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• W2027111342 abstract "We report our experience with dexmedetomidine for acute sickle cell pain crisis. Our observations are based on a convenience sample of four patients, in whom we were attempting sympathetic nervous system modulation to achieve analgesia. In the first two patients, we used phentolamine in the hope that microvascular dilatation and peripheral sympathetic nervous system interruption might prove efficacious. This was unsuccessful. We tried dexmedetomidine in two subsequent cases, with profound results. Although most patients report less than one pain crisis per year, 5% of HbSS (sickle cell hemoglobin) patients account for 30% of all episodes.1Platt O.S. Thorington B.D. Brambilla D.J. et al.Pain in sickle cell disease. Rates and risk factors.N Engl J Med. 1991; 325: 11-16Crossref PubMed Scopus (1245) Google Scholar In our emergency department, approximately 24% of patients presenting for pain because of vaso-occlusive crisis (VOC) require hospital admission for pain control. No specific form of therapy has proven consistently effective for VOC. Sickle cell disease has at least two phenotypes, and disease severity is determined by a complex interplay between genetic and environmental factors.2Steinberg M.H. Predicting clinical severity in sickle cell anaemia.Br J Haematol. 2005; 129: 465-481Crossref PubMed Scopus (241) Google Scholar Leading manifestations of the Type I phenotype are painful crises, dactilytis, acute chest syndrome, and stroke, whereas Type II is mainly characterized by leg ulcers.3Weatherall M.W. Higgs D.R. Weiss H. Weatherall D.J. Serjeant G.R. Phenotype/genotype relationships in sickle cell disease: a pilot twin study.Clin Lab Haematol. 2005; 27: 384-390Crossref PubMed Scopus (39) Google Scholar VOC is initiated and sustained by interactions between sickle cells, vascular endothelial cells, and proinflammatory molecules. Chronic pain occurs because of leg ulcers and destruction of bones, joints, and internal organs as a result of recurrent crises. Bone marrow necrosis, osteonecrosis, magnetic resonance imaging (MRI) evidence of marrow infarction, and abnormal bone marrow blood flow have been demonstrated in patients with VOC and bone pain.4Yale S.H. Nagib N. Guthrie T. Approach to the vaso-occlusive crisis in adults with sickle cell disease.Am Fam Physician. 2000; 61: 1349-1354PubMed Google Scholar The course of the acute pain crisis occurs in four phases. The initial phase is characterized by increasingly severe pain, decrease in red blood cell (RBC) deformability, and an increase in the number of dense RBCs. Deoxygenation promotes HbS molecule polymerization, which leads to formation of a heterogeneous population of dense, sickle-shaped cells. RBC shrinkage is brought about by activation of a Ca2+-sensitive K+ channel, causing loss of intracellular K+ with water efflux.5Ballas S.K. The sickle cell painful crisis in adults: phases and objective signs.Hemoglobin. 1995; 19: 323-333Crossref PubMed Scopus (57) Google Scholar Increased levels of free hemoglobin scavenge nitric oxide, leading to decreased cyclic guanosine monophosphate (cGMP) formation in vascular smooth muscle and a vasoconstrictive phenotype.6Rother R.P. Bell L. Hillmen P. Gladwin M.T. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease.JAMA. 2005; 293: 1653-1662Crossref PubMed Scopus (1142) Google Scholar Serum nitric oxide levels are decreased and may inversely relate to the severity of pain in sickle cell patients.7Lopez B.L. Davis-Moon L. Ballas S.K. Ma X.L. Sequential nitric oxide measurements during the emergency department treatment of acute vasoocclusive sickle cell crisis.Am J Hematol. 2000; 64: 15-19Crossref PubMed Scopus (49) Google Scholar Despite the growing evidence for the role of the inflammatory cascade in VOC, traditional anti-inflammatory agents have shown variable efficacy and their use is often limited by potential toxicity and side effect profiles. We explored the role of sympatholytic drugs. Phentolamine, an α1-adrenoreceptor antagonist, blocks alpha receptors at peripheral nerves and blood vessels and it has been used both as a blood pressure lowering agent and to relieve sympathetically mediated pain, typically involving the extremity. Alpha receptor blockers also have been reported to improve flow by decreasing blood viscosity and increasing deformability of RBCs in essential hypertension.8Shir Y. Cameron L.B. Raja S.N. Bourke D.L. The safety of intravenous phentolamine administration in patients with neuropathic pain.Anesth Analg. 1993; 76: 1008-1011Crossref PubMed Scopus (31) Google Scholar Dexmedetomidine (Precedex, Abbott Laboratories, Abbott Park, IL) is a parenterally administered imidazoline derivative, which activates all α2-adrenoreceptor subtypes. Dexmedetomidine binds to α2 receptors eight times more avidly than clonidine and is shorter acting. Slow bolus loading over 20 minutes results in minimally decreased heart rate and blood pressure. Continuous infusion maintains unique sedation (patients appear to be asleep, but are readily roused), analgesic sparing effect, and minimal depression of respiratory drive. Its action at the spinal cord α2 receptor diminishes sympathetic tone and serves as an analgesic at the dorsal horn.9Coursin D.B. Coursin D.B. Maccioli G.A. Dexmedetomidine.Curr Opin Crit Care. 2001; 7: 221-226Crossref PubMed Scopus (222) Google Scholar Although this agent has shown sedative and analgesic properties in the perioperative and intensive care setting, the use of α2 agonists in the treatment of VOC has not been reported. Intravenous phentolamine mesylate (Regitine, Benvenue Laboratories, Bedford, OH; 25 mg in 250 ml 0.9% saline infused over 45 minutes) was given to two patients (Table 1, Patients 1 and 2) with typical acute VOC. Both patients also received generous hydration and supplemental oxygen. No effect was observed from the phentolamine and both patients required moderate amounts of parenteral opioids for adequate analgesia.Table 1Patient CharacteristicsPatient 1Patient 2Patient 3Patient 4History and chief complaint on admission Age (yr)21272726 GenderMaleMaleFemaleFemale RaceAfrican AmericanAfrican AmericanAfrican AmericanAfrican American Medications•Morphine sulfate sustained release, 60 mg, BID•Hydrocodone 5 mg with acetaminophen on, as needed•Hyroxyurea 1000 mg/day•Morphine sulfate sustained release, 60 mg, BID•Hydrocodone 5 mg with acetaminophen on, as needed•Oxycodone extended release 40 mg BID•Morphine sulfate sustained release 30–60 mg BID Previous VOC-related admission to EDSeveralYesYesYes Pain level (verbal scale 1–10)10/109/1010/108/10Vital signs on admission Body weight (kg)55686065 Heart rate (beat/min)1209665114 Blood pressure (mmHg)164/71108/78125/68 Oral temperature (°C)36.435.236.936.8 Respiratory rate (1/min)18181816 O2 saturation on room air (%)96989798Lab results on admission WBC (1/μL)17,50016,80018,70019,200 DifferentialNormalNormalNormalNormal Platelet count (1/μL)435,00398,000348,000360,000 Hemoglobin (g/dL)8.57.78.07.6 Hematocrit26%24.623.922.1 SicklingYesYesYesYesPhysical exam ScleraIctericNormalNormalNormal CardiopulmonaryNormalNormalChest painNormal AbdomenNormalNormalTenderNormal MusculoskeletalTender quadriceps and calf, no erythema, swelling, or warmthTender back, quadriceps and calf, no erythema, swelling, or warmthTender left calf, no erythema, swelling, or warmthLumbar tenderness, no erythema, swelling, or warmthBID = twice a day Open table in a new tab BID = twice a day In two subsequent cases, dexmedetomidine was administered as an intravenous loading dose of 1 mcg/kg over 2.5 minutes, followed by an infusion of 0.5 mcg/kg/hr, titrated based on pain or side effects. The infusion was continued with gradual dose reduction of 0.1 mcg/kg/hr every 30–45 minutes and discontinued after a total of four hours. Both patients experienced profound analgesia, required no opioid analgesics, and were able to be discharged with no pain. Orthostatic vital signs were normal before discharge. Dexmedetomidine is an adrenergic agonist with 1600-fold greater affinity for the α2 than the α1 receptor. Postreceptor signaling through Gαi/o proteins decrease adenylyl cyclase activity, which leads to decreased cellular cyclic adenosine monophosphate (cAMP) levels at the spinal cord dorsal horn.10Fairbanks C.A. Stone L.S. Kitto K.F. et al.Alpha(2C)-Adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy.J Pharmacol Exp Ther. 2002; 300: 282-290Crossref PubMed Scopus (165) Google Scholar This central spinal cord action is in contrast to the peripheral sympathetic nervous system modulating effect of phentolamine. The role of the α2-adrenoreceptor includes dorsal horn presynaptic inhibition of neurotransmitter release, diminished spinal cord sympathetic outflow, and opioid-adrenergic synergy at the dorsal horn. Activation of spinal cord α2-adrenoreceptors potentiate endogenous pain inhibitory spinal pathways, which explains the analgesic effect of epidural and intrathecal α2-adrenoreceptor agonists.10Fairbanks C.A. Stone L.S. Kitto K.F. et al.Alpha(2C)-Adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy.J Pharmacol Exp Ther. 2002; 300: 282-290Crossref PubMed Scopus (165) Google Scholar Clinically, dexmedetomidine produces sedative, analgesic, and mild amnestic effects, with a dose-dependent reduction in heart rate and systemic vascular resistance. A high degree of patient arousability is maintained.9Coursin D.B. Coursin D.B. Maccioli G.A. Dexmedetomidine.Curr Opin Crit Care. 2001; 7: 221-226Crossref PubMed Scopus (222) Google Scholar In contrast to systemic opioids, α2 agonists do not produce clinically significant respiratory depression, muscle rigidity, or gastrointestinal or pruritic effects. Dexmedetomidine does not cause long-lasting tolerance or cross-tolerance with morphine and may remain an effective analgesic when tolerance has developed to opioids.9Coursin D.B. Coursin D.B. Maccioli G.A. Dexmedetomidine.Curr Opin Crit Care. 2001; 7: 221-226Crossref PubMed Scopus (222) Google Scholar In summary, we observed a profound analgesic effect in two patients with acute sickle cell pain crisis from the α2 agonist dexmedetomidine, but no effect from α1 blocking agent phentolamine. A further study to validate these observations is in progress at this institution." @default.
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