose-dependent decrease in arterial pressure within 2 min. The effect of anandamide is most pronounced within the first 1–3 min after intravenous administration, and arterial pressure returns to baseline values within 10–15 min (32). In our study, 16 patients in group 1 exhibited a sudden decrease in systolic blood pressure of more than 20% at t2 associated with an increase in ANA and 2-AG levels. Blood pressure returned to baseline within 5 min in all of the patients with hypotension.
In our study, in group 1, ANA and 2-AG levels increased by t2, with a peak at t3, and no tendency to decrease was demonstrated at t5. However, the lowest mean arterial blood pressure was observed at t2 (Fig. 1). The properties of cannabinoids, the biologically active constituents of the marijuana plant, are well recognized (5). Tolerance may be an important contributor to these findings (5). Tolerance develops rapidly during continual administration of cannabinoids. Receptor desensitization or uncoupling has been consistently implicated as one of the molecular events underlying the onset of tolerance in many systems (33,34). Jin et al., in an experimental study of Xenopus oocytes, reported that desensitization of cannabinoid CB1 receptors was observed after prolonged (8-min) exposure to CB1 agonist (35). Prolonged exposure to cannabinoids with cement may result in tolerance and desensitization of cannabinoid receptors, and may be related to the recovery of blood pressure observed from t3.
In addition, in our study, no measurements of CB1 receptors density were performed. It is possible that up- or down-regulation of endothelial CB1 receptors occurred and this is an area for future study.
In conclusion, we have demonstrated for the first time significant increases in levels of ANA and 2AG, members of a newly identified class of neurohumoral vascular mediators, in the course of cemented hip cement arthroplasty. This observation strongly suggests that ANA and 2AG are mediators of the hemodynamic variables associated with bone cement implantation shock. Therefore, targeting of the biosynthesis of, specific receptors for and biological degradation systems of endocannabinoids might be useful as new strategies for the prevention and clinical management of BCIS.
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