Lakshmi N. Kurnutala
Suren Soghomonyan
Sergio D. Bergese- 1Department of Anesthesiology, Henry Ford Hospital, Wayne State University, Detroit, MI, USA
- 2Department of Anesthesiology, Wexner Medical Center, Ohio State University, Columbus, OH, USA
- 3Department of Neurological Surgery, Wexner Medical Center, Ohio State University, Columbus, OH, USA
Arterial hypertension (AH) is one of the most common pathological conditions affecting the general population which contributes to pathogenesis of various diseases and worsens the treatment outcome (James et al., 2014). It increases the perioperative morbidity and mortality, frequently result in cancelation of surgical procedures and increases treatment-associated costs (Handler, 2006). Perioperative hypertension may occur in patients with pre-existing arterial hypertension or manifest as a de novo phenomenon (Vuylsteke et al., 2000; Varon and Marik, 2008).
Induction of general anesthesia is related with significant stress and sympathetic over-activation. The systolic blood pressure (SBP) in normotensive patients may increase by up to 20–30 mm Hg, while hypertensive patients may have an exaggerated reaction—SBP in these patients may increase up to 90 mm Hg (Ahuja and Charap, 2010). On the other hand, anesthesia-induced sympathetic suppression with diminished baroreceptor reflex takes place during the maintenance phase which frequently causes sustained arterial hypotension. Postoperatively, these patients present with labile BP, frequent and rebound hypertension, and have an increased risk of postoperative complications (Goldman and Caldera, 1979; Wolfsthal, 1993).
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7 and JNC-8) classifications and guidelines are currently applicable to perioperative patients as well (James et al., 2014; Chobanian et al., 2003).
According to JNC-7 guidelines for evaluation and treatment of hypertensive emergencies, an immediate intervention is required in cases of hypertensive emergencies to reduce the SBP by 10–15% (no more than 25%) within the first hour. Reduction of the absolute BP to 160/110 mmHg should be done gradually over the following 2–6 h (Aggarwal and Khan, 2006; Flanigan and Vitberg, 2006; Pollack and Varon, 2008; Varon, 2008; De Gaudio et al., 2009; Hays and Wilkerson, 2010; Kuppasani and Reddi, 2010; Smithburger et al., 2010; Polly et al., 2011). Only in patients with aortic dissection, the SBP should be reduced to less than 120 mmHg within 20 min. In hypertensive emergencies associated with ischemic stroke, BP must be decreased to less than 180/110 before thrombolytic therapy may be administered (Pollack and Varon, 2008; Varon, 2008; De Gaudio et al., 2009; Hays and Wilkerson, 2010; Polly et al., 2011). Abrupt BP reduction should be avoided as it can result in critical blood flow reduction and ischemic end organ damage (Varon, 2008; De Gaudio et al., 2009; Smithburger et al., 2010; Polly et al., 2011).
Since overshooting a target BP in hypertensive patients is associated with worse outcome, many treatment protocols require invasive arterial blood pressure monitoring during anesthesia in high risk cases (Pollack and Varon, 2008; Rhoney and Peacock, 2009).
Hypertensive emergencies should be treated aggressively, using quick-onset intravenous medications, whereas hypertensive urgencies do not always require such aggressive treatment. Longer acting oral medications (labetalol, clonidine, etc.) may be more appropriate in situations of hypertensive urgency. However, caution should be exercised when using anti-hypertensive agents in the acute setting. An overly aggressive treatment approach may lead to organ hypoperfusion (Rodriguez et al., 2010). Once the immediate threat of organ damage is diminished, BP should be gradually brought to baseline level within a period of 24–48 h (Peacock et al., 2009).
Characteristics of an ideal intravenous hypertensive agent are rapid onset and offset of action, low risk of hypotension, minimal drug interaction with other medications, lack of adverse reactions, wide therapeutic window, ease of titration, preservation of renal and hepatic functions, selectivity, low cost, possibility of easy transition to oral therapy, predictable response, and lack of effects on intracranial pressure (Levy, 1999; Oparil et al., 1999). Multiple intravenous medications are currently used to control the BP in the perioperative period, and all these medications have specific advantages and limitations (Kurnutala et al., 2013).
Selection of an optimal antihypertensive therapy for the perioperative period depends on the patient's individual characteristics and locally adopted guidelines (Pollack and Varon, 2008; Belsha, 2013).
Clevidipine butyrate is a Ca2+-channel antagonist that acts on the L-type Ca2+ channels regulating the influx of Ca2+ ions into the arteriolar smooth muscle cells during depolarization. It has recently raised significant interest among anesthesiologists and surgeons as a valuable agent to control AH during surgery because of its fast and selective action and ease of BP control. Clevidipine selectively dilates the arterioles and reduces peripheral resistance, thus increasing stroke volume and cardiac output. Like nicardipine and nifedipine, it belongs to the subclass of dihydropyridines—a group of drugs considered a first-line treatment for hypertensive emergencies because of strong vasodilating effects and low propensity to cause cardiac conduction and contractility abnormalities (Eisenberg et al., 2004; Nordlander et al., 2004; FDA/CDER, 2008; Bergese and Puente, 2010; The Medicines Company, 2011; Tulman et al., 2012).
Clevidipine butyrate was approved by FDA in 2008. Interestingly, it was the only intravenous antihypertensive drug approved during the past 10 years.
The pharmacologic characteristics of clevidipine are beneficial for its use during the perioperative period. The drug formulation represents a racemic mixture of equipotent S- and R-enantiomers (Noviawaty et al., 2008; Sorbera and Castanera, 2004). The preparation is a sterile lipid emulsion with pH of 6.0–8.0 ready for intravenous use (Sorbera and Castanera, 2004; Noviawaty et al., 2008). As with other lipid solutions (intralipid, propofol), strict asepsis must be maintained during administration to prevent bacterial contamination and growth. Clevidipine must be discarded 12 h after puncturing the stopper. The drug is metabolized by plasma and tissue esterases to inactive metabolites with a mean blood clearance rate of 0.121 lit. min−1 kg−1 (Ericsson et al., 1999a). Up to 99.7% of circulating clevidipine is bound to plasma proteins. The elimination rate does not depend on hepatic and renal clearance and it can be safely administered in patients with hepatic and renal pathology (Ericsson et al., 1999b).
During anesthesia, clevidipine is administered as a slow rate intravenous infusion. As with other lipid solutions, the drug is contraindicated in cases of allergy to soy and egg products and in patients with defective lipid metabolism. The drop in BP equaling 4–5% of the initial value takes place within 2–4 min after starting the infusion.
Clevidipine has many features of an ideal antihypertensive drug that can be used in emergency situations. These features include fast onset and offset of clinical effects, ease of titration, small volume of distribution and fast elimination independent on hepatic and renal clearance (Ericsson et al., 1999a,b; Prlesi and Cheng-Lai, 2009).
Clinical trials showed that the racemic formulation of clevidipine is superior to L or R enantiomers in controlling AH (Schwieler et al., 1999; Ericsson et al., 2000).
In patients undergone elective cardiac interventions, clevidipine was effective in controlling the mean BP and systemic vascular resistance in a dose-dependent manner. The drug did not cause any cardiovascular instability or metabolic changes (Kieler-Jensen et al., 2000; Ericsson et al., 2001; Bailey et al., 2002).
Two randomized double blind, placebo controlled trials performed in cardiosurgical patients (ESCAPE1 and ESCAPE2) showed that in 92.5–91.8% of patients the desired SBP values could be achieved within 4–7 min after starting the drug infusion (Levy et al., 2007; Singla et al., 2008). Aronson et al., compared clevidipine with other commonly used antihypertensive drugs in cardiac surgery (Aronson et al., 2008). In this study, the clevidipine group achieved superior BP control compared with other drugs and had a significantly lower 30-day mortality rate than sodium nitroprusside. Pollack et al. (2009) evaluated the efficacy and safety of prolonged infusion of clevidipine (up to 96 h) (Pollack et al., 2009). In 88.9% of patients, the target SBP could be achieved within half an hour after starting the infusion. In 1.6% of cases the SBP dropped below the target range.
The ACCELERATE trial evaluated the efficacy of clevidipine in management of severe AH associated with intracerebral hemorrhage (Graffagnino et al., 2013). Again, the clevidipine infusion helped to rapidly reduce the BP to the desired level (<160 mm Hg) within a few minutes.
Clevidipine can be effectively used during elective neurosurgical procedures, including neurovascular interventions, to control the BP during intraoperatively and in the postoperative period (Bekker et al., 2010; Varelas et al., 2014).
Another area of surgery, where clevidipine can be used with success is surgical resection of pheochromocytoma (Kline, 2010; Bettesworth et al., 2013).
More research is required to clarify the safety of clevidipine in pregnant and breastfeeding patients. In these patients, the drug should be used with caution and only when the benefits of such therapy will clearly outweigh the potential risks (The Medicines Company, 2011). Another area of research is pediatric population, even though several case reports suggest that clevidipine may be considered a safe option in pediatric patients (Tobias et al., 2009, 2011, 2013; Towe and Tobias, 2010; Tobias and Hoernschemeyer, 2011).
As a conclusion, Clevidipine butyrate is an easily controlled and effective drug that can be safely used in various surgical patients to control the BP. The drug has minimal side effects and can be titrated to reach the desired clinical effect. It can be safely used in patients with hepato-renal pathology. Further research is required to clarify clevidipine's efficacy, safety and limitations in pregnant and breastfeeding women and pediatric surgical patients.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
Aggarwal, M., and Khan, I. A. (2006). Hypertensive crisis: hypertensive emergencies and urgencies. Cardiol. Clin. 24, 135–146. doi: 10.1016/j.ccl.2005.09.002
Ahuja, K., and Charap, M. H. (2010). Management of perioperative hypertensive urgencies with parenteral medications. J. Hosp. Med. 5, E11–E16. doi: 10.1002/jhm.629
Aronson, S., Dyke, C. M., Stierer, K. A., Levy, J. H., Cheung, A. T., Lumb, P. D., et al. (2008). The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients. Anesth. Analg. 107, 1110–1121. doi: 10.1213/ane.0b013e31818240db
Bailey, J. M., Lu, W., Levy, J. H., Ramsay, J. G., Shore-Lesserson, L., Prielipp, R. C., et al. (2002). Clevidipine in adult cardiac surgical patients: a dose-finding study. Anesthesiology 96, 1086–1094. doi: 10.1097/00000542-200205000-00010
Bekker, A., Didehvar, S., Kim, S., Golfinos, J. G., Parker, E., Sapson, A., et al. (2010). Efficacy of clevidipine in controlling perioperative hypertension in neurosurgical patients: initial single-center experience. J. Neurosurg. Anesthesiol. 22, 330–335. doi: 10.1097/ANA.0b013e3181e3077b
Belsha, C. W. (2013). “Management of hypertensive emergencies,” in Pediatric Hypertension, Clinical Hypertension and Vascular Diseases: Pediatric Hypertension, eds J. T. Flynn, J. R. Ingelfinger, and R. J. Portman (New York, NY: Springer Science+Business Media), 557–571.
Bergese, S. D., and Puente, E. G. (2010). Clevidipine butyrate: a promising new drug for the management of acute hypertension. Expert Opin. Pharmacother. 11, 281–295. doi: 10.1517/14656560903499293
Bettesworth, J. G., Martin, D. P., and Tobias, J. D. (2013). Intraoperative use of clevidipine in a patient with von Hippel-Lindau disease with associated pheochromocytoma. J. Cardiothorac. Vasc. Anesth. 27, 749–51. doi: 10.1053/j.jvca.2011.12.005
FDA/CDER. (2008). New Molecular Entity (NME) Drug and New Biologic Approvals for Calendar Year 2008 FDA Public Health Advisory. Washington, DC: FDA/Center for Drug Evaluation and Research. Available online at: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/NMEDrugandNewBiologicApprovals/UCM081805.pdf (Accessed September 16, 2009).
Chobanian, A. V., Bakris, G. L., Black, H. R., Cushman, W. C., Green, L. A., Izzo, J. L. Jr., et al. (2003). Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 42, 1206–1252. doi: 10.1161/01.HYP.0000107251.49515.c2
De Gaudio, A. R., Chelazzi, C., Villa, G., and Cavaliere, F. (2009). Acute severe arterial hypertension: therapeutic options. Curr. Drug Targets 10, 788–798. doi: 10.2174/138945009788982450
Eisenberg, M. J., Brox, A., and Bestawros, A. N. (2004). Calcium channel blockers: an update. Am. J. Med. 116, 35–43. doi: 10.1016/j.amjmed.2003.08.027
Ericsson, H., Bredberg, U., Eriksson, U., Jolin-Mellgård, A., Nordlander, M., and Regårdh, C. G. (2000). Pharmacokinetics and arteriovenous differences in clevidipine concentration following a short and a long term intravenous infusion in healthy volunteers. Anesthesiology 92, 993–1001. doi: 10.1097/00000542-200004000-00016
Ericsson, H., Fakt, C., Höglund, L., Jolin-Mellgård, A., Nordlander, M., Sunzel, M., et al. (1999b). Pharmacokinetics and pharmacodynamics of clevidipine in healthy volunteers after intravenous infusion. Eur. J. Clin. Pharmacol. 55, 61–67. doi: 10.1007/s002280050594
Ericsson, H., Fakt, C., Jolin-Mellgård, A., Nordlander, M., Sohtell, L., Sunzel, M., et al. (1999a). Clinical and pharmacokinetic results with a new ultrashort-acting calcium antagonist, clevidipine, following gradually increasing intravenous doses to healthy volunteers. Br. J. Clin. Pharmacol. 47, 531–538. doi: 10.1046/j.1365-2125.1999.00933.x
Ericsson, H., Schwieler, J., Lindmark, B. O., Löfdahl, P., Thulin, T., and Regårdh, C. G. (2001). Enantioselective pharmacokinetics of the enantiomers of clevidipine following intravenous infusion of the racemate in essential hypertensive patients. Chirality 13, 130–134. doi: 10.1002/1520-636X(2001)13:3<130::AID-CHIR1009>3.0.CO;2-2
Flanigan, J. S., and Vitberg, D. (2006). Hypertensive emergency and severe hypertension: what to treat, who to treat, and how to treat. Med. Clin. North Am. 90, 439–451. doi: 10.1016/j.mcna.2005.11.008
Goldman, L., and Caldera, D. L. (1979). Risks of general anesthesia and elective operation in the hypertensive patient. Anesthesiology 50, 285–292. doi: 10.1097/00000542-197904000-00002
Graffagnino, C., Bergese, S., Love, J., Schneider, D., Lazaridis, C., LaPointe, M., et al. (2013). Clevidipine rapidly and safely reduces blood pressure in patients with acute intracerebral hemorrhage: the ‘ACCELERATE’ trial. Cerebrovasc. Dis. 36, 173–180. doi: 10.1159/000351149
Handler, J. (2006). Hypertensive urgency. Clin. Hypertens. 8, 61–64. doi: 10.1111/j.1524-6175.2005.05145.x
Hays, A. J., and Wilkerson, T. D. (2010). Management of hypertensive emergencies: a drug therapy perspective for nurses. AACN Adv. Crit. Care. 21, 5–14. doi: 10.1097/NCI.0b013e3181c69f87
James, P. A., Oparil, S., Carter, B. L., Cushman, W. C., Dennison-Himmelfarb, C., Handler, J., et al. (2014). 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 311, 507–520. doi: 10.1001/jama.2013.284427
Kieler-Jensen, N., Jolin-Mellgård, A., Nordlander, M., and Ricksten, S. E. (2000). Coronary and systemic hemodynamic effects of clevidipine, an ultra-short-acting calcium antagonist, for treatment of hypertension after coronary artery surgery. Acta Anaesthesiol. Scand. 44, 186–193. doi: 10.1034/j.1399-6576.2000.440210.x
Kline, J. P. (2010). Use of clevidipine for intraoperative hypertension caused by an undiagnosed pheochromocytoma: a case report. AANA J. 78, 288–290.
Kuppasani, K., and Reddi, A. S. (2010). Emergency or urgency? Effective management of hypertensive crises. JAAPA 23, 44–49. doi: 10.1097/01720610-201008000-00009
Kurnutala, L. N., Sandhu, G., Vandse, R., Soghomonyan, S., and Bergese, S. D. (2013). Innovative approaches to the management of acute arterial hypertension - clevidipine butyrate. Int. J. Anesthesiol. Res. 1:401.
Levy, J. H. (1999). Treatment of perioperative hypertension. Anesthesiol. Clin. North Am. 17, 567–579. doi: 10.1016/S0889-8537(05)70118-8
Levy, J. H., Mancao, M. Y., Gitter, R., Kereiakes, D. J., Grigore, A. M., Aronson, S., et al. (2007). Clevidipine effectively and rapidly controls blood pressure preoperatively in cardiac surgery patients: the results of the randomized, placebo-controlled efficacy study of clevidipine assessing its preoperative antihypertensive effect in cardiac surgery-1. Anesth. Analg. 105, 918–925. doi: 10.1213/01.ane.0000281443.13712.b9
Nordlander, M., Sjöquist, P. O., Ericsson, H., and Rydén, L. (2004). Pharmacodynamic, pharmacokinetic and clinical effects of clevidipine, an ultrashort-acting calcium antagonist for rapid blood pressure control. Cardiovasc. Drug Rev. 22, 227–250. doi: 10.1111/j.1527-3466.2004.tb00143.x
Noviawaty, I., Uzun, G., and Qureshi, A. I. (2008). Drug evaluation of clevidipine for acute hypertension. Expert. Opin. Pharmacother. 9, 2519–2529. doi: 10.1517/14656566.9.14.2519
Oparil, S., Aronson, S., Deeb, G. M., Epstein, M., Levy, J. H., Luther, R. R., et al. (1999). Fenoldopam: a new parenteral antihypertensive: consensus roundtable on the management of perioperative hypertension and hypertensive crises. Am. J. Hypertens. 12, 653–664. doi: 10.1016/S0895-7061(99)00059-X
Peacock, W. F., Angeles, J. E., Soto, K. M., Lumb, P. D., and Varon, J. (2009). Parenteral clevidipine for the acute control of blood pressure in the critically ill patient: a review. Ther. Clin. Risk Manag. 5, 627–634. doi: 10.2147/TCRM.S5312
Pollack, C. V., and Varon, J. (2008). Hypertensive emergencies: acute care evaluation and management. Emerg. Med. Cardiac Res. Educ. Group Int. 3, 1–9.
Pollack, C. V., Varon, J., Garrison, N. A., Ebrahimi, R., Dunbar, L., and Peacock, W. F. 4th. (2009). Clevidipine, an intravenous dihydropyridine calcium channel blocker, is safe and effective for the treatment of patients with acute severe hypertension. Ann. Emerg. Med. 53, 329–338. doi: 10.1016/j.annemergmed.2008.04.025
Polly, D. M., Paciullo, C. A., and Hatfield, C. J. (2011). Management of hypertensive emergency and urgency. Adv. Emerg. Nurs. J. 33, 127–136. doi: 10.1097/TME.0b013e318217a564
Prlesi, L., and Cheng-Lai, A. (2009). Clevidipine: a novel ultra-short-acting calcium antagonist. Cardiol. Rev. 17, 147–152. doi: 10.1097/CRD.0b013e31819fe23c
Rhoney, D., and Peacock, W. F. (2009). Intravenous therapy for hypertensive emergencies, part 1. Am. J. Health Syst. Pharm. 66, 1343–1352. doi: 10.2146/ajhp080348.p1
Rodriguez, M. A., Kumar, S. K., and De Caro, M. (2010). Hypertensive crisis. Cardiol. Rev. 18, 102–107. doi: 10.1097/CRD.0b013e3181c307b7
Schwieler, J. H., Ericsson, H., Löfdahl, P., Thulin, T., and Kahan, T. (1999). Circulatory effects and pharmacology of clevidipine, a novel ultra short acting and vascular selective calcium antagonist, in hypertensive humans. J. Cardiovasc. Pharmacol. 34, 268–274. doi: 10.1097/00005344-199908000-00013
Singla, N., Warltier, D. C., Gandhi, S. D., Lumb, P. D., Sladen, R. N., Aronson, S., et al. (2008). ESCAPE-2 Study Group. Treatment of acute postoperative hypertension in cardiac surgery patients; an efficacy study of clevidipine assessing its postoperative antihypertensive effect in cardiac surgery-2 (ESCAPE-2), a randomized double-blind, placebo-controlled trial. Anesth. Analg. 107, 59–67. doi: 10.1213/ane.0b013e3181732e53
Smithburger, P. L., Kane-Gill, S. L., Nestor, B. L., and Seybert, A. L. (2010). Recent advances in the treatment of hypertensive emergencies. Crit. Care Nurse. 30, 24–30. doi: 10.4037/ccn2010664
Sorbera, L. A., and Castanera, J. (2004). Clevidipine. Drugs Future 29, 105–111. doi: 10.1358/dof.2004.029.02.783228
The Medicines Company. (2011). Cleviprex® (Clevidipine Butyrate) Injectable Emulsion for Intravenous Use: US Prescribing Information [online]. Available online at: http://www.cleviprex.com/clev-pdfs/Cleviprex%20US%20PI%20December%202011.pdf
Tobias, J. D., Allee, J., Ramachandran, V., and Groshong, T. (2009). Clevidipine controls intraoperative blood pressure in an adolescent with renal failure. J. Pediatr. Pharmacol. Ther. 14, 144–147. doi: 10.5863/1551-6776-14.3.144
Tobias, J. D., and Hoernschemeyer, D. G. (2011). Clevidipine for controlled hypotension during spinal surgery in adolescents. J. Neurosurg. Anesthesiol. 23, 347–351. doi: 10.1097/ANA.0b013e31821f92b7
Tobias, J. D., Schechter, W. S., Phillips, A., Weinstein, S., Michler, R., Berkenbosch, J. W., et al. (2011). Clevidipine for perioperative blood pressure control in infants and children undergoing cardiac surgery for congenital heart disease. J. Pediatr. Pharmacol. Ther. 16, 55–60.
Tobias, J. D., Tulman, D. B., and Bergese, S. D. (2013). Clevidipine for perioperative blood pressure control in infants and children. Pharmaceuticals (Basel) 6, 70–84. doi: 10.3390/ph6010070
Towe, E., and Tobias, J. D. (2010). Preliminary experience with clevidipine in the pediatric population. J. Intensive Care Med. 25, 349–352. doi: 10.1177/0885066610377977
Tulman, D. B., Stawicki, S. P., Papadimos, T. J., Murphy, C. V., and Bergese, S. D. (2012). Advances in management of acute hypertension: a concise review. Discov. Med. 13, 375–383.
Varelas, P. N., Abdelhak, T., Corry, J. J., James, E., Rehman, M. F., Schultz, L., et al. (2014). Clevidipine for acute hypertension in patients with subarachnoid hemorrhage: a pilot study. Int. J. Neurosci. 124, 192–198. doi: 10.3109/00207454.2013.836703
Varon, J. (2008). Treatment of acute severe hypertension: current and newer agents. Drugs 68, 283–297. doi: 10.2165/00003495-200868030-00003
Varon, J., and Marik, P. E. (2008). Perioperative hypertension management. Vasc. Health Risk Manag. 4, 615–627.
Vuylsteke, A., Feneck, R. O., Jolin-Mellgård, A., Latimer, R. D., Levy, J. H., Lynch, C. 3rd., et al. (2000). Perioperative blood pressure control: a prospective survey of patient management in cardiac surgery. J. Cardiothorac. Vasc. Anesth. 14, 269–273. doi: 10.1053/cr.2000.5856
Keywords: perioperative period, arterial hypertension, anti-hypertensive medications, calcium channel blockers, dihydropyridine, Clevidipine
Citation: Kurnutala LN, Soghomonyan S and Bergese SD (2014) Perioperative acute hypertension—role of Clevidipine butyrate. Front. Pharmacol. 5:197. doi: 10.3389/fphar.2014.00197
Received: 29 March 2014; Accepted: 08 August 2014;
Published online: 27 August 2014.
Edited by:
Nicoleta Stoicea, Ohio State University Wexner Medical Center, USAReviewed by:
Nicoleta Stoicea, Ohio State University Wexner Medical Center, USAGurgen Harutyunyan, 9 de Octubre, Spain
Copyright © 2014 Kurnutala, Soghomonyan and Bergese. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: drnarasimhulu_k@yahoo.com