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Bio3s.com.coAdvance Access Publication 6 October 2004 Original Article
Ozone Therapy on Cerebral Blood Flow: A Preliminary Report
Bernardino Clavo1,2,7, Luis Catalá3,7, Juan L. Pérez2,4,7, Victor Rodríguez5 and
Departments of 1Radiation Oncology and 2Research Unit, 3Radiology, 4Medical Physics and 6Chronic Pain Unit,Dr Negrín Hospital, 5La Paterna Medical Center and 7Canary Islands Institute for Cancer Research (ICIC),Las Palmas (Canary Islands), Spain Ozone therapy is currently being used in the treatment of ischemic disorders, but the underlying mech-anisms that result in successful treatment are not well known. This study assesses the effect of ozonetherapy on the blood flow in the middle cerebral and common carotid arteries. Seven subjects wererecruited for the therapy that was performed by transfusing ozone-enriched autologous blood on 3 alter-nate days over 1 week. Blood flow quantification in the common carotid artery (n ϭ 14) was performedusing color Doppler. Systolic and diastolic velocities in the middle cerebral artery (n ϭ 14) were esti-mated using transcranial Doppler. Ultrasound assessments were conducted at the following three timepoints: 1) basal (before ozone therapy), 2) after session #3 and 3) 1 week after session #3. The commoncarotid blood flow had increased by 75% in relation to the baseline after session #3 (P Ͻ 0.001) and by29% 1 week later (P ϭ 0.039). In the middle cerebral artery, the systolic velocity had increased by 22%after session #3 (P ϭ 0.001) and by 15% 1 week later (P ϭ 0.035), whereas the diastolic velocity hadincreased by 33% after session #3 (P Ͻ 0.001) and by 18% 1 week later (P ϭ 0.023). This preliminaryDoppler study supports the clinical experience of achieving improvement by using ozone therapy inperipheral ischemic syndromes. Its potential use as a complementary treatment in cerebral low perfu-sion syndromes merits further clinical evaluation.
Keywords: color Doppler – ischemia – low perfusion – transcranial Doppler
With regard to this, the effect of ozone therapy on the blood flow in the middle cerebral artery (MCA) and the common Cerebral low perfusion syndromes have significant clinical carotid artery (CCA) was investigated in the current study.
and social repercussions. An important field in neurologicalresearch includes the search for more effective drugs and othermethods in order to ameliorate this problem. Ozone therapy is Subjects and Methods
a non-conventional therapy that has been used for several yearsin the treatment of ischemic disorders, particularly of the Patients
lower limbs (1–3). However, to date, very few studies have In this study, the blood flow in 28 arteries (14 MCA and systematically evaluated blood flow changes resulting from 14 CCA) was evaluated in 7 subjects—5 patients and 2 healthy volunteers. The subjects were from our university hospital.
The patients who underwent elective ozone therapy, which wasunrelated to the treatment of their cerebral vascular diseases, For reprints and all correspondence: Bernardino Clavo, MD, Department of were from the Radiation Oncology department. Their scheduled Radiation Oncology and Research Unit, Dr Negrín Hospital, C/ Barranco la medication was not modified during the study period. The vol- Ballena s/n, 35020 Las Palmas (Canary Islands), Spain. Fax: ϩ34 928449127; Tel: ϩ34 928 450284. E-mail: firstname.lastname@example.org unteers were members of the clinical staff of the departments The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open accessversion of this article provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the originalplace of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated.
2004, the authorsEvidence-based Complementary and Alternative Medicine, Vol. 1, Issue 3 Oxford University Press 2004; all rights reserved 316
Ozone therapy on cerebral blood flow involved in the investigation. The study included 5 males and Common Carotid Blood Flow Quantification
2 females with a mean age of 58 years (range, 34–78).
Blood flow quantification of CCA was performed using Informed consent was obtained from all the participants prior a color Doppler, Philips Ultrasound P-800 unit®, with time- to inclusion in the study. The study was approved by the domain processing. This technique simultaneously evaluates Institutional Ethical Committee. Table 1 summarizes the the velocity and the vessel diameter, and the data is presented details of the subjects that participated in this study.
in terms of ml/min. The usefulness and validity of this tech-nique has been previously described (4,5). The patient was Ozone Therapy
alert, relaxed and in the supine position when the absence of Ozone therapy was administered by autologous blood transfu- significant stenoses in the extracranial carotid arteries was sion on 3 alternate days over 1 week. The procedure involved confirmed. A 7.5 MHz linear high-definition probe with a the collection of 200 ml venous blood into a blood bag con- Doppler insonation angle of Ͻ60Њ was used. We obtained taining heparin (25 IU/ml) and CaCl2 (5 mM). The O3/O2 gas information regarding the volume of blood flow (in ml/min) in mixture was prepared from clinical-grade O2 using the OZON both CCAs at Ն2 cm prior to the carotid bifurcation.
2000 medical device (Zotzmann ϩ Stahl GmbH, Plüderhausen, All ultrasound studies were performed bilaterally by the Germany). The blood was mixed with 200 ml of O3/O2 gas same radiologist in order to minimize interobserver variability mixture at a concentration of 60 g/ml in a sterile single-use (6). When an optimal image of stable blood flow was obtained, 300 ml container. Subsequently, the blood was slowly recordings over at least three cardiac cycles were made. This re-introduced into the patient via the antecubital vein, after was repeated at least three times in order to preclude operator- being passed through a sterile 0.20 m filter. The blood induced or technical inaccuracies. The median values that remained outside the body for approximately 15–30 min, and were obtained were used in the statistical analyses.
Neither blood pressure nor hemoglobin levels were measured.
Doppler studies were conducted on the following three occasions: 1) before session #1; 2) after session #3; and 3) Statistical Analysis
The SPSS 7.0 for Windows software package (SPSS-Ibérica,Madrid, Spain) was used throughout the study. The normality Transcranial Doppler Velocimetry
of distribution of data was assessed by the Kolmogorov– Systolic and diastolic velocities (in cm/s) were measured in the Smirnov test. Two-sided tests were applied. The data are MCA by the transtemporal approach using a transcranial expressed as mean Ϯ SD. The paired t-test was used to com- Doppler (TCD) with a 2 MHz probe from an Angiodine-2 pare differences between the baseline and the two time-point Fluo-Link 300® device. The patient was alert, relaxed and measurements following the ozone therapy. Linear correlation seated when the absence of stenoses was confirmed. The was assessed by the Pearson’s r test. The differences were Doppler insonation angle was Ͻ60Њ.
considered to be significant when P Ͻ 0.05.
Table 1. Patients and control subjects included in the study
aComplementary treatment during radiochemotherapy for advanced carcinoma of hypopharynx.
bArterial hypertension under drug treatment and hyperglycemia under dietary treatment.
aComplementary treatment during radiochemotherapy for advanced carcinoma of base of tongue.
bChronic obstructive bronchitis (COB) under treatment with bronchodilator inhalers.
aComplementary treatment during radiochemotherapy for advanced carcinoma of supraglottis.
bHyperuricemia treated with allopurinol. Multiple sclerosis treated with baclofen.
aRadiation-induced necrosis of thyroid cartilage (radiotherapy was administered for carcinoma of glottis several years ago).
aChronic ulceration with calcaneous exposure and transplant failure.
bInsulin-dependent diabetes, arterial hypertension under drug treatment. Stroke 1 year ago. Duodenal ulcers.
aReason for ozone therapy. bConcomitant diseases or treatments (no changes were made in the medications during the period of Doppler evaluation). The studywas planned with three ozone therapy sessions to evaluate the initial effects under the same conditions. Patient #1, #2 and #3 (cancer patients) were required tocommence their scheduled radiochemotherapy after session #3; therefore, ethical considerations precluded delay in the cancer treatment. Ozone therapy wascontinued during the radiochemotherapy; however, radiotherapy of the cervical and carotid areas altered the subsequent Doppler evaluations. Patient #4 sufferedfrom hemorrhage of the larynx. Ozone therapy was stopped after session #3 to enable the patient to undergo surgery. The usual complications associated with thesurgical treatment of this radiation-induced necrosis were absent. Patient #5 who suffered from several vascular diseases was treated with systemic and localozone therapy for a chronic wound. Patient #6 and #7 (healthy subjects recruited from among the hospital staff) also received 3 sessions of ozone therapy toevaluate the Doppler Effect. Further sessions were neither scheduled nor administered.
MCA diastolic velocity - cm/s
MCA systolic velocity - cm/s
Figure 1. Transcranial Doppler during ozone therapy. Left. Diastolic velocity (in cm/s) in the middle cerebral artery (MCA) increased by 33% at the end of session
#3 (P Ͻ 0.001), and an 18% increase persisted for 1 week after session #3 (P ϭ 0.023). Right. Systolic velocity in MCA increased by 22% at the end of session #3
(P ϭ 0.001), and a 15% increase persisted for 1 week after session #3 (P ϭ 0.035). The error bars are the 95% confidence intervals. Significant differences
(P Ͻ 0.05) are indicated with an asterisk (*).
Transcranial Doppler Velocimetry
The baseline systolic velocity in MCA was 90.9 Ϯ 6.1 cm/s.
After session #3, it increased to 111 Ϯ 7.3 cm/s (increase 22%, P ϭ 0.001), and 1 week later, it was 104.3 Ϯ 8 cm/s (increase 15%, P ϭ 0.035). The baseline diastolic velocity in MCA was 41.1 Ϯ 4.4 cm/s. After session #3, it increased to 54.6 Ϯ 4.6 cm/s (increase 33%, P Ͻ 0.001), and 1 week later, it was 48.6 Ϯ CCA blood flow - ml / min
5 cm/s (increase 18%, P ϭ 0.023) (Fig. 1).
Figure 2. Carotid blood flow during ozone therapy. Blood flow quantification
Common Carotid Blood Flow Quantification
(in ml/min) in the common carotid artery (CCA) increased by 75% at the endof session #3 (P Ͻ 0.001), and a 29% increase persisted for 1 week after The baseline CCA blood flow was 233 Ϯ 19 ml/min. After session #3 (P ϭ 0.039). The error bars are the 95% confidence intervals.
session #3, it increased to 407 Ϯ 38 ml/min (increase 75%, Significant differences (P Ͻ 0.05) are indicated with an asterisk (*).
P Ͻ 0.001), and 1 week later, it was 301 Ϯ 22 ml/min(increase 29%, P ϭ 0.039) (Fig. 2).
The baseline CCA blood flow directly correlated with the ϭ 0.557; P ϭ 0.039) and inversely correlated with age (r ϭ 0.825; P Ͻ 0.001) (Fig. 3). The per- centage increase in CCA blood flow 1 week after session #3 was directly correlated with age (r ϭ 0.735; P ϭ 0.004)(Fig. 4) and inversely correlated with the initial values of the CCA blood flow (r ϭ 0.691; P ϭ 0.009). In older patients, the increase in CCA blood flow was higher and that in basal per- fusion was lower (Fig. 5) (Note: in Figs 4 and 5, the Dopplerdata for the left arteries of one patient 1 week after session #3 were not available due to technical reasons).
Although biomedical applications of ozone therapy can be traced back to the end of the 19th century, numerous aspects of Basal CCA blood flow - ml/min
the effects of the therapy remain unexplored.
The airways are precluded in this therapy, which uses ozone- Figure 3. Relationship between baseline blood flow and age. Baseline values
enriched autologous blood transfusion; therefore, lung toxicity of the common carotid artery (CCA) blood flow were inversely correlated withthe age of the patients (r resulting from oxidative stress is avoided. Ozone, per se, does ϭ 0.825; P Ͻ 0.001). A lower blood flow was not enter the organism; the effects that are observed are mediated 318
Ozone therapy on cerebral blood flow changes in the MCA and/or CCA blood flow occurring during ozone therapy were assessed in the present study that did not include non-ozonized blood transfusion and each patient was As indicated by the CCA measurements, the increase in diastolic velocity in the MCA is compatible with a decrease in vascular resistance, a rheological improvement (1,12) and an overall increase in blood flow. The inverse correlation between the percentage increase in CCA blood flow and theinitial values is compatible with a microvascular redistribution resulting in better oxygenation in tissues with poor blood sup- ply. This was tentatively demonstrated in our previous studies by the direct measurement of muscle and tumor oxygenation using polarographic electrodes (13,14).
These rheological and vascular effects suggest that coadjuvant ozone therapy could decrease the vasoconstriction that is sec- ondary to hyperoxia. Techniques such as carbogen breathing or Figure 4. Relationship between age and blood flow increase post-ozone
hyperbaric chambers are used to increase the amount of O2 dis- therapy. The percentage increase in CCA blood flow 1 week after session #3 solved in arterial blood. However, when prolonged for Ͼ15–30 was directly correlated with age (r ϭ 0.735; P ϭ 0.004). A higher increasewas observed after ozone therapy in older patients.
min, these therapies can lead to an increase in peripheral vascularresistance along with a generalized vasoconstriction in mostorgans (15). Decreased cerebral blood flow secondary to hyper- oxia has indeed been documented in humans by transcranialDoppler (16) and magnetic resonance (17) studies.
The above-mentioned effects of ozone therapy and data from the present study, especially the potentially greater effect inolder patients or in those with lower initial blood flow, augur well for its use in cerebral low perfusion syndromes and stroke.
This is further supported by the clinical experience gained in a study that assessed 150 patients with ischemic cerebrovasculardisease treated with prolonged ozone therapy (18).
The present Doppler study was planned with only three ozone therapy sessions for several reasons. Firstly, we wanted 1 week after ozone therapy
to evaluate the effect of ozone therapy and to observe whether % increase in CCA blood flow
the effect could be maintained for a prolonged period, which has been suggested by the clinical experience gained from itsuse in sessions widely separated over several days. Hence, we Basal CCA blood flow - ml/min
decided to perform the third session approximately 1 week Figure 5. Relationship between the baseline blood flow and its increase post
later without any intervening sessions. Secondly, we wanted to ozone therapy. The correlation in CCA blood flow between baseline values administer the same number of sessions to all the patients in and the percentage increase 1 week after session #3 was highly significant the study. However, some of them were cancer patients who (r ϭ 0.691; P ϭ 0.009), i.e., there is a higher percentage increase in CCAcorresponding to a lower initial blood flow. Note: the percentages under 100% needed to commence their scheduled radiochemotherapy.
indicate a decrease in blood flow at this time point.
Therefore, in order to avoid interference with the scheduledradiochemotherapy, the present ozone study was performed by the rapid oxidation of certain substances in the blood in the during the period when oncologic staging and planning of the transfusion recipient. In appropriate concentrations, this can radiotherapy were carried out. Hence, the number of ozone up-regulate the synthesis of antioxidants in blood (7). This therapy sessions for Doppler evaluation was less than that property has been very actively investigated with respect to the considered necessary for a full-fledged ozone therapy, which protection against free radical damage associated with heart usually lasts for several weeks or even months. The Doppler (8), kidney (9) and liver (10) disorders. The mechanisms Effect after several additional sessions could indeed be higher proposed to explain the vascular effects include the liberation than that currently observed. Data on the optimal separation of vasoactive substance as well as the improvement in erythrocyte between the ozone therapy sessions are not currently available.
flexibility and blood rheology (1,11,12).
Further, the schedule could vary depending on the desired Several studies that included control subjects have indicated clinical effect (antioxidant, enhancing the immune or vascular that when ozone-free oxygen is used, the beneficial biochemical system, etc.). Nevertheless, the current study supports the (7,10) and rheological (1) responses are not observed. The clinical experience gained in the treatment of vascular disorders, 319
employing widely separated sessions over extended periods the equipment. Editorial assistance was provided by (2,3). Two or three applications per week appear to be suffi- Dr Peter R. Turner, t-SciMed, Reus, Spain.
cient in providing significant vascular improvement. However,changes observed over a mere 1 or 2 weeks are usually not Conflict of Interest
sufficient to improve chronic clinical conditions. The current The study was supported in part by a grant (FUNCIS 98–31) findings regarding a residual effect, which is still significantly from the Health and Research Foundation of the Autonomous elevated over baseline 1 week after the last session, support Government of the Canary Islands, Spain.
our postulation that one or two additional sessions per weekcan be effective during the initial maintenance period. Themode and timing of administration of additional sessions over References
a period of months need to be explored for the optimization of 1. Giunta R, Coppola A, Luongo C, Sammartino A, Guastafierro S, Grassia A, et al. Ozonized autohemotransfusion improves hemorheologicalparameters and oxygen delivery to tissues in patients with peripheral In the course of this study, our hospital facilities were trans- occlusive arterial disease. Ann Hematol 2001;80:745–8.
ferred to a different location in our city, and we were unable to 2. Romero A, Menéndez S, Gómez M, Ley J. La Ozonoterapia en los estadios conduct further Doppler studies using the same equipment.
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3. Rovira G, Galindo N. La ozonoterapia en el tratamiento de las úlceras Therefore, we decided to increase the study sample by including crónicas de las extremidades inferiores. Angiología 1991;2:47–50.
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the scarcity of patients. Only patient #5 had suffered a 5. Westra SJ, Levy DJ, Chaloupka JC, Hill JA, Robert JM, Sayre JW, et al.
CVA/stroke that may modify the Doppler evaluation in the Carotid artery volume flow: in vivo measurement with time-domain pro- carotid and middle cerebral arteries. However, patients with cessing US. Radiology 1997;202:725–9.
6. Schoning M, Scheel P. Color duplex measurement of cerebral blood flow localized tumors do not appear to have a systemic vascular volume: intra- and interobserver reproducibility and habituation to serial alteration or an altered vascular response. Therefore, we measurements in normal subjects. J Cereb Blood Flow Metab assumed that the effect observed in these arteries is a general 7. León OS, Menéndez S, Merino N, Castillo R, Sam S, Pérez L, et al.
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free radicals. Mediators Inflamm 1998;7:289–94.
Further studies, which include new technologies such as 8. Hernández F, Menéndez S, Wong R. Decrease of blood cholesterol and stimulation of antioxidative response in cardiopathy patients treated with interstitial multichannel laser Doppler used to quantify fluctu- endovenous ozone therapy. Free Radical Biol Med 1995; 19:115–9.
ations in microvascular perfusion during ozone therapy, are in 9. Barber E, Menendez S, Leon OS, Barber MO, Merino N, Calunga JL, progress in order to ascertain some of the remaining doubts et al. Prevention of renal injury after induction of ozone tolerance in ratssubmitted to warm ischemia. Mediators Inflamm 1999;8:37–41.
regarding the efficacy of ozone therapy.
10. Peralta C, León OS, Xaus C, Prats N, Jalil EC, Sala-Planell E, et al.
In conclusion, this preliminary Doppler study demonstrates, Protective effect of ozone treatment on the injury associated with hepatic albeit in a small number of subjects, that ozone therapy ischemia reperfusion: antioxidant-pro-oxidant balance. Free Rad Res1999;31:191–6.
increases blood flow in CCA and MCA with a prolonged 11. Bocci V. Autohaemotherapy after treatment of blood with ozone: a effect such that it can be very easily assessed by TCD and reappraisal. J Int Med Res 1994;22:131–43.
carotid ultrasound. These data support the clinical experience 12. Verrazzo G, Coppola L, Luongo C, Sammartino A, Giunta R, Grassia A, et al. Hyperbaric oxygen, oxygen-ozone therapy, and rheologic para- of achieving improvement using ozone therapy in peripheral meters of blood in patients with peripheral occlusive arterial disease.
ischemic syndromes. Its potential use as a complementary Undersea Hyperb Med 1995;22:17–22.
treatment in cerebral low perfusion syndromes warrants 13. Clavo B, Pérez JL, Catalá L, López L, Suárez G, Lloret M, et al. Effect of ozone therapy on muscle oxygenation. J Altern Complem Med 14. Clavo B, Perez JL, Lopez L, Suarez G, Lloret M, Rodriguez V, et al.
Ozone therapy for tumor oxygenation: a pilot study. Evid Based Acknowledgements
Complement Alternat Med 2004;1:93–8.
15. Bergo GW, Tyssebotn I. Cardiovascular effects of hyperbaric oxygen with The study was supported in part by a grant (FUNCIS 98–31) and without addition of carbon dioxide. Eur J Appl Physiol from the Health and Research Foundation of the Autonomous 16. Omae T, Ibayashi S, Kusuda K, Nakamura H, Yagi H, Fujishima M. Effects Government of the Canary Islands, Spain.
of high atmospheric pressure and oxygen on middle cerebral blood flow We wish to thank Dr R. Reyes (Department of Interventional velocity in humans measured by transcranial Doppler. Stroke 1998;29:94–7.
and Vascular Radiology) and Dr G. Rovira-Dupláa (Ozone 17. Watson NA, Beards SC, Altaf N, Kassner A, Jackson A. The effect of hyper- oxia on cerebral blood flow: a study in healthy volunteers using magnetic therapy Unit of the Quirón Clinic, Barcelona, Spain) for their resonance phase-contrast angiography. Eur J Anaesthesiol 2000;17:152–9.
valuable advice in conducting this study. We also thank 18. Rodriguez MM, Garcia JR, Menéndez S, Devesa E, Valverde S.
R. Martin-Oliva (Head of Department of Medical Physics) and Ozonoterapia en la enfermedad cerebrovascular isquémica. Revista CenicCiencias Biológicas 1998;29:145–8.
Dr M. A. Hernández (Head of Department of RadiationOncology) for their administrative and clinical support with Received February 29, 2004; accepted August 20, 2004
IMPARTING THE LANGUAGE OF CRITICAL THINKING WHILE TEACHING PROBABILITY Ben Gurion University of the Negev, Israel This paper reports a preliminary study of imparting to students a new kind of language, incorporating elements of critical thinking (CT), in the course of a mathematics (probability) lesson. In the paper, we describe and analyse one probability lesson, which is part of a