Presentation on theme: "Jim Steppan PhD1 Thomas Meaders BS1 Kieran Murphy MD FRCPC2"— Presentation transcript:
1 A MetaAnalysis of the Effectiveness and Safety of Ozone Treatments for Herniated Lumbar Discs Jim Steppan PhD1Thomas Meaders BS1Kieran Murphy MD FRCPC2Mario Muto MD3.1 ActiveO, Salt Lake City, Utah2 University of Toronto3 A. Cardarelli Hospital, Naples, Italy
9 Patient Prepped and Needle Positioned into Herniated Disc Using CT GuidanceNeedle Penetration in L2 L3 Disc of Patient 027
10 Ozone-Oxygen Gas Injection Contained Intradiscal3 cc Oxygen/Ozone GasCT Image of L2-L3 Disc of Patient 027 from the ActiveO Clinical Trial prior toOzone-Oxygen Gas InjectionCT Image of L2-L3 Disc of Patient 027 from the ActiveO Clinical Trial afterOzone-Oxygen Gas Injection
21 MOA StudiesRelationship between MOA studies, clinical and animal trials, and previous Italian studies
22 Disc Anatomy and Composition A). Side View Sketch of Intervertebral DiscB). Sketch of Nucleus Pulposus PP Raj, Intervertebral Disc: Anatomy-Physiology-Pathophysiology-Treatment,” Pain Practice, 8(1), 18-44, (2008).
23 Disc Anatomy and Composition Aggrecan, the major proteoglycan of the disc, is responsible for maintaining tissue hydration through the osmotic pressure provided by its constituent chondroitin and keratan sulfate chainsAggregan consists of a large (over 2000 amino acids) core protein with multiple carbohydrate side chains (glycosaminoglycans (GAGs))GAG chains of chondroitin sulfate and keratan sulfate covalently bonded to a polypeptide coreIGD: Interglobular domain between G1 and G2KS: keratan sulfate regioncp: core proteinGAG: glycosaminoglycan chainsCS: chondroitin sulfate brush regionN: amine-terminalC: carboxyl-terminalG1, G2, G3: globular domainsSchematic of Aggrecan2 (PG)AFM Image of Fetal Episeal Aggrecan Monomer 2 L. Ng., etal., “Individual cartilage aggrecan macromolecules and their constituent glycosaminoglycans visualized via atomic force microscopy,” J. Structural Biology, 1453, , (2003).
24 AO-1000 Mechanism of Action (MOA) The AO-1000™ creates ozone which subsequently cleaves (directly or indirectly) the proteoglycans (PG) in the nucleus pulposus (NP)It is well known , that ozone can react with organic compounds (like PG) in aqueous media both directly via Reaction 1 and indirectly via Reactions 2, 3, and 4. “Alternative Disinfectants and Oxidants,” EPA Guidance Manual, Chapter 3: Ozone, (1999). B Langlais, et al., “Fundamental Aspects,” Ozone in Water Treatment Application and Engineering, , (1991).
25 Ozone Reaction with GAGs ActiveO and Dr. Balagurunathan (U of Utah) characterized the reaction of ozone with GAGsA Chinese hamster ovary (CHO) cell line (CHO was also used in Dewey’s benchmark work on thermal necrosis) was used to obtain GAGs that were similar in composition to those found in human NP.GAG samples were treated with 2 wt% ozone in oxygen from the AO-1000™ device and the samples were then analyzed by high performance liquid chromatography (HPLC) with radioisotope detection.Ozone fragments the GAGs as indicated by the appearance of an elution peak at 13.5 minutes and a decrease in the amount of GAGs eluting at retention time over 40 minutesExposure of GAGs to an oxygen-only control did not cause any fragmentation.MW = 23,800MW = 6600a. GAGs with no ozone exposure b. GAGs after exposure to ozone
26 MOA StudiesRelationship between MOA studies, clinical and animal trials, and previous Italian studies
27 MOA Studies: Cytokine Testing Left: Image showing puncture and harvest sitesBelow: Harvested discs – transverse aspectDiscs frozen in LychronDiscs shipped to U of U for homogenationHomogenates shipped to Pierce Bio in Mass. for ELISA
28 MOA Study: Why Cytokines? IL-1b, IL-6, and TNF-a are believed to be associated with disc degeneration (IL-1 is neurotoxic)IL-8 linked to enhanced disc healing (IL-8 is neuroprotective)IL-1βIL-6IL-8TNFStudied 4 unique cytokinesEach cytokine measured in triplicateSamples measured “neat”, e.g. no dilution
30 MOA Study: Cytokine Analysis Results IL-6 shows similar increasing trend (w/ 2 wt% being optimal)Observed very elevated levels of IL-6 compared to other cytokines
31 MOA Study: Cytokine Analysis Results IL-8 shows similar increasing trend (w/ 2 wt% being optimal)
32 MOA Study: Cytokine Analysis Results 2 wt% ozone induces highest response for all cytokinesIL-1b and TNF-a (pro-inflammatory) cytokine levels found to increase in response to treatment/needle injectionIL-8 (anti-inflammatory) found to increase in response to treatmentIncrease in IL-1b and TNF-a 2-days after treatment believed to be due to recent stab incision and needle injection into discIL-8 produced in response to increased levels of proinflammatory cytokines (IL-1b and TNF-a)
33 Ozone’s Mechanism of Action Primary mechanism of action of the oxygen-ozone mixture injected into the herniated disc is volume reduction (disc decompression)Ozone reacts with the GAGs in the NP which ultimately results in subtle dehydration (volume reduction) of the discSecondary mechanism of action is related to analgesic/antiinflammatory factors
34 EssentiallyOur model shows that volume removal of 0.28 cc (height reduction of inch ( cm) results in a pressure reduction of 10 psi or dV of 30ul = 1 psiOur model confirms that significant reductions in intradiscal pressure can result from small volume (height) reduction that may be undetectable by CT or MR
35 PurposeThe purpose of this literature review and analysis was to determine representative outcomes of oxygen/ozone treatment for herniated discs with respect to pain relief, reduction of disability, and risk of complications
36 Oxygen/Ozone Treatment Contained Intradiscal3 cc Oxygen/Ozone GasCT Image of L2-L3 Disc of Patient 027 from the ActiveO Clinical Trial prior toOzone-Oxygen Gas InjectionCT Image of L2-L3 Disc of Patient 027 from the ActiveO Clinical Trial afterOzone-Oxygen Gas Injection
37 MethodsA random-effects meta-analysis (DerSimonian and Laird Weighted Least Squares) was used to estimate treatment outcomes for oxygen/ozone treatment of herniated discs.A literature search was performed, using search terms associated with ozone treatment of herniated discs, to obtain the relevant studies for the meta-analysis.
38 MethodsDue to the wide range of study quality, each study was weighted in the meta-analysis by a study-quality score that was based onType of study – randomized, prospective, or retrospectiveWhether a control arm was usedWhether a statistical analysis was performedWhether the study was multi-center or single center
39 MethodsSeparate meta-analyses were performed for each of the pain and function scales most frequently used in the studies:Visual Analog Scale (VAS) – Pain assessment (analyzed mean VAS reduction)Oswestry Disability Index (ODI) – Pain and function assessment (analyzed mean ODI reduction).Modified MacNab Scale – Pain and function assessment (analyzed percentage of patients improving 1 category or more).A meta-analysis for the overall complication rate, based on the reported study complications, was also performed.
40 Literature Search Results Twelve (12) articles met the inclusion criteria from our literature search and were included in the meta-analysis.The included articles summarized data from the ozone treatment of over 8000 patients from multiple centers in multiple locations.
41 Meta-analyses Results The overall estimated mean improvement:VAS = 3.9 (3.2 – 4.5, 95% CI)ODI = 25.7 (18.8 – 32.6, 95% CI)The estimated chance of improvement:Modified MacNab = 79.7% (74.2% – 84.2%, 95%CI)The means for the VAS and ODI outcomes are well above both the minimum clinically important difference and the minimum (statistically-significant) detectable change.The estimated chance of complication:= 0.003% (0.000% – 0.024%, 95% CI)There were no serious complications reported.
42 Improvement in VAS Scores after Oxygen/Ozone Treatment of Herniated Discs
43 Improvement in ODI Scores after Oxygen/Ozone Treatment of Herniated Discs
44 Improvement in Modified MacNab Scores after Oxygen/Ozone Treatment of Herniated Discs
45 Complication Rate during and/or after Oxygen/Ozone Treatment of Herniated Discs
46 Summary of Reported Complications Qing 2005A few patients demonstrated Hypogastric, lumbar, and lower-extremities pain and distention and difficulty urinatingSymptoms resolved without intervention in 24 hoursAndreula 2003Two patients had impaired sensitivity in the lower limb due to periganglionic injection of anestheticSymptoms resolved without intervention in 2 hoursYing 2005A few patients had mild pain in the lumbar spine or leg after ozone injection – resolved without intervention in several minutesEight patients had mild respiratory impairment, dyspnea and cornea stimulates due to breathing ozone – resolved upon leaving the ozone environment and breathing oxygenOder 20076% of the patients complained of transient aggravation of the symptoms
47 Check for BiasBias - possibility of published articles under-estimating or over-estimating the treatment effectTo assess for bias we used a quantitative linear regression test.An unbiased meta-analysis should have good linearity between studies when the precision of each study is plotted against the standardized effect.If the neutral (unbiased) linear regression line (forced through zero on the y-axis) is within the 90% CI of the “biased” linear regression line, then there is no statistical evidence of bias.Deviation of the “biased” linear regression line from the neutral (unbiased) line shows the amount of bias between studies.
50 Discussion of ResultsPain and function outcomes are similar to the outcomes for lumbar discs treated with surgical discectomy, but the complication rate is much less (<0.1%)In addition, the recovery time is significantly shorter for the oxygen/ozone injection than for the discectomy