Application of Medicinal Ozone/Oxygen in Patients with Sickle Cell Anemia

Townsend Letter for Doctors. #138, 48-52 (January 1995) ↗ View original PDF

M. Gomez, E. Espinosa, and J.A. Caplan

National Center for Scientific Research (CNIC), Havana, Cuba

Insitutute of Hematology and Immunology, Havana, Cuba

CAPMED/USA, Bryn Mawr, Pennsylvania

Abstract

In patients with sickle cell anemia, the reduction in the availability of oxygen for the cells, produces painful crises, organ infarction, abdominal and/or muscular pains, ulcers, etc. On the basis of some medical properties of ozone, concerning ability to increase the rate and the capacity of absorption oxygen in erythrocytes, an evaluation about the effectiveness this treatment for the prevention and/or the timely resolution of the crisis was made. For the controlled clinical trial, 55 adult sickle cell anemia patients were studied, each suffering from painful crisis. Two groups were established: control group, comprised of 25 patients who received conventional treatment and ozone/oxygen treated group, comprising 30 patients who received the same treatment plus ozone therapy, by intrarectal administration, during 15 sessions. The average time required for resolution of painful sickle cell crisis in ozone/oxygen treated patients was half the number of hours required to solve pa inful crisis in control patients. Frequency and severity of painful crises in sickle cell anemia patients who received ongoing ozone/oxygen therapy diminished in the six month follow-up period, in comparison with control group patients.

Introduction

Sickle cell anemia, a genetic disease which involves the sickle shape of erythrocytes, when blood oxygen tension is low, is represented by a modified hemoglobin, HbS, due to the substitution of glutamic acid by valine in the amino acid chain. The crystallization or intracellular polymerization of the molecules of HbS occurs when those cells are deprived of oxygen up to a partial pressure of oxygen (pO2) below the threshold level at which the cells sickle. In these conditions, the erythrocytes lose their normal elasticity and shape, also losing their capacity to take and deliver oxygen and increasing the viscosity of the blood. This leads to a reduction in the availability of oxygen to the cells, producing painful crisis, infarction, abdominal and/or muscular pain, ulcers, etc. This process is reversible in the early stages, for when the HbS molecule is reoxygenated the cell distortion disappears and resumes its normal shape. The longer the period of time necessary for the reoxy genation of the molecules of HbS, the greater number of red cells die. Therefore, the increase in the partial pressure of oxygen and the promptness with which it is normalized are determining factors for the symptoms to diminish and disappear.¹ Attempts have been made to establish effective treatment for this disease, but their value and absence of side effects has not been confirmed in medical practice.^2-4

Numerous reports have been published on the safety and clinical results obtained by the application of medical ozone/oxygen in diseases related to insufficient oxygen supply to tissues and various organs, and/or the disruption of its utilization in the cells. Ozone virucidal effect has been reported at dose levels at which no undesirable side effects take place, offering promise as a means to inactivate human retroviruses in human body fluids and blood products preparation.

Among the medical properties of ozone documented are the ability to increase the rate and capacity of oxygen absorption in erythrocytes and the activation of glycolisis in the cells via the pentose pathway. This enhances the production of 2,3 DPG, which is known to act as a coadjuvant of oxygen release from oxyhemoglobin at tissue level.^7-8 Both effects lead to significant improvement in oxygen supply to the body, demonstrated in vivo by the measurement of pO2 increase in arterial blood as well as the reduction in venous.⁹

In addition, the rheological properties of the blood improve, especially in regard to erythrocytes aggregation (preventing rouleaux formation and clumping) and membrane permeability and flexibility, because of the effect of ozone/oxygen on it. As a consequence of these effects, reduction of blood viscosity and enhancement of blood flow are achieved.^10-12

Numerous preclinical experiments have been performed in vitro and in vivo to test possible ozone/oxygen toxicity related to the therapeutic methods and ways of administration according to which medical ozone/oxygen is currently applied. Controlled in vitro testing on the degree of hemolysis and "Heinz Body Formation" induced by the administration of ozone to blood at adequate dosage was performed¹³, not finding any significant effect, neither on the hemolysis level nor in the resistance of erythrocytes to further oxidative stress. These results are consistent with the fact that ozone stimulates several enzymatic redox systems responsible for cells protection against oxidation.¹¹

Doses up to more than ten times the maximum therapeutic levels were tested for toxicity. These studies^14-21 comprised cytotoxicity, organs function, hematological parameters, histological studies by electron microscopy, teratogenicity and cytogenetic testing. All the results demonstrated the non-toxic nature of medical ozone/oxygen within the range of therapeutic dose levels when administered intravascularly, intramuscularly and intrarectally.

Based on the major role blood deoxygenation and hypoxia play in the onset and persistence of painful sickle cell crisis, and considering the established therapeutic properties of medical ozone/oxygen, and the absence of negative side effects, an evaluation of the possible effectiveness of this treatment for the prevention and/or the timely resolution of the crisis was made, by means of controlled in vitro and clinical trials. It was encouraged by our extensive successful practice in numerous Havana City Hospitals, fundamentally that regarding the treatment of patients suffering circulatory insufficiencies, diabetes and many other diseases related to insufficient supply of oxygen to tissue.²²

Materials and Methods

Ozone/oxygen was obtained from a pure (medical grade) oxygen by means of a medical ozone generator (Ozomed, a device manufactured in N.C.S.R., Havana, Cuba), at a concentration of 50 mg ozone/L oxygen (ca. 3.7%).

The ability of ozone/oxygen to in vitro raise pO2 of normal bank blood was compared to that of pure medical oxygen. To each one often paired (5 + 5) blood samples (5mL each) contained in closed 10 ml vials, 2.5 mL of pure oxygen or ozone/oxygen mixture respectively were carefully bubbled through. Gasometric analyses were performed in test samples 5 minutes after gas administration and also in control untreated samples.

Preliminary clinical trials were performed comparing two modes of administration of medical ozone/oxygen: autohemotherapy (5 mg) and rectal insufflation (10 mg). Similar responses were obtained in both groups. Taking into account these results and considering the frequent difficulties encountered with the veins of these sickle cell patients, the intra rectal mode was chosen. Ozone was administered daily (5 days per week) for 3 weeks. For the controlled clinical trial, 55 adult sickle cell anemia patients were studied, each suffering from painful crisis in different degrees of intensity, who were admitted to the emergency service of the Institute of Hematology and Immunology, Havana, Cuba. Informed consent was gotten from patients before entering the study.

After resolution of the crises, a 6-month follow-up was performed in every patient. Two groups were established with patients selected at random:

• Group 1: Control group, comprised of 25 patients who received conventional treatment with analgesics, vasodilators, and i.v. hydration (saline solution).
• Group 2: Ozone/oxygen treated group, comprising 30 patients who received the same treatment plus ozone therapy.

The distribution of patients by sex and age in both groups is presented in Table 1.

There were not significant differences in age and sex among groups. Also both had similar mean values of hemoglobin, reticulocytes, fetal hemoglobin, hemoglobin S and oxygen partial pressure (pO2). No patient received a blood transfusion in the period of 6 months prior to this study. Severity of crisis were classified according to:

• Mild crisis: Lasting not more than 12 hours; treated with analgesics, not needing i. v. saline solution for relief. Relatively low intensity pain, located in one or two body regions.
• Moderate crisis: Within 12 and 24 hours duration. In addition to analgesics, also requiring continuous i.v. saline solution for relief. Moderate pain, localized in two or more regions in the body.
• Severe crisis: More than 24 hours duration. Requiring analgesics, continuous i.v. saline solution and other therapeutic procedures (including whole blood transfusions). Intensive pain localized in 3 or more regions in the body.

Results and Discussion

The in vitro experiments with stored venous blood demonstrated considerably higher capacity for oxygen absorption in the samples treated with ozone/oxygen. These results are reported in Table 2.

Table 2 shows pO2 and hemoglobin saturation values in control untreated blood, and those achieved in samples of the same blood after respective oxygen or ozone/oxygen administration. The relative rise (%) in pO2 obtained with ozone/oxygen nearly doubled that obtained with only pure oxygen. There were no significant differences in pH values among samples.

In the controlled clinical study comprising the aforementioned 55 patients, several hematological parameters were evaluated before and after treatment. These results are shown in Table 3.

Mean arterial blood pO2 value in control group patients remained virtually unchanged whereas a significant increase (17%) was achieved for this parameter in group 2 (ozone/oxygen treated) patients after 15 treatments. The remaining blood parameters did not show any significant change in any group. It should be noted that the rise in pO2 was obtained with no reduction in hemopoiesis, (hemoglobin values remained stable), the latter reported to occur when hyperbaric oxygen is administered. Thus, ozone/oxygen therapy improved oxygen transport to tissue without adverse effects on the blood.

At the moment of inclusion in the study, the crises of patients included in the control and treated groups presented the characteristics shown in Table 4.

It was clinically observed, that by virtue of the better reoxygenation of blood in ozone-treated patients, demonstrated objectively by the rise in arterial blood pO2 (shown in Table 3) the promptness with which all crises (whether mild, moderate or severe) were resolved was significantly accelerated in the ozone/oxygen treated group as compared to the control group. These values are shown in Table 5.

After resolution of the initial crisis, ozone/oxygen treatments were continued prophylactically. They were administered one every 14 days over a period of 6 months to patients in the treated group. The number of subsequent crises per patient in this period were significantly smaller in the ozone/oxygen treated group, compared to the control group (receiving conventional therapy).

The proportion of severe crises also diminished very sharply in the treated group, compared to the initial proportion.

There were no adverse reactions observed during or after the administration of ozone in any of the patients treated. Additionally, it is of interest to mention that some of the patients in the treated group who suffered from associated clinical manifestations including: acute severe chest syndrome, priapism and duodenal ulcer, showed remarkable favorable resolution of such conditions.

Conclusions

• Medical ozone significantly raises blood pO2 in vitro.
• Ozone/oxygen therapy produces significant rise in arterial blood pO2 of patients, which is an objective effect, without significant alterations in other blood parameters. It does not inhibit hemopoiesis, as is the case with hyperbaric oxygen treatment.
• The average time required for resolution of painful sickle cell crises (mild, moderate and severe) in ozone treated patients was about half of that required to resolve painful crisis in control patients.
• pO2 values in the ozone/oxygen treated group during the follow-up remained high enough to significantly reduce the incidence of crisis as compared to the control group, regardless of whether their crises were classified as mild, moderate or severe.
• Frequency and severity of painful crises in sickle cell anemia patients receiving ozone/oxygen therapy during the six month follow-up was significantly lower in comparison with control group patients.
• No adverse reactions were observed objectively or subjectively in the patients who received ozone/oxygen therapy.

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