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Perf t oran : Russian Experience

Perf t oran : Russian Experience. Maria Irwin, MD , PhD Clinical Assistant Professor Department of Anesthesiology Congenital Heart Center University of Florida. History 1. 1984-85 first clinical trials (> than 600 patients) Trial and research stopped

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Perf t oran : Russian Experience

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  1. Perftoran: Russian Experience Maria Irwin, MD, PhD Clinical Assistant Professor Department of Anesthesiology Congenital Heart Center University of Florida

  2. History1 1984-85 first clinical trials (> than 600 patients) Trial and research stopped 1992-95 clinical trial restarted (more than 200 patients) 1996 Perftoran approved by Russian Pharm Committee - Administered to 964 patients during trials - 3528 patients received in 1997-2004

  3. - 1997, St.Petersburg - All army scientific conference “Physiologically active compounds based on PFCs in military medicine” Conclusion: Ministry of Defense recommended PFC for Russian army - 1998, Pushino, Institute of Theoretical and Experimental Biophysics of RAS - Xth international conference “PFCs in biology and medicine” Reseachers from 12 cities of Russia and Ukraine presented clinical data in surgery, internal medicine, ophthalmology and critical medicine. History2 Felix Beloyartsev Henrih Ivanitsky

  4. Formulation - Glass bottles 100, 200, 400 ml - Storage at -18oC up to 3 years. Can refreeze ≤ 3 times. at -4oC up to 2 weeks - Defrosting: 1 day in fridge ➝ few hours at room temp (<36oC) - No shaking

  5. Effects and mechanism of action - Improves O2 delivery (beyond O2 transport) - Improves microcirculation and blood rheology (NO) O Rafikova et al.Circulation. 2004;110

  6. Pharmacokinetics - Route of administration: IV or local (wound and cavities irrigation) - No enzymatic metabolism in mammals* - LD50 140-240 ml/kg IV (animal studies) - doses ≤ 20 ml/kg not teratogenic, embryotoxic or carcinogenic Y.Kokoz et al. DAN 1983 S.Vorobiev et al. DAN 1988 N.Krylov et al. Research Institute of General Reanimatology of RAS

  7. PFCs • PFCs are not artificial blood. • PFCs are plasma expanders with gas transporting properties • Advantages of PFCs vs. donor blood: • - no risk of infection • - no need for type and cross • - better gas transporting function • - long shelf life • - potential for mass production and immediate use • - allows to decrease use of donor blood

  8. Indications - Acute anemia (trauma, cardiac surgery) - Microcirculatory ischemia (infection, trauma, neuro trauma, peripheral vascular disease, myocardial infarction, CPB, CHF, ischemic stroke, burn, CPR, hemolysis, PE, fat embolism, DT..) - Transplant organ preservation (prior to harvest, for organ storage and after transplant) - CPB, ECMO prime - 10-40 ml/kg, cardioplegia - Liquid ventilation in ARDS - cancer treatment for augmentation of tumor oxygenation - detoxification (DT, toxicology), anaerobic infections - patients refusing blood products

  9. Side effects Usually correlate with material operations: 1) handling (affect size of emulsion particles) Lower complication rate in institutions using large volumes of Perftoran 2) packaging (plastics leak dioxylphtholate) 3) sterility

  10. Side effects - allergic reactions: anaphylaxis, skin rash - tachycardia - hypotension - fat embolism (chest pain, back pain) - hyperthermia - coagulopathy (hemodilution, transient thrombocytopenia) - immunosupression* overall rate 1.8-8% Maevsky et al., 2001

  11. Contraindications - anaphylaxis - hemophilia - uncontrolled surgical hemorrhage* (uncontrolled severe hypovolemia) - pregnancy*

  12. Patient distribution according to indications, doses of Perftoran and frequency of side effects during clinical trials (n=964)

  13. Patients distribution Total number of patients=3528 including 1921 Perftoran-treated (1997-2002)

  14. Trauma Main indication during initial clinical trials (238 patients) EBL<25% - exclusive PFC and XL resuscitation EBL > 40% - Perftoran 1.2-3.5L and FiO2 0.4-0.6 (Experience of transfusion 5.4 L) When EBL >50% & Hgb fell 3.5-7.5 g/dL ➝ FFP and separate plasma expanders were added (200 ml per 400 ml of PFC) ➝ allowed delay, reduction x2-3 of blood transfusion Effects: normalization of O2 transport, hemodynamics stabilization, improved blood rheology, anti oxidation, membrane stabilization Victor Moroz V. Moroz, 1995, 1999 L.Bogdanova et al, Medline, 2001 E.Polozova et al, Medline, 2004

  15. Changes in trauma, even after hemodilution and normalization of central hemodynamics: - blood rheology and coagulation - microcirculation In PFC group: - faster normalization of tissue perfusion, resolution of metabolic acidosis and organ function - Decreased mortality by 5-8.5% in massive GI hemorrhage - Decreased intra-operative mortality by 12.5% - Decreased use of donor PRBCs x1.5 times Trauma E.Shiburt et al, Pacific Medical J, 2004 E.Kligunenko et al, Materials of Conference on PFCs,Pushino,1999 L.Gerasimov kmn Dissert.Moscow,2005 (in Russ.) S.Radayev kmn Dissert Moscow,2001(in Russ). E.Shishkina kmn Dissert,Moscow,1999(in Russ).

  16. Transfusion therapy in acute massive blood loss (Wt 70 kg) Blood Center of Russian Ministry of Health, Moscow E.Shiburt et al, Pacific Medical J, 2004

  17. Dagestan Medical Academy, Dnepropetrovsk Medical Academy, MMA St.Petersburg 1.5-2 ml/kg x 3 days (max dose <100 ml) Results: - pts reported “feeling better,” less chest pain - positive ECG changes, less arrhythmias (PVCs by 24.2%, sinus bradycardia by 17.3%, no V.Fib) - decreased CVP and SVR with preservation of systemic BP - resolution of tachycardia - increased SV and SI, CO and CI Based on ECHO: reduction of ischemic area x2.5 Acute myocardial infarction L.Bogdanova et al, Medline, 2001 S.Shuvalov, V UshakovCardiovasl therapy and prophylaxis, 2006 A.Abusuev Bulletin of new med technologies, 2009 Usenko et al., 2002 Aliev et al., 2002

  18. Experience of Institute of Surgery of Vishnevky, Institute of Cardio-Vascular Surgery of Bakulev, Center of Transplantology of Shumakov and Military Medical Academy in St.Petersburg - Bypass prime - PFC in cardioplegia solutions 1:1-1:3 Effects: - prolongs cardioplegic preservation x2-3 times - improves return of spontaneous contractility post bypass - decreased arrhythmias and improves contractility post bypass - increased pulse pressure Cardiac surgery L.Bogdanova et al, Medline, 2001 Beloyartsev et al., 1986 Golubev, 1999 Islamov et al., 1986

  19. - 22 pts with CAD for elective multi vessel bypass - Hct <35% 5-7 ml/kg of Perftoran Cardiac surgery N.Karpun, V.Moroz General Reanimatology,2012

  20. Peripheral vascular disease D.Krilov, V.Moroz, 1995 G.Ivanitsky et al., 2003 Tissue pO2 after PFC Before treatment 2 hr after 100 ml of Perftoran

  21. Peripheral vascular disease - improved tissue oxygenation (O2 delivery and extraction) by 30% - ↓ lactate level x 2-3 times - ↓ blood viscosity and RBCs trauma - ↑ blood flow (by doppler) - immediate ↑ in skin temperature - pain relief and functional improvement up to few months after • Kruchenkov, 1998 • Moroz et al., 1995 • Ivanitsky et al, 2004 • N.Karmen et al, 2005

  22. 85 pts with severe PVD (atherosclerosis, endarteritis) 77.6% with trophic ulcers. 27.9% with necrosis of digits. PFC group: amputation rate ~50% vs. >80% decreased pain, improved function Peripheral vascular disease healed no change decreased Control group (n=28) Perftoran group (n=38) • S.Bagnenko et al. Chirurgia, 2005(6)

  23. - Organ preservation during apnea test to confirm organ brain death: Perftoran 200 ml IV > maintained PaO2 without affecting PaCO2 levels Transplantology A.Kolzanof et al, TTS international congress, 2010

  24. Renal transplantology - 2 L of PFC into donor to alleviate kidney transplant ischemic injury for up to 2 days - 400 ml of PFC to recipient - Infusion (4-6 ml/kg) into recipient diminished reperfusion damage and rejection Animal studies: - maintained 2x higher ATP/ADP, - decreased lactate/purivate ratio x5, - decreased serum Cr and urea x4, - increased kidney graft lifespan x2-3 Onishenko, 1990 Shumakov et al., 1999

  25.  Other indications - Brain and spinal cord trauma - Acute and chronic infections (anaerobic, HIV, hepatitis) - Prophylaxis of adhesions (intraperitoneal…) - microvascular surgery (plastics, eye, oncology) - hemolytic anemias, sickle cell anemia - non invasive imaging (MRI) - Cosmetology (Aquaftem emulsion=PFC) Faberlic - O2 cosmetics … L.Bogdanov et al, Medline,2001:2(5):30-6. Faberlic

  26. Perftoran and black caviar Perftoran improves condition of female sturgeons after caviar extraction surgery N.Shevlyakova, A.Lozovsky Physiologic parameters of Russian Sturgeon post-operatively for caviar extraction, after administration of Perftoran. MedLine,2004(5):227-8

  27. Perftoran today Major indication in Russia today is non hemorrhagic disease: neurotrauma, acute stroke, PVD, myocardial infarction, cardiac surgery, plastic surgery, wound healing, viral hepatitis, activation of detoxication function of liver… would benefit ANY patients Maevstky, Ivanitsky, 2005, 2006 Rafikova et al., 2004 Obraztsov et al., 1985, 2000

  28. References 1. G.Ivanitsky, C.Vorobiev. Blood substitute Perftoran. Institute of Theoretical and Experimental Biophysics of Russian Academy of Science Vestnik of Russian Academy of Science, 1997,66(11):998-1013. 2) C.Vorobiev, G.Ivanitsky, Y.Ladilov et al. Modification of cell membranes by PFCs as a possible mechanism to decrease level of ischemic myocardial injury. DAN 1988,299(2):228-30. 3) Y.Kokoz, E.Kobrinsky, E.Freidin et al. Gasotransport effect of Perftoran on myocardium (ion transport, contractility and sensitivity to mediators). DAN 2983,270(2):459-62. 4) V.Moroz, L.Krilov, G.Ivanitsky et al. Effect of Perftoran in clinical medicine. Anesth and Reanimatology 1995,6:12-7. 5) I.Kuznetsova Functional activity and stability of perfluorocarbon emulsions. Autoref doc dissertation (Biophysics), St.Petersburg, 1999:38. 6) O.Rafikova et al. Control of plasma nitric oxide bioactivity by perfluorocarbons. Physilogical mechanisms and clinical implications. Circulation 2004;110:3573-80. 7) P.Katunyan et al. Anti-elastase effect of Perftoran in treatment of patients with acute spinal cord injury. 7th Internat Neurotrauma Symporium, Adelaide,Australia, 2004,Sept:99-101. 8) N.Krylov et al. Ways and duration of removal of perfluoro organic compounds (PFOC) from human and animal body. N.N.Burdenko Main Military Clinical Hospital, Moscow, Research institute of General Reanimatology of Russian Academy of Medical Sciences, Moscow, Institute of Technological and Experimental Biophysics of Russian Academy of Science, Pushino. 9) The use of Perftoran in toxicology (methodical recommendations) Defense Ministry of the Russian Federation. Main Military Medical Department. S.M.Kirov Military Medical Academy, St.Petersburg, 2006.

  29. References 10) S.Shuvalov, V.Ushakov Perftoran therapy perspective in reperfusion syndrome prevention among acute myocardial infarction patients. Cardiovasc therapy and prophylaxis,2006:5(4)82-5. 11) A.Abusuev Influence of Perftoran on microcirculation of patients with acute myocardial infarction. Bulletin on new med technologies, 2009:16(1):111. 12) P.Seeber, A.Shander Basics of blood management, 2nd ed, 2003 13) R.Winslow Blood substitutes, Elsevier 2006;26:288-97. 14) E.Maevsky, L.Gervits Perfluorocarbon-based blood substitute - Perftoran. Russian Experience. Chemistry today, 2008;26(3):3407. 15) E.Maevky, G.Ivanistky Oxygen-dependent and Oxygen-independent effects of perftoran//Keio university international symposia for life sciences and medicine, meds.: K.Koboyasi, E.Tsuchida, H.Horinouchi/Artifical Oxygen Carriers:its front line.Springen-VErlag Tokyo,2005;12:221-8. 16) V.Obraztsov, G.Neslund et al. In vitro cellular effectsof perfluorochemical correlate with their lipid solubility, Am J Physiol Lung Cell Mol Physiol,2002;278:1018-24. 17) V.Obraztsov, D.Shethman et al., Induction of rat liver microsomal cytochrome P-450 after intravenous infusion of perfluoroorganic emulsion.Biochemia,1985;50(7):1220-6. 18) A.Kolsanov, A.Mironov, E.Neljubina et al. Organ preservation and procurement. Apnea oxygenation test safety and accessibility with the Perftoran solution. TTS international congress, 2010. 19) E.Zhiburt et al., Modernd therapy in acute massive hemorrhage. Center for blood of Russian Ministry of Health, Pacific Medica J,2004;4:11-5. 20) N.Karpun,V.Moroz.General anesthesia in the surgical treatment of coronary heart disease.General reanimatoogy,2012:8(4):126-32. 21) L.Bogdanova at el. Brief review of clinical application of Perftoran. Medline,2001:2(5):30-6.

  30. References 22) C.Bagnenko, V.Soroka, S.Nohrin et al. Use of Perftoran in critical lower extremities ischemia. Chirurgia,2005(6):683-93. 23) N.Karmen, A.Zararov,I.Lezshenva. Peftroran influence on the blood stream at the ischemic vessel disorders. Somatology,2007(8);566-72. 24) E.Kligunenko et al. PFC in biology and medicine: Materials of Conference,1999,Pushino:76-87. 25) E.Polozova et al. Effect of Perftoran on dynamics of parameters of endogenic intoxication and processes of lipid oxidation in patients with severe thermal trauma. Medline, 2004;5(17):75-6. 26) L.Gerasimov Hemorheologic disorders and hemolysis in patients with severe concomitant injury and blood loss and their correction with perfluorane. kmn Dissert.Moscow,2005 (in Russ.) 27) S.Radayev The structural and functional properties of red blood cells and blood loss. kmn Dissert.Moscow,2001(in Russ). 28) E.Shishkina Hypoxic disorders and their correction in patients with blunt chest injury. kmn Dissert,Moscow,1999(in Russ).

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