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Clinical Results of Perftoran Application:Present and Future

Eugene Maevsky, Genrih Ivanitsky, Ludmila Bogdanova, Olga

Axenova, and Natalia KarmenInstitute of Theoretical and Experimental Biophysics of RAS,

Moscow Region, Russia

Eugene ZhiburtCenter of Industrial Transfusiology of Russian Ministry of

Health, Moscow, Russia

Raisa Senina, Sergey Pushkin, and Igor MaslennikovOA Scientific-Productive Company Perftoran,

Moscow Region, Russia

Andrey Orlov and Irina MarinichevaCentral Scientific-Research Institute of Stomatology,

Moscow, Russia

Abstract: Clinical experience of Perftoran (commercial drug of low concentratedperfluorocheminal emulsion) applications is presented in some statistical data andin brief analysis of clinical trials and following clinical studies described in theRussian scientific literature. Observed data allow us to suppose that Perftoranfacilitates oxygen delivery together with remaining red blood cells at bloodreplacements and will have more wider area for application than just a bloodsubstitute. Its infusion alleviates symptoms of ischemia at different types ofocclusion vessels disease, improves grafting in plastic surgery, diminishes inflam-mation and prevents rejection of transplants, activates detoxication functions ofliver, inhibits retro-virus infection development. Local PF applications is ableto accelerate wounds and ulcers healing.

We thank T. N. Kharybina and her colleagues in Pushchino Library, ProfessorG. A. Sofronov and his coworkers from the Military Medical Academy in Saint-Petersburg for their help in looking for information about Perftoran applications.Address correspondence to Eugene Maevsky, Institute of Theoretical and

Experimental Biophysics of RAS, 142290, Pushchino, Institutskaya, 3, MoscowRegion, Russia. E-mail: [email protected]

Artificial Cells, Blood Substitutes, and Biotechnology, 33: 37–46, 2005

Copyright Q Taylor & Francis, Inc.

ISSN: 1073-1199 print/1532-4184 online

DOI: 10.1081/BIO-200046654

37

Keywords: Perftoran, review clinical usage

1. GENERAL PICTURE OF PERFTORAN APPLICATION

This paper presents a generalization of the widely used clinical appli-cation of Perftoran (PF). PF contains 10 vol.% perfluorochemicals(PFCs): perfluorodecalin and perfluoro-N-(4-methylcyclohexyl)-piperidine in ratio 7:3 emulsified by non ionic surfactant Proxanol-268in an isotonic electrolyte solution with average emulsion particle size ofabout 0.07 mm (Table 1).

The whole composition of PF is packed in one bottle and has to bestored either frozen (at�18�C to�4�C for 3 years) or under refrigeration(at 4�C for 2 weeks). PF is manufactured by Scientific-Productive Com-pany ‘‘Perftoran.’’ PF was registered in Russia in 1996 as an oxygen-carrying blood substitute. The various opportunities of PF applications(and not only for blood replacement) have already been revealed on thebasis of analysis of patients distribution (Table 2) during preregistrationclinical trials [1–4].

As is shown in Table 2, PF was administered in dosages from 4 to30ml=kg depending on the disease. The largest summary doses were from1000 to 5300ml for the treatment of severe anemia.

In 1997, Scientific-Productive Company ‘‘Perftoran’’ began to sellPF to Central Regional Stations of Blood Transfusion and different hos-pitals. Judging the volume of the wholesale and assuming that a singlepatient received about 1000ml, we deduced that PF had been adminis-tered to about 4500 patients. Information about PF use was collected

Table 1. Perftoran composition and its physical-chemical properties

F-decalin and its satellites 7.0mlF—N-(4-methylcyclohexyl)-piperidine and its satellites 3.0mlProxanol-268 4.0 gNaCl 0.6 gKCl 0.039 gMgCl2 0.019 gNaHCO3 0.065 gNaH2PO4 0.02 gGlucose 0.2 gH2O to 100ml[F�] 10 mMOsmotic pressure 300mOsMpH 7.3Viscosity 2.3 cP

38 E. Maevsky et al.

with the help of questionnaires from 21 regions of Russia. The answers ofrespondents gave total evaluation of PF efficiency, which looked as fol-lows: positive effects�88,3%, negative effects�3,3%, absence of anyeffect�8,3%; different side effects were listed in 4% of cases.

Analysis of the Russian scientific literature from 1997 to 2002 let usfind a listing of 1823 patients treated with PF in comparative studies witha total of 3332 patients (Table 3). The new fields of PF usage in clinicalpractice are much wider than was found out during clinical trials. Almost

Table 2. Distribution of patients according to indications during clinical trials

IndicationsDoses,

ml per kg BWSummarydoses, L

Patientsdistributions

% sidereactions

1. Acute blood loss andhemorrhagic shock

6–30 1.0–5.0 23.5% 2%

2. Polytrauma, cranial-cerebral trauma, shock

4–12 0.4–1.2 20% 0%

3. Toxic-infection shock 4–8 0.4–1.0 12,7% 0%4. Occlusion of blood vessels

and acute heart infarct4–6 0.4–0.8 20,7% 20%

5. Cardioplegia – 1.0–2.0 11.1% 0%6. Transplantation 30 1.0–2.0 4,8% 0%7. Burns, oncology & others 2–8 0.1–1.0 8.2% 25%Total 912 patients 100% 6,9%

Table 3. Indications and distribution of patients treated with Perftoran in com-parative studies listed in Russia scientific literature for the period up to 2002

Indications

Total 3332=Perftoran

treated 1823

Distribution ofpatients withPerftoran

1. Blood losses, multiple organ failure 862=401 22.0%2. Disorders of perfusion and

microcirculation (without blood loss)490=292 16.02

3. Dysfunction of inflammatory response 269=163 8.9%4. Detoxication 375=170 9.3%5. Lung function damage, RDSA 197=152 8.3%6. Cranial-cerebral trauma 184=134 7.3%7. Burns, thermal shock 123=53 2.9%8. Transplantation 206=87 4.8%9. Cardioplegia, cardiopulmonary bypass 165=72 3.9%10. Local application: wound & ulcer of

mucous, skin, spinal cord461=299 16.2%

Clinical Results of Perftoran Application 39

the complete reference list of PF applications for the period up to 2001was published in Russian by G.A. Sofronov et al. [5].

2. THE PLACE OF PERFTORAN IN INFUSION-TRANSFUSION

THERAPY OF BLOOD LOSSES

According to the initial conception, PF was developed and manu-factured as a blood substitute. Correspondingly, Perftoran should havebeen used in lieu of allogeneic blood and banked red blood cells (RBC)during the substitution of massive blood losses (about 1000–2500ml). Atmassive blood replacement PF was used together with a combination ofplasma expanders (dextran 60 or hydroxyethylstarch was infused intoother veins or immediately after PF into the same vessel). Simul-taneously it was necessary to provide the patients with breathing ofair enriched with supplementary O2. In these cases PF was used withoutpure oxygen for breathing when the fraction of O2 in air did not exceed0.4–0.6 [1–3, 6–9]. It enabled us to maintain venous pO2 at the level of45–65mmHg and did not block HbO2 desaturation in the remainingerythrocytes.

Analysis of PF usage at massive, moderate and small blood losses hasshown that PF was able to significantly improve tissue oxygenation dueto oxygen delivery together with the remaining RBC and to facilitateblood rheology at early stages of infusion-transfusion therapy. PF turnedout to be useful even if the level of circulating erythrocytes and hemoglo-bin was still sufficient (did not reach the trigger level of blood trans-fusion) and there was no need to use banked donor blood or RBCs[10–12]. Consequently, a conclusion was made that PF should beadministered at early stages of blood loss treatment immediately aftercrystalloid solutions (Table 4) when the symptoms of hypoxia, ischemiaand microcirculation disorders appeared.

The basic results of Perftoran application at blood replacement werean increase in efficiency of reanimation treatment and shortening of rean-imation period, duration of lung artificial ventilation, an improvement ofoxygen transport and its consumption, a decrease in the demand in bankedblood and blood components more than 2-fold and even avoidance ofdonor blood infusion [1–3, 6–9]. Side reactions such as hypotension andpulmonary complications were observed at massive blood replacementwith PF in about 1% of cases. The stomach-duodenal bleeding and oper-ation blood losses are good examples when PF provided maintenance ofarterial PO2 on the higher level than crystalloids or colloids [6–12]. In com-parison with dextran 60 Perftoran decreased more efficiently heart rate,blood viscosity and erythrocytes rigidity, augmented the arterial pressure,cardiac output and central venous pressure, maintained vessel resistance


Table 4. The place of perftoran in infusion-transfusion therapy of blood losses

Blood loss volume Transfusion means and doses (ml)

ml

% Circulat.

Blood

Volume Crystalloids Perftoran Colloids Albumin 10%

Fresh

frozen

plasma

Red blood

cells

& platelets

<750 <15 1500 200–300 – – – –

750–1500 15–30 1500–2000 500–700 600–800 – – –

1500–2000 30–40 1000–1500 800–1000 800 –1200 100–200 1000–1500 on indications

>2000 >40 800–1000 1000–1500 1200–1500 200–300 1500–2000 2–6 units

41

and circulating blood volume. Thanks to that, Perftoran diminished aci-dosis. Here it is necessary to mention that in most cases the positive effectof PF was reached after its usage in small doses of 4–6ml per kg bodyweight when the supplementary oxygen capacity of PFC emulsion wasinsignificant. These doses of PF accelerated patients’ resuscitation aftercranial-cerebral trauma [12] and burns shock [9].

Significant antiacidosis effect and improvement of tissue oxygenationwere obtained within cardiopulmonary bypass with PF during recon-struction operation on heart in more than 45 patients [13].

3. PERFTORAN IMPROVES TISSUE OXYGENATION AT THE

TREATMENT OF OCCLUSIVE VESSELS DAMAGES

V. Moroz et al. [1,2] obtained 30% of skin PO2 augmentation measuredwith transcutaneal device after infusion of 400ml of PF, while dextran40 gave only 6% of tissue PO2 increase. Ultrasound dopplerometryand thermovision images demonstrated an improved resuscitation ofthe blood flow immediately after infusion of 200ml PF. Summary effectsreceived on 92 patients in the Rehabilitation Center of GovernmentMedical Department are shown in Table 5. Treatment with repeatedPerftoran infusion eliminated pain at rest and significantly enhancedpainfree distances.

L. V. Usenko et al. [14] and later a number of other researchers [15],described the diminishing of necrotic region after heart infarct treatedwith very small doses of PF: 100ml per infusion.

4. IN TRANSPLANTOLOGY PF DECREASED KIDNEY GRAFTS

REJECTION 2-FOLD

Infusion of 1000–2000ml of PF into kidney cadaver donors who had noheart function alleviated symptoms of kidney ischemia and decreased

TABLE 5. Results of Perftoran treatment at the occlusive vessels diseases of legs(Rehabilitation Center of Government Medical Department, 1999–2002)

Quantity &average ageof patients Treatment

Painfree distances,m (% of patients)

Painsat rest

Stages ofdiseases

N ¼ 92

before Perftoran � 180 (100%) 50% 2–3b

Perftoran 200ml� 2–3every 6–9 months

1200 750 200 0 1–2a

68 years (87%) (9%) (4%)


graft reperfusion injury. Reperfusion damages and graft rejections dimin-ished also after infusion of PF in dosage of 4–6ml per kg body weightinto recipients after transplantation [16,17].

5. UNEXPECTED PERFTORAN APPLICATIONS

A. The first clinical experience of PF application for detoxication aim hasbeen recently presented at the treatment of poisoning with carbofosand psyhotropic drugs [18]. PF usage was based on its capabilitiesto sorb lipophylic substances in blood stream and to induce the syn-thesis de novo of cytochrom P450 in liver [19].

B. Taking into account the fact that PF is able to inhibit functions ofhyperactivated macrophages and primed neutrophils [20], which canproduce viral particles and a lot of cytotoxic products, an attemptwas made to treat 14 patients infected by human immunodeficiencyvirus (HIV) and suffered the last 2–3 years from secondary infections,weakness, tiredness, body weight loss, and in-ability to work [21].After PF courses, which included several intravenous infusions, 12patients felt much better, could return to work, stopped losing weight.Two patients did not undergo PF treatment because of side reactions.Within the year of treatment with PF, the secondary infections did notmanifest. No significant changes in blood analysis were found exceptfor some shifts in concentrations of HIV-1 and p24 protein in blood.

C. An antiinflammatory effect of PF infusions applied at chronic uveitisof different etiology was obtained in the Center of Eye Microsurgeryin Moscow [22]. A stable recovery was found after supplementary PFinfusions (100ml two times only) in 39 patients out of 40 in cases whenprevious traditional treatment did not produce any positive effect. PFinfusion has been stopped in 1 case because of a side reaction after thefirst 5 drops of PF. Blood analysis revealed that concentrations of cir-culating immune complexes and CD-4 lymphacytes in this patient’sblood had an unusual response to PF.

D. Original data were submitted by neurosurgeon Pavel Katunyan fromMoscowMedicalAcademy [23].He used oxygenatedPF for local lavageof injured spinal cord at the decompression operation and simul-taneously administered 200ml of PF intravenously. Additionally,5–6 intravenous infusions were made in the post–operation period.When PF was administered during the first days after trauma, theelastase activity of neutrophils in peripheric blood of patientsdropped and this phenomenon was accompanied by the improve-ment of neorulogic state within 3 months. But delayed PF appli-cation or traditional therapy either slightly improved neurologicstate or did not produce any improvement at all.


E. Acceleration of healing was shown after PF lavage and local PFapplications on the surface of stomach ulcer, skin wounds and evenon leprosy chronic ulcers [24,25].

CONCLUSION

The data described in the Russian scientific literature seem to show theplace of PF among other blood substitutes as an antihypoxic and anti-ishemic drug that is worth administering on early stages of blood lossas it improves the functions of the remaining RBC, and thanks to thatincreases tissue oxygenation, delays usage of donor RBC and decreasesdemand in banked blood. Analyzed clinical experience enables us tosuppose that, thanks to its various biophysical properties, PF will havea wider area of application than just as a blood substitute. Its infusionalleviates symptoms of ischemia in different types of occlusion vesselsdiseases, improves grafting in plastic surgery, diminishes inflammationand prevents rejection of transplan, activates detoxication functions ofliver, and inhibits retrovirus infection development. Local PF applicationis able to accelerate wound and ulcer healing.

REFERENCES

1. Klylov, Nikolay L., Moroz, Victor V., Beloyarzev, Felix F. (1985). Clinicaluse the fluoro-carbon blood substitute perftoran. (Russian) Voen Med Zh.8: 36–40.

2. Moroz, VictorV.,Klylov,NikolayL., Ivanitsky,GenrihR.,Kaidash,AtnoldN.,Onishchenko, NinaA., Simanov, VladimirA., Vorobev, Sergei I. (1995). The useof perftoran in clinical medicine. (Russian) Anesteziol Reanimatol. 6: 12–17.

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